British Journal of Pharmacology最新文献

{"title":"JAK-STAT inhibitory effect of IN-115314, a novel small molecule inhibitor, and pharmacokinetic/pharmacodynamic study in canine.","authors":"Jae-Hun Ahn, Joohwan Kim, Jina Kwak, Jooil Kim, Na-Young Lee, Heejin Choi, Hee-Jin Bae, So-Hyun Cho, Sung-Gu Jung, Hye-Mi Kwon, Euna Kwon, Donghyun Kim, Myeongjoong Kim, Daseul Yoon, Seohyun Kim, Bongtae Kim, Byeong-Cheol Kang","doi":"10.1111/bph.70055","DOIUrl":"https://doi.org/10.1111/bph.70055","url":null,"abstract":"<p><strong>Background and purpose: </strong>The JAK-STAT signalling pathway has been extensively spotlighted as a therapeutic target for various diseases. This study assessed the inhibitory effects of a novel small molecule, IN-115314, on JAK-STAT pathway.</p><p><strong>Experimental approach: </strong>The IC₅₀ values of IN-115314 for JAK1-pSTAT3 and JAK2-pSTAT5 were determined in canine whole blood cells and TF-1 cells. IN-115314 administered intragastrically (0.2 to 0.9 mg·kg^-1), while oclacitinib was given orally as a positive control. Both drugs were administered twice daily for 7 days. Pharmacokinetics and pharmacodynamics were analysed on Days 1 and 7, respectively.</p><p><strong>Key results: </strong>IC₅₀ values for IN-115314 and oclacitinib against JAK1-pSTAT3 were 9.4 and 61.3 nM, while IC₅₀ values against JAK2-pSTAT5 were 749 and 1214 nM, respectively. Plasma concentrations of IN-115314 increased in a dose-dependent manner without accumulation, whereas oclacitinib displayed a 1.65-fold increase in exposure (AUC relative to Day 1) across 7 days of repeated dosing. The ex vivo IL-6-induced pSTAT3 activation in circulating CD4⁺ T lymphocytes was maximally suppressed between 1 and 3 h after administration of IN-115314, and the inhibitory efficacy of IN-115314 at a dose of 0.45 mg·kg^-1 was -31.2% ± 30.7%, comparable with that of oclacitinib at doses of 0.4-0.6 mg·kg^-1 (-31.4% ± 15.8%).</p><p><strong>Conclusion and implications: </strong>In summary, this study confirmed IN-115314 JAK-STAT inhibitory effect, along with data on its pharmacokinetics, pharmacodynamics, safety, efficacy and optimal dosage. We anticipate that IN-115314 will be developed as a new therapeutic agent for various diseases involving the JAK-STAT pathway.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966994","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":"Unlocking the power of immune checkpoint inhibitors: Targeting YAP1 reduces anti-PD1 resistance in skin cutaneous melanoma","authors":"Szonja Anna Kovács,&nbsp;Tamás Kovács,&nbsp;András Lánczky,&nbsp;Ágnes Paál,&nbsp;Zsombor I. Hegedűs,&nbsp;Nabil V. Sayour,&nbsp;Lilla Szabó,&nbsp;Andrea Kovács,&nbsp;Giampaolo Bianchini,&nbsp;Péter Ferdinandy,&nbsp;Alberto Ocana,&nbsp;Zoltán V. Varga,&nbsp;János Tibor Fekete,&nbsp;Balázs Győrffy","doi":"10.1111/bph.70052","DOIUrl":"10.1111/bph.70052","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Immune checkpoint inhibitors, such as anti­PD1, revolutionized melanoma treatment. However, resistance and low response rates remain problems. Our goal was to pinpoint actionable biomarkers of resistance to anti-PD1 treatment and verify therapeutic effectiveness in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Using receiver operating characteristic (ROC) and survival analysis in a database of 1434 samples, we identified the strongest resistance-associated genes. Inhibitors were evaluated in C57BL/6J mice using wild-type B16­F10, and BRAF, -PTEN, -CDKN2A-mutant YUMM1.7 melanoma cell lines. We investigated the synergistic impact of anti­PD1 therapy and yes­associated protein 1 (YAP1) inhibition by non-photoactivated Verteporfin. Tumour volume was determined at fixed cutoff points, normalized to body weights.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>In the anti­PD1­treated melanoma cohort, YAP1 was the strongest druggable candidate overexpressed in non­responder patients (ROC AUC = 0.699, FC = 1.8, <i>P=1.1E−8</i>). The baseline YAP1 expression correlated with worse progression-free survival (HR = 2.51, <i>P=1.2E−6,</i> FDR = 1%), and overall survival (HR = 2.15, <i>P = 1.2E−5,</i> FDR = 1%). In YUMM1.7, combination of Verteporfin plus anti-PD1 reduced tumour size more than anti-PD1 monotherapy (<i>P=0.008</i>), or control (<i>P=0.021</i>). There was no difference between the cohorts in B16­F10 inoculated mice. We found increased expression of YAP1 in YUMM1.7 mice compared to B16-F10. The combination therapy induced a more-immune-inflamed phenotype characterized by increased expression of T cell and M1 macrophage markers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Verteporfin with anti-PD1 exhibited antitumor potential by promoting a pro-inflammatory tumour microenvironment in melanoma. We believe that YAP1 acts as a master regulator of anti-PD1 resistance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 16","pages":"3903-3922"},"PeriodicalIF":6.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983121","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":"Macrocyclic diterpenoids from Stellera chamaejasme roots alleviate imiquimod-induced psoriasiform inflammation via STAT1/S100A9 signalling pathway","authors":"Yi-Wen Nie,&nbsp;Xin Liu,&nbsp;Ying Peng,&nbsp;Chun-Yan Zhang,&nbsp;Ruo-Fan Xi,&nbsp;Xiao-Xue Jiang,&nbsp;Yi Wang,&nbsp;Han-Zhi Lu,&nbsp;Dong-Jie Guo,&nbsp;Wan-Jun Guo,&nbsp;Yan-Juan Duan,&nbsp;Hua Nian,&nbsp;Kou Wang,&nbsp;Jian-Yu Chen,&nbsp;Fu-Lun Li,&nbsp;Jian-Yong Zhu","doi":"10.1111/bph.70059","DOIUrl":"10.1111/bph.70059","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Psoriasis is a multisystem inflammatory disease with a significant impact on quality of life. <i>Stellera chamaejasme</i>, a medicinal plant used in traditional Chinese medicine, shows promise for the treatment of psoriasis. We identified diterpenoids in <i>S. chamaejasme</i>, including a new compound, stellchamain A (SA, <b>1</b>), with notable antipsoriasis properties. This study explored the effects of SA on psoriasis to determine the mechanisms underlying the therapeutic efficacy of <i>S. chamaejasme</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Compounds isolated by column chromatography were structurally identified using NMR spectroscopy. The effects of SA on IL-17A-treated HaCaT cell viability and apoptosis were assessed using CCK-8 and TUNEL assays. In vivo anti-psoriasis activity of SA was evaluated in a mouse model of imiquimod (IMQ)-induced psoriasis. Network pharmacology, surface plasmon resonance (SPR), drug affinity responsive target stability (DARTS), and cellular thermal shift assays (CETSA) were elucidated the interactions between SA and the targets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>SA was isolated from <i>S. chamaejasme</i> along with nine known analogues (<b>2</b>–<b>10</b>). In vivo, SA reduced IMQ-induced epidermal thickness, hyperkeratosis, and perivascular inflammatory cell infiltration. Network pharmacology indicated that SA may function via the interleukin IL-17A/STAT1/S100A9 pathway. The results of SPR assays and molecular docking showed that SA binds to STAT1 with a <i>K</i>_D value of 9.24 nM. DARTS and CETSA analyses confirmed a direct and relevant interaction between SA and STAT1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>SA modulates the immunological microenvironment to treat psoriasis by targeting the IL-17A/STAT1/S100A9 axis, representing a potential new treatment for psoriasis and other IL-17A-mediated skin disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 16","pages":"3884-3902"},"PeriodicalIF":6.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A subtype-selective photoswitchable agonist for precise manipulation of GABAA receptors","authors":"Simon Miguel M. Lopez,&nbsp;Jay-Ron Lee,&nbsp;Wan-Chen Lin","doi":"10.1111/bph.70066","DOIUrl":"10.1111/bph.70066","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Neuronal inhibition is largely mediated by type-A GABA receptors (GABA_ARs), a family of ligand-gated chloride-permeable channels, which can be sub-classified by their subunit composition. Unravelling the function and distribution of each GABA_AR subtype is essential for a holistic understanding of GABAergic inhibition in health and diseases. Photopharmacology, a technique that utilises light-sensitive compounds to precisely manipulate endogenous proteins, is powerful for this purpose. To resolve the molecular complexity of neuronal inhibition, we aimed to develop subtype-selective photoswitchable agonists for GABA_ARs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Inspired by THIP (gaboxadol), an agonist selective for δ subunit-containing GABA_ARs (δ-GABA_ARs), we merged a photoswitch moiety (<span><b>az</b></span>obenzene) with an analogue of THIP (<span><b>i</b></span>so<span><b>gu</b></span>vacine) to construct <b>Az-IGU</b>. Using whole-cell voltage-clamp recording, <b>Az-IGU</b> was tested on 13 GABA_AR subtypes expressed in human embryonic kidney (HEK) cells. Optical activation of endogenous GABA_ARs was examined via electrophysiology in cultured cortical neurons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>In HEK cells, <b>Az-IGU</b> exerted reversible photo-agonism selectively for α4β3δ and α6β3δ GABA_ARs, two major mediators of tonic inhibition. Pharmacological and mutagenesis studies suggested that activation of the α4β3δ GABA_AR involves interaction between <b>Az-IGU</b> and the GABA-binding pocket and is strongly correlated with the spontaneous activity of the receptor. In cultured cortical neurons, photoisomerisation of <b>Az-IGU</b> triggered responses that enabled reversible control of action potential firing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>GABA_ARs are potential therapeutic targets for many disorders. However, their physiological and pathophysiological roles remain largely unexplored. <b>Az-IGU</b> may enable photopharmacological studies of α4/6β3δ GABA_ARs, providing new opportunities for biomedical and neurobiological applications.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 16","pages":"3870-3883"},"PeriodicalIF":6.8,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959772","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":"Colon-targeted complement C5a1 receptor inhibition using pH-sensitive nanoparticles ameliorates experimental colitis","authors":"Cedric S. Cui,&nbsp;Titaya Lerskiatiphanich,&nbsp;Xaria X. Li,&nbsp;Rabina Giri,&nbsp;Ning Liu,&nbsp;Vinod Kumar,&nbsp;Andrew K. Whittaker,&nbsp;Felicity Y. Han,&nbsp;Richard J. Clark,&nbsp;Jakob Begun,&nbsp;John D. Lee,&nbsp;Trent M. Woodruff","doi":"10.1111/bph.70056","DOIUrl":"10.1111/bph.70056","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The complement system is associated with inflammatory bowel disease (IBD) pathology. Complement activation induces C5a production, which signals through the C5a₁ receptor (C5aR1) to drive inflammatory responses that may underlie IBD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We examined mucosal biopsies from ulcerative colitis patients and identified C5a₁ receptor up-regulated in active lesions, supporting the C5a₁ receptor as a target for therapeutic intervention. Cyclic peptide C5a₁ receptor antagonists such as PMX205 are orally efficacious in preclinical colitis models; however, their clinical application may be limited by rapid metabolism. We therefore encapsulated PMX205 within pH-sensitive polymers to target drug for colon delivery following oral administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>PMX205 nanoparticles were non-toxic and released bioactive PMX205 in simulated colon fluid. In vivo imaging of Cy5-labelled nanoparticles demonstrated rapid entry and persistence in the mouse colon for up to 48 h. Next, we utilised the dextran sodium sulphate-induced colitis model to examine efficacy of the C5a₁ receptor-antagonist formulation. We show that oral administration of PMX205 nanoparticles every 2 days from symptom onset significantly mitigated weight loss, clinical illness, colon length reduction and epithelial damage to a similar degree as C5a₁ receptor^−/− mice. Notably, unformulated PMX205 was markedly less effective in this dosing regimen.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>This novel colon-targeted formulation therefore offers a potent therapeutic strategy for translating C5a₁ receptor antagonists for IBD conditions such as ulcerative colitis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 16","pages":"3852-3869"},"PeriodicalIF":6.8,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982723","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":"Time-evolved metrics for safety pharmacological assessments of small molecules and biologics","authors":"Bharath Srinivasan","doi":"10.1111/bph.70064","DOIUrl":"10.1111/bph.70064","url":null,"abstract":"<p>Safety of a small-molecule drug is oftentimes a more important criterion than efficacy in determining drug approval. Aspects of safety pharmacological and toxicological liabilities, often resulting from dose-dependent undesirable interaction with either the primary target of interest or secondary targets, have a huge role to play in determining ‘first-in-human’ dosage and phase I clinical trials. Given the open thermodynamic nature of the human subjects, it is mandatory that kinetics of drug-target and drug-off-target interactions govern the way selectivity margins are assessed, and dose is decided. However, lack of sufficient thrust on kinetics in guiding early drug discovery decisions has resulted in an overreliance on IC₅₀ measure (a proxy for thermodynamic <i>K</i>_<i>i</i>) as a means of computing safety across the target of interest and potential off-targets. Moreover, based on established practises and known weight of evidence of targets with safety adverse events, the primary panel of secondary pharmacology targets are biased with greater preference for G-protein coupled receptors, transporters and ion-channels with a paucity of enzymes. This can pose unique challenges in assessing safety, especially for advancing and emergent modalities. In this perspective, the critical role kinetic margins should play in assessing safety is emphasised given the myriad assay conditions that can modulate the equilibrium thermodynamic measure as embodied in the proxy report of IC₅₀. Further, it advocates selective and judicious expansion of primary safety panels with greater representation of enzymes and reduced redundancy in eventual read-outs based on potential for correlative output among the off-target classes assessed.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 13","pages":"2831-2841"},"PeriodicalIF":6.8,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965437","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":"Functional MRP1 activity in human skeletal muscle","authors":"Matthias Jackwerth,&nbsp;Severin Mairinger,&nbsp;Markus Zeitlinger,&nbsp;Oliver Langer","doi":"10.1111/bph.70062","DOIUrl":"10.1111/bph.70062","url":null,"abstract":"&lt;p&gt;Statins, or 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitors, are commonly prescribed medications that lower cholesterol, used to treat hypercholesterolemia and prevent cardiovascular events. Despite their clinical benefits, statin use is often discontinued due to statin-associated muscle symptoms. We have read with great interest the article by Hoste et al. (&lt;span&gt;2025&lt;/span&gt;), in which the authors demonstrate that the adenosine triphosphate-binding cassette (ABC) transporter multidrug resistance-associated protein 1 (MRP1/ABCC1) is highly expressed in primary cultures of differentiated human skeletal muscle myotubes and regulates the intracellular concentration of atorvastatin. The authors also suggest that MRP1-mediated efflux transport may help protect skeletal muscle cells from statin-induced myopathy. This raises the possibility of MRP1-mediated drug–drug interactions (DDIs) in skeletal muscle cells, when patients receiving statin therapy are concurrently treated with MRP1-inhibiting drugs, such as the uricosuric agent probenecid (Dorajoo et al., &lt;span&gt;2008&lt;/span&gt;). These drug–drug interactions may occur without noticeable changes in plasma statin concentrations, potentially leading to increased intramuscular accumulation of statins and exacerbating statin-related muscle side effects. However, Hoste et al. (&lt;span&gt;2025&lt;/span&gt;) observed some differences in transporter expression between primary cultures of differentiated myotubes and uncultured muscle biopsies, noting that their findings may not fully reflect the &lt;i&gt;in vivo&lt;/i&gt; situation. To improve the clinical relevance of the findings by Hoste et al. (&lt;span&gt;2025&lt;/span&gt;) and of other studies (Dorajoo et al., &lt;span&gt;2008&lt;/span&gt;; Knauer et al., &lt;span&gt;2010&lt;/span&gt;), obtaining &lt;i&gt;in vivo&lt;/i&gt; evidence of functional MRP1 activity in human skeletal muscle would be highly desirable. Positron emission tomography (PET) imaging can be employed to assess the role of membrane transporters in the tissue distribution of radiolabelled drugs (Tournier et al., &lt;span&gt;2018&lt;/span&gt;). We recently conducted a first-in-human study using the PET tracer 6-bromo-7-[&lt;sup&gt;11&lt;/sup&gt;C]methylpurine ([&lt;sup&gt;11&lt;/sup&gt;C]BMP), which distributes to different tissues via passive diffusion and is rapidly and quantitatively converted intracellularly into the corresponding glutathione conjugate &lt;i&gt;S&lt;/i&gt;-(6-(7-[&lt;sup&gt;11&lt;/sup&gt;C]methylpurinyl))glutathione ([&lt;sup&gt;11&lt;/sup&gt;C]MPG) (Figure 1a) (Jackwerth et al., &lt;span&gt;2025&lt;/span&gt;). The latter compound has a limited passive membrane permeability and is eliminated from tissues primarily via MRP1 and potentially by other MRP subtypes, such as MRP4/ABCC4. 6-bromo-7-[&lt;sup&gt;11&lt;/sup&gt;C]methylpurine ([&lt;sup&gt;11&lt;/sup&gt;C]BMP) PET scans were performed in healthy human subjects, both with and without pre-treatment with a single oral dose of probenecid (Jackwerth et al., &lt;span&gt;2025&lt;/span&gt;). In addition to inhibiting organic anion transporters 1 (OAT1/SLC22A6) and 3 (OAT3/SLC22A8), probeneci","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 13","pages":"2829-2830"},"PeriodicalIF":6.8,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970174","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":"High-throughput screen identifies MAS9 as a novel inhibitor of the C-type lectin receptor-2 (CLEC-2)–podoplanin interaction","authors":"Marcin A. Sowa,&nbsp;Yan Wu,&nbsp;Jan van Groningen,&nbsp;Ying Di,&nbsp;Helma van den Hurk,&nbsp;Johannes A. Eble,&nbsp;Jonathan M. Gibbins,&nbsp;Ángel García,&nbsp;Alice Y. Pollitt","doi":"10.1111/bph.70036","DOIUrl":"10.1111/bph.70036","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The C-type lectin-like receptor-2 (CLEC-2) is a platelet receptor for the endogenous ligand podoplanin. This interaction contributes to several (patho)physiological processes, such as lymphangiogenesis, preservation of blood and lymphatic vessel integrity organ development, and tumour metastasis. Activation of CLEC-2 leads to the phosphorylation of its cytoplasmic hemITAM domain and initiates a signalling cascade involving the kinase Syk. The aim of this study was to identify and characterise a novel small molecule inhibitor of CLEC-2.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>An AlphaScreen-based high-throughput screening was used to identify a small molecule inhibitor of the CLEC-2–podoplanin interaction. Binding site interactions were assessed using in silico modelling. Functional assays, including light transmission aggregometry, platelet spreading and phosphorylation assays, were used to evaluate the effect of a small molecule on CLEC-2-mediated platelet activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>A total of 18,476 small molecules were screened resulting in 14 candidates. Following secondary screening, one novel small molecule, MAS9, was taken forward for further characterisation. The binding sites of MAS9 to CLEC-2 were predicted to share binding sites with the CLEC-2 ligands podoplanin and rhodocytin. MAS9 inhibited CLEC-2-mediated platelet aggregation, spreading and signalling. MAS9 also resulted in inhibited fibrinogen binding.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>MAS9 inhibits CLEC-2-mediated aggregation, platelet spreading and signalling, showing selectivity of CLEC-2 inhibition over GPVI. This study paves the way for future preclinical assays to test the potential of MAS9 as a novel therapeutic tool to treat pathologies such as thromboinflammation and cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 16","pages":"3838-3851"},"PeriodicalIF":6.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959958","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":"Dehydroabietic acid protects against cerebral ischaemia–reperfusion injury by modulating microglia-mediated neuroinflammation via targeting PKCδ","authors":"Luyao Li,&nbsp;Hao Tang,&nbsp;Lingyu She,&nbsp;Zhen lin,&nbsp;Qin Yu,&nbsp;Yuqing Zeng,&nbsp;Linjie Chen,&nbsp;Fan Chen,&nbsp;Guang Liang,&nbsp;Xia Zhao,&nbsp;Namki Cho,&nbsp;Yi Wang","doi":"10.1111/bph.70030","DOIUrl":"10.1111/bph.70030","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Cerebral ischaemia–reperfusion injury (CIRI) is a major contributor to global morbidity and mortality, although its underlying mechanisms remain only partly understood. Emerging evidence indicates that inhibiting microglia-mediated neuroinflammation would be an effective therapeutic approach for CIRI, and pharmacological interventions targeting this pathway hold significant therapeutic promise. This study aimed to identify a potent anti-inflammatory drug from a natural compound library as a potential treatment for CIRI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We used oxygen–glucose deprivation/reperfusion (OGD/R) and middle cerebral artery occlusion in male C57BL/6 mice to evaluate the efficacy of DHA in neurological deficits and the anti-inflammatory effects. Using BV2 cells and murine brain tissue, liquid chromatography–tandem mass spectrometry was used to identify potential molecular targets of DHA, followed by bio-layer interferometry, molecular docking, molecular dynamics simulations and cellular thermal shift assays to validate DHA's binding interactions with protein kinase C delta (PKCδ).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>DHA decreased production of pro-inflammatory cytokines following OGD/R, thereby inhibiting microglia-mediated neuroinflammation to protect neurons and reducing brain infarct size and improving neurological outcomes. Mechanistically, DHA directly bound to PKCδ, inhibiting its phosphorylation and downstream NF-κB signalling. This binding interaction involved TRP⁵⁵ and LEU¹⁰⁶ on PKCδ, as confirmed by molecular docking and other biophysical techniques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>DHA specifically interacts with PKCδ, preventing its phosphorylation induced by ischaemia–reperfusion injury. These results suggest that DHA is a novel inhibitor of PKCδ and provide solid experimental foundations for using DHA in treating neuroinflammation-related conditions, such as CIRI.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 16","pages":"3818-3837"},"PeriodicalIF":6.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982654","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":"EXPRESSION OF CONCERN: Novel proline endopeptidase inhibitors do not modify Aβ40/42 formation and degradation by human cells expressing wild-type and Swedish mutated β-amyloid precursor protein","authors":"","doi":"10.1111/bph.70068","DOIUrl":"10.1111/bph.70068","url":null,"abstract":"<p>\u0000 <b>EXPRESSION OF CONCERN</b>: <span>A. Petit</span>, <span>H. Barelli</span>, <span>P. Morain</span>, <span>F. Checler</span>, “ <span>Novel proline endopeptidase inhibitors do not modify Aβ40/42 formation and degradation by human cells expressing wild-type and Swedish mutated β-amyloid precursor protein</span>,” <i>British Journal of Pharmacology</i> <span>130</span>, no. <span>7</span> (<span>2000</span>): <span>1613</span>–<span>1617</span>, https://doi.org/10.1038/sj.bjp.0703440</p><p>This Expression of Concern is for the above article, published online on 29 January 2009 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Péter Ferdinandy; the British Pharmacological Society; and John Wiley &amp; Sons Ltd. A third party reported to the journal that the Aβ 40 (Aβ 42) panel in Figure 4A had been duplicated in Figure 5A and that the last two gel panels of βAPP in Figure 4B appear to have been duplicated in Figure 5B. An investigation by the publisher and journal confirmed this report and that both sets of data are presented as having different experimental conditions. The authors responded to an inquiry by the publisher and stated that the βAPP images are the same, but that these cells were treated with two different inhibitors in Figures 4B and 5B and that each had different Aβ 42 expressions. The authors stated that the original data are not available due to the considerable time since publication. This Expression of Concern has been agreed to because the data included in this article cannot be validated. Therefore, the journal has decided to issue an Expression of Concern to inform and alert the readers. Author F. Checler disagrees with the Expression of Concern. Authors A. Petit, H. Barelli, and P. Morain did not respond to our notice regarding the Expression of Concern.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 12","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989390","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}