British Journal of Pharmacology最新文献

{"title":"Systemic EP4 receptor agonist and Arginase-1 therapy in a murine model of chronic asthma and influenza virus-induced asthma exacerbation.","authors":"Tim Lange, Tobias Brunn, Charlotte Vetter, Konstantin Bloch, Nora Vedder, Chiel van Geffen, Philipp Gercke, Saeed Kolahian","doi":"10.1111/bph.17473","DOIUrl":"https://doi.org/10.1111/bph.17473","url":null,"abstract":"<p><strong>Background and purpose: </strong>Myeloid-derived suppressor cells (MDSCs) play important roles in the pathogenesis of asthma. Recent studies demonstrate that their function can be modulated by different pharmacological approaches. In this study, we focussed on the effects of systemically administered prostaglandin EP₄ receptor agonist L-902,688 and pegylated human Arginase-1 on MDSCs in a murine model of chronic asthma and asthma exacerbation.</p><p><strong>Experimental approach: </strong>BALB/c mice were challenged with house dust mite (HDM) over a period of 5 weeks, establishing a chronic asthma phenotype. To induce asthma exacerbation, mice were infected with Influenza Virus H1N1 A/Puerto Rico/8/1934. In vivo lung function, lung inflammatory features, number and suppressive activity of MDSCs, number of different T cell subsets in lung and spleen and viral titer in the bronchoalveolar lavage fluid (BALF) were assessed.</p><p><strong>Key results: </strong>In asthmatic mice, treatment with the EP₄ receptor agonist or Arginase-1 significantly reduced the number of eosinophils in the BALF. Both treatments improved lung function and ameliorated airway hyperresponsiveness (AHR) in asthma exacerbation. The number and suppressive activity of MDSCs in the lung were increased by virus-induced asthma exacerbation.</p><p><strong>Conclusion and implications: </strong>We found beneficial effects of systemic EP₄ receptor agonist and Arginase-1 therapy in a murine model of chronic asthma and influenza virus-induced asthma exacerbation. Our findings highlight the potential efficacy of EP₄ receptor agonists, Arginase-1, and MDSCs, as novel therapeutic approaches in asthma and asthma exacerbation.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603949","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":"Vestibular modulation by stimulant derivatives in a pentameric ligand-gated ion channel.","authors":"Emelia Karlsson, Olivia Andén, Chen Fan, Zaineb Fourati, Ahmed Haouz, Yuxuan Zhuang, Rebecca J Howard, Marc Delarue, Erik Lindahl","doi":"10.1111/bph.70011","DOIUrl":"https://doi.org/10.1111/bph.70011","url":null,"abstract":"<p><strong>Background and purpose: </strong>Allosteric modulation of pentameric ligand-gated ion channels (pLGICs) are critical for the action of neurotransmitters and many psychoactive drugs. However, details of their modulatory mechanisms remain unclear, especially beyond the orthosteric neurotransmitter-binding sites. The recently reported prokaryotic symbiont of Tevnia jerichonana ligand-gated ion channel (sTeLIC), a pH-gated homologue of eukaryotic receptors in the pLGIC family, is thought to be modulated by aromatic compounds via a relatively uncharacterised modulatory site in the extracellular vestibule.</p><p><strong>Experimental approach: </strong>We have characterised the effects of psychostimulant derivatives on sTeLIC using two-electrode voltage-clamp electrophysiology in the presence and absence of engineered mutations, and determined X-ray and cryo-EM structures of the channel in both closed and open states.</p><p><strong>Key results: </strong>We have shown that sTeLIC is sensitive to potentiation by several amphiphilic compounds, which preferentially bind to a vestibular pocket in the contracted open-state extracellular domain.</p><p><strong>Conclusions and implications: </strong>This work provides a detailed structure-function mechanism for allosteric potentiation via a noncanonical ligand site, with potential conservation of the eukaryotic pentameric ligand-gated ion channels.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596249","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":"Identification of active ingredients from Lamiophlomis rotata that increase wound repair in mouse skin.","authors":"Huan Li, Chang Chen, Xinzhu Chen, Jiale Liu, Chen Luo, Huilin Chen, Xiaoyu Geng, Zheng Pan","doi":"10.1111/bph.17452","DOIUrl":"https://doi.org/10.1111/bph.17452","url":null,"abstract":"<p><strong>Background and purpose: </strong>We previously showed that the iridoid glycoside extract of Lamiophlomis rotata (IGLR) induces M2 macrophage polarisation to accelerate wound healing. The potentially active compounds (quality markers) in IGLR that accelerate wound healing have not been elucidated; we here identified quality markers that accelerate wound healing.</p><p><strong>Experimental approach: </strong>After IGLR gavage of dorsal excisional wound mice and normal mice for 7 days, the tissues were analysed using the matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry imaging (MSI) method and were further validated by liquid chromatography/mass spectrometry (LC/MS) coupled with multivariate analyses to identify quality markers.</p><p><strong>Key results: </strong>Using the MSI assay, Shanzhiside methyl ester (SM), 8-O-acetylshanzhiside methyl ester (ASM) and Phlorigidoside C (PhC) were identified as the quality markers in IGLR and overlapped with endogenous metabolites (lactate, citrate and itaconate) in the same class by UMAP manifold analysis. Additionally, the results were also confirmed by UPLC-Q/TOF-MS coupled with multivariate analyses of the skin tissues in normal and wound groups. MSI data from the livers and kidneys revealed that the accumulation of SM, ASM and PhC in the livers significantly increased in the model group, and the ion intensity of their glucuronide conjugates in the kidneys was decreased compared to the normal group. These results suggested that bioavailability of these compounds was improved in the wound group.</p><p><strong>Conclusions and implications: </strong>The overall data demonstrated that SM, ASM and PhC were selectively increased in new granulation tissues, and are most likely the quality markers that accelerate wound healing.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596209","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":"SEW2871 attenuates myocyte necroptosis in heart failure through inhibition of oxidative stress and inflammatory cytokines.","authors":"Hong-Xia Guo, Run-Nan Tantai, Bin Yang, Li-Guo Yang, Yuan Ma, Hui-Ping Zhao, Jing Wang, Xiao-Juan Zhang, Rui-Hua Wang, Fei Wang, Jia-Pu Wang, Rui-Fang Chi, Fu-Zhong Qin, Bao Li, Ya-Xin Liu","doi":"10.1111/bph.70005","DOIUrl":"https://doi.org/10.1111/bph.70005","url":null,"abstract":"<p><strong>Background and purpose: </strong>Sphingosine-1-phosphate (S1P)/S1P receptor signalling exerts cardioprotective effects. However, the effect of the selective S1P₁ receptor agonist SEW2871 on myocyte necroptosis in heart failure and the underlying mechanisms are unknown. In the present study, we tested the hypothesis that SEW2871 attenuates myocyte necroptosis in heart failure through inhibition of oxidative stress and inflammatory cytokines.</p><p><strong>Experimental approach: </strong>Eight-week-old male C57BL/6J mice underwent myocardial infarction (MI) or sham operation. The animals were randomized to receive SEW2871 (5 mg·kg^-1·day^-1, i.p) or placebo for 4 weeks.</p><p><strong>Key results: </strong>MI mice exhibited the increases in left ventricular (LV) end-diastolic dimension, LV end-systolic dimension, LV mass and lung weight and a decrease in LV ejection fraction, indicating LV dilation, LV systolic dysfunction and lung congestion, and these alterations were attenuated by the SEW2871 treatment. Myocardial expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, inflammatory cytokines tumour necrosis factor-α (TNF-α), interleukin-1β and interleukin-6, and phosphorylated RIPK1 (p-RIPK1), p-RIPK3 and p-MLKL, reflective of their respective kinase activities, markers of necroptosis, was markedly increased in the MI placebo group, and the increase was abolished by the SEW2871 treatment. Similarly, intracellular levels of reactive oxygen species, inflammatory cytokines, p-RIPK1, p-RIPK3 and p-MLKL protein expression were increased in H9C2 cardiomyocytes under mimic ischaemia and the increases were prevented by the SEW2871 treatment.</p><p><strong>Conclusion and implications: </strong>The selective S1P₁ receptor agonist SEW2871 attenuates myocyte necroptosis through inhibition of oxidative stress and inflammatory cytokines, leading to improvement of LV remodelling and function in heart failure.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596244","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":"Clemastine attenuates subarachnoid haemorrhage pathology in a mouse model via Nrf2/SQSTM1-mediated autophagy.","authors":"Yan Zou, Zhen'xing Tao, Peng'peng Li, Jie'qiong Yang, Qin'yi Xu, Xing Xu, Zeng'li Miao, Xu'dong Zhao","doi":"10.1111/bph.17465","DOIUrl":"https://doi.org/10.1111/bph.17465","url":null,"abstract":"<p><strong>Background and purpose: </strong>Subarachnoid haemorrhage (SAH) is an uncommon and severe subtype of stroke, but the availability of drugs for its treatment is limited. Enhanced autophagy is believed to attenuate SAH pathology; however, autophagy level is tentatively up-regulated and then down-regulated after SAH onset in mice. Clemastine, a first-generation histamine H1R antagonist, is believed to persistently enhance autophagy. However, the precise mechanism of clemastine in the treatment of SAH remains largely elusive.</p><p><strong>Experimental approach: </strong>Haemoglobin-induced neuron injury model and autologous-blood-injected SAH-model mice were used to investigate the effects of clemastine in vitro and in vivo, respectively. The expressions of Nrf2/Keap1 and autophagy-related proteins were detected using western blotting and immunofluorescence. Neuronal injury and hyperoxide level were measured via Fluoro-Jade C and dihydroethidium staining. Neurological behaviours were evaluated using modified Garcia Scale, beam balance test, Morris water maze, Y-maze and novel object recognition test. The structures of autophagosomes and mitochondria were visualised using transmission electron microscope. The binding sites of clemastine was predicted and verified using database and drug affinity-responsive target stability.</p><p><strong>Key results: </strong>Clemastine ameliorated SAH pathogenesis in vivo and in vitro. Moreover, the intraperitoneal injection of clemastine and its oral administration reduced neuronal death and improved cognitive deficits in SAH-model mice. Mechanistically, clemastine directly bound to muscarinic acetylcholine receptor M4, prevented Nrf2 degradation via Nrf2/Keap1/SQSTM1 pathway and promoted Nrf2 nuclear translocation, thus enhancing autophagy-related gene transcription and autophagy activation.</p><p><strong>Conclusions and implications: </strong>Clemastine can attenuate SAH pathology via the activation of Nrf2/SQSTM1 autophagy and could be a useful therapeutic in the context of SAH.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572020","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":"7 I, a structurally modified sinomenine, exerts dual anti-GBM effects by inhibiting glioblastoma proliferation and inducing necroptosis which further mediates lysosomal cell death.","authors":"Hong Yang, Bin Jiang, Wan Li, Guanhua Du, Fang Xu, Yizhi Zhang, Yihui Yang, Sen Zhang, Wanxin Cao, Xiaoxue Li, Xu Zhang, Tengfei Ji, Jinhua Wang","doi":"10.1111/bph.17464","DOIUrl":"https://doi.org/10.1111/bph.17464","url":null,"abstract":"<p><strong>Background and purpose: </strong>Glioblastoma multiforme (GBM) is an aggressive brain tumour which drug treatment has no overall significant effect on survival rate. Sinomenine is a natural product extracted from the traditional Chinese medicine Qingteng and was found to have a certain anti-tumour effect. Although, its short biological half-life, unstable physicochemical properties, large dosage and causes histamine release have hindered its use but it may form the basis for novel drug therapy of GBM.</p><p><strong>Experimental approach: </strong>We designed, synthesised and screened sinomenine derivative-7 I with high anti-GBM activity and investigated its mechanism of action. Its actions on GBM cells were detected by cell viability assay, RNA-Seq, Western blot, transmission electron microscopy, immunofluorescence along with other methods described.</p><p><strong>Key results: </strong>7 I exerted anti-GBM effects through a dual mechanism. 7 I arrested the cell cycle of GBM cells at the G2/M phase by the activation of the P53/P21/CDK1/cyclin B pathway, inhibiting GBM cells proliferation. Secondly, 7 I induced necroptosis of GBM cells through the classical RIPK1/RIPK3/MLKL-dependent pathway causing lysosomal damage and membrane permeabilization leading to lysosomal-mediated cell death. Finally, in vivo xenograft experiments, 7 I significantly inhibited the growth of glioblastoma, effectively reducing inflammation in mice and showing good safety profile.</p><p><strong>Conclusions and implications: </strong>7 I, a structurally modified sinomenine, has excellent in vitro and in vivo anti-GBM activity and exerts dual anti-GBM effects by inhibiting glioblastoma proliferation and inducing necroptosis, which further mediates lysosomal cell death. In summary, 7 I is a promising candidate agent for GBM treatment.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555880","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":"An antisense oligonucleotide targeting the heat-shock protein HSPB5 as an innovative therapeutic approach in pulmonary fibrosis.","authors":"Pierre-Marie Boutanquoi, Lenny Pommerolle, Lucile Dondaine, Julie Tanguy, Pierre-Simon Bellaye, Léo Biziorek, Marine Gautier-Isola, Bernard Mari, Denis Masnikov, Palma Rocchi, Pascal Finetti, Patricia Korczak, Brune Vialet, Philippe Barthelemy, Carmen Garrido, Philippe Bonniaud, Olivier Burgy, Françoise Goirand","doi":"10.1111/bph.17470","DOIUrl":"https://doi.org/10.1111/bph.17470","url":null,"abstract":"<p><strong>Background and purpose: </strong>Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by fibroblast activation and abnormal accumulation of extracellular matrix in the lungs. We previously demonstrated the importance of the heat shock protein αB-crystallin (HSPB5) in TGF-β1 profibrotic signalling, which suggests that HSPB5 could be a new therapeutic target for the treatment of IPF. The purpose of this study was thus to develop antisense oligonucleotides targeting HSPB5 and to study their effects on the development of experimental pulmonary fibrosis.</p><p><strong>Experimental approach: </strong>Specific antisense oligonucleotides (ASO) were designed and screened in vitro, based on their ability to inhibit human and murine HSPB5 expression. The selected ASO22 was characterized in vitro in human fibroblast CCD-19Lu cells and A549 epithelial pulmonary cells, as well as in vivo using a mouse model of bleomycin-induced pulmonary fibrosis.</p><p><strong>Key results: </strong>ASO22 was selected for its capacity to inhibit TGF-β1-induced expression of HSPB5 and additional key markers of fibrosis such as plasminogen activator inhibitor-1, collagen, fibronectin and α-smooth muscle actin in fibroblastic human CCD-19Lu cells as well as plasminogen activator inhibitor-1 and α-smooth muscle actin in pulmonary epithelial A549 cells. Intra-tracheal or intravenous administration of ASO22 in bleomycin-induced pulmonary fibrotic mice decreased HSPB5 expression and reduced fibrosis, as demonstrated by decreased pulmonary remodelling, collagen accumulation and Acta2 and Col1a1 expression.</p><p><strong>Conclusion and implications: </strong>Our results suggest that an antisense oligonucleotide strategy targeting HSPB5 could be of interest for the treatment of IPF.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540297","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":"2-Hydroxyl hispolon reverses high glucose-induced endothelial progenitor cell dysfunction through the PI3K/Akt/eNOS and AMPK/HO-1 pathways.","authors":"Ta-Jung Wang, Wen-Chi Hou, Bu-Yuan Hsiao, Tsung-Hao Lo, Yu-Ta Chen, Chang-Hang Yang, Yu-Tsung Shih, Ju-Chi Liu","doi":"10.1111/bph.70002","DOIUrl":"https://doi.org/10.1111/bph.70002","url":null,"abstract":"<p><strong>Background and purpose: </strong>In diabetes (DM), elevated blood sugar levels contribute to the overproduction of reactive oxygen species (ROS), leading to endothelial progenitor cell (EPC) dysfunction. This study aimed to determine the potential of 2-hydroxy hispolon (2HH), a derivative of hispolon, to reverse high glucose-induced EPC dysfunction.</p><p><strong>Experimental approach: </strong>Under in vitro high-glucose (HG) conditions, we investigated the effects of 2HH on three types of angiogenic cells: outgrowth endothelial cells (OECs), circulating angiogenic cells (CACs) and endothelial cells (ECs). In vivo, high-fat diet and streptozotocin-induced diabetic mice with hindlimb ischaemia were used to evaluate the effects of 2HH on angiogenesis and CAC mobilisation.</p><p><strong>Key results: </strong>Treatment with 2HH significantly improved the proliferation, migration, tube formation, NO synthesis and ROS reduction in EPCs (OECs and CACs) under HG conditions by activating the AMP-activated protein kinase (AMPK)/haem oxygenase-1 (HO-1) and phosphoinositide 3-kinase (PI3K)/Akt/endothelial NOS (eNOS) signalling pathways but failed to restore EC dysfunction. In the in vivo hindlimb ischaemia model, 2HH administration in DM mice enhanced blood flow recovery in ischaemic hindlimbs, improved limb salvageability, increased the number of circulating CACs and increased capillary density in the ischaemic muscle. Furthermore, 2HH activated the AMPK/HO-1 and PI3K/Akt/eNOS pathways in CACs and ischaemic muscles.</p><p><strong>Conclusion and implications: </strong>2HH treatment effectively reduced oxidative stress and increased NO synthesis, thereby preventing HG-induced EPC dysfunction, primarily through the PI3K/Akt/eNOS and AMPK/HO-1 pathways. These findings offer a promising therapeutic avenue for attenuating susceptibility to critical limb ischaemia in patients with DM.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555879","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":"Chemosensory signalling in human sperm is controlled by Ca²⁺ influx via CatSper and Ca²⁺ clearance via plasma membrane Ca²⁺ ATPases.","authors":"Leonie Herrmann, Christoph Brenker, Teresa Mittermair, Vesna Bojovic, Jens Münchow, W Felix Zhu, Carla Trugge, David Fußhöller, Jan Jikeli, Louisa Temme, U Benjamin Kaupp, Timo Strünker","doi":"10.1111/bph.70009","DOIUrl":"https://doi.org/10.1111/bph.70009","url":null,"abstract":"<p><strong>Background and purpose: </strong>Loss of function of the sperm-specific Ca²⁺ channel CatSper is a common channelopathy that causes male infertility. CatSper controls the intracellular Ca²⁺ concentration and, thereby, the motility of human sperm. Activation of CatSper by oviductal ligands evokes a transient Ca²⁺ increase, which entails changes in the flagellar beat that are required for fertilisation. The CatSper-mediated Ca²⁺ influx has been studied extensively, whereas the mechanisms underlying Ca²⁺ clearance and recovery from Ca²⁺ influx have remained ill-defined.</p><p><strong>Experimental approach: </strong>We examined how pharmacological suppression of Ca²⁺ export from the cytosol into the extracellular space or Ca²⁺ uptake into intracellular stores affects the resting Ca²⁺ concentration and CatSper-mediated Ca²⁺ signals in human sperm. We studied sperm of healthy volunteers and infertile men lacking functional CatSper channels, using kinetic Ca²⁺- and pH-fluorometry as well as patch-clamp recordings.</p><p><strong>Key results: </strong>We show that Ca²⁺ entering human sperm via CatSper is predominantly, if not exclusively, exported by plasma membrane Ca²⁺ ATPases (PMCAs). Na⁺/Ca²⁺ exchange and Ca²⁺ uptake into intracellular stores or mitochondria play no or only a negligible role in Ca²⁺ clearance in human sperm.</p><p><strong>Conclusions and implications: </strong>Ca²⁺ signalling in human sperm is controlled by the functional interplay of CatSper and PMCAs, that is, the balance between Ca²⁺ influx and Ca²⁺ export that is required for human sperm function and fertilisation.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522625","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":"Ibuprofen inhibits human sweet taste and glucose detection implicating an additional mechanism of metabolic disease risk reduction.","authors":"Emily C Hanselman, Caroline P Harmon, Daiyong Deng, Sarah M Sywanycz, Lauren Caronia, Peihua Jiang, Paul A S Breslin","doi":"10.1111/bph.70004","DOIUrl":"https://doi.org/10.1111/bph.70004","url":null,"abstract":"<p><strong>Background and purpose: </strong>The human sweet taste receptor, TAS1R2-TAS1R3, conveys sweet taste in the mouth and may help regulate glucose metabolism throughout the body. Ibuprofen and naproxen are structurally similar to known inhibitors of TAS1R2-TAS1R3 and have been associated with metabolic benefits. Here, we determined if ibuprofen and naproxen inhibited TAS1R2-TAS1R3 responses to sugars in vitro and their elicited sweet taste in vivo, in humans under normal physiological conditions, with implications for effects on glucose metabolism.</p><p><strong>Experimental approach: </strong>Human psychophysical taste testing and in vitro cellular calcium assays in HEK293 cells were performed to determine the effects of ibuprofen and naproxen on sugar taste signalling.</p><p><strong>Key results: </strong>Ibuprofen and naproxen inhibited the sweet taste of sugars and non-nutritive sweeteners in humans, dose-dependently. Ibuprofen reduced cellular signalling of sucrose and sucralose in vitro with heterologously expressed human TAS1R2 (hTAS1R2)-TAS1R3 in human kidney cells. To mirror internal physiology, low concentrations of ibuprofen, which represent human plasma levels after a typical dose, inhibit the sweet taste and oral detection of glucose at concentrations nearing post-prandial plasma glucose levels.</p><p><strong>Conclusion and implications: </strong>Ibuprofen and naproxen inhibit activation of TAS1R2-TAS1R3 by sugar in humans. Long-term ibuprofen intake is associated with preserved metabolic function and reduced risk of metabolic diseases such as Alzheimer's, diabetes and colon cancer. In addition to its anti-inflammatory properties, we present here a novel pathway that could help explain the associations between metabolic function and chronic ibuprofen use.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499457","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}