British Journal of Pharmacology最新文献

{"title":"Cordycepin ameliorates autoimmunity by promoting STING degradation via autophagy pathway","authors":"Daidi Yang,&nbsp;Niannian Peng,&nbsp;Hongqian Zhang,&nbsp;Zuocheng Qiu,&nbsp;Lingxiao Xu,&nbsp;Mingyu Pan","doi":"10.1111/bph.17425","DOIUrl":"10.1111/bph.17425","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Stimulator of interferon response cGAMP interactor 1 (STING), a central hub protein of cyclic GMP-AMP synthase (cGAS)–STING signalling pathway, has a crucial role in regulating type I interferons (IFNs) production and response. Recent studies indicate that excessive activation of STING is strongly associated with autoimmune diseases, including systemic lupus erythematosus (SLE). Searching immunomodulators that negatively regulate STING might greatly contribute to the suppression of autoimmunity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>The peripheral blood mononuclear cells (PBMCs) of SLE patients, Hela cells, L929 cells and bone marrow-derived macrophages (BMDMs) from mice were used as <i>in vitro</i> models. While, Trex1 KO mouse autoimmune disease model was used as <i>in vivo</i> model. After treatment with cordycepin, a nucleoside from Cordyceps mushrooms, type I IFNs production and response were determined by western blotting, real-time polymerase chain reaction (PCR), dual-luciferase assay, enzyme-linked immunosorbent assay (ELISA), haematoxylin–eosin staining and RNA-seq.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Cordycepin inhibited type I IFNs production and response in human and murine systems following cGAS–STING signalling activation. Importantly, cordycepin markedly attenuates the autoinflammatory and autoimmune responses in <i>Trex1</i> KO BMDMs and <i>Trex1</i> KO mice. Furthermore, cordycepin effectively suppressed the production of type I IFNs and interferon-stimulated genes (<i>ISG</i>s) in the PBMCs of SLE patients. Mechanistically, cordycepin promoted STING degradation via autophagy pathway upon DNA stimulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>This study shows that cordycepin promotes STING autophagic degradation to alleviate autoimmunity upon DNA stimulation. Cordycepin might be a potential therapeutic candidate for alleviating aberrant type I IFNs in autoimmune and autoinflammatory diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1546-1560"},"PeriodicalIF":6.8,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827403","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":"Atractylodes macrocephala Koidz polysaccharide ameliorates DSS-induced colitis in mice by regulating the gut microbiota and tryptophan metabolism","authors":"Qian-Wen Zhang,&nbsp;Meng-Jiao Yang,&nbsp;Chun-Yu Liao,&nbsp;Reham Taha,&nbsp;Qing-Yu Li,&nbsp;Mohammed Ismail Abdelmotalab,&nbsp;Si-Yu Zhao,&nbsp;Yan Xu,&nbsp;Zhen-Zhou Jiang,&nbsp;Cheng-Han Chu,&nbsp;Xin Huang,&nbsp;Chun-Hua Jiao,&nbsp;Li-Xin Sun","doi":"10.1111/bph.17409","DOIUrl":"10.1111/bph.17409","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease, and the range of current clinical treatments is not ideal. We previously found that polysaccharide of <i>Atractylodes macrocephala</i> Koidz (PAMK) is beneficial in DSS-induced colitis, and we aimed to investigate the underlying mechanisms in this study.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>PAMK was used to treat DSS-induced colitis in mice, 16S rRNA sequencing analysis was used to detect changes in the intestinal microbiota, targeted metabolomics analysis was used to determine the content of tryptophan-metabolizing bacteria, and western blotting was used to determine aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) levels. Furthermore, antibiotic-mediated depletion of gut microbiota and faecal microbiota transplantation were performed to assess the role of the gut microbiota in PAMK alleviation of colitis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>PAMK treatment relieved intestinal microbiota dysbiosis in mice with colitis, contributed to the proliferation of tryptophan-metabolizing bacteria, and increased the levels of tryptophan metabolites, resulting in a significant increase in the nuclear translocation of PXR and expression of PXR and its target genes, but not AhR. The gut microbiota is important in PAMK treatment of colitis, including in the alleviation of symptoms, inhibition of inflammation, maintenance of the integrity of the intestinal barrier, and the regulation of the Th17/Treg cell balance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Based on our findings, we elucidate a novel mechanism by which PAMK alleviates DSS-induced colitis and thus provides evidence to support the potential development of PAMK as a new clinical drug against UC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1508-1527"},"PeriodicalIF":6.8,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817385","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":"Inhibition of the upregulated phosphodiesterase 4D isoforms improves SERCA2a function in diabetic cardiomyopathy","authors":"Zhenduo Zhu,&nbsp;Qiuyun Guan,&nbsp;Bing Xu,&nbsp;Sherif Bahriz,&nbsp;Ao Shen,&nbsp;Toni M. West,&nbsp;Yu Zhang,&nbsp;Bingqing Deng,&nbsp;Wei Wei,&nbsp;Yongsheng Han,&nbsp;Qingtong Wang,&nbsp;Yang K. Xiang","doi":"10.1111/bph.17411","DOIUrl":"10.1111/bph.17411","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a) is impaired in heart failure. Phosphodiesterases (PDEs) are implicated in the modulation of local cAMP signals and protein kinase A (PKA) activity essential for cardiac function. We characterise PDE isoforms that underlie decreased activities of SERCA2a and reduced cardiac contractile function in diabetic cardiomyopathy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Wild type mice were fed with either normal chow or a high-fat diet (HFD). Cardiomyocytes were isolated for excitation–contraction coupling (ECC), fluorescence resonant energy transfer PKA biosensor and proximity ligation assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>The upregulated PDE4D3 and PDE4D9 isoforms in HFD cardiomyocytes specifically bound to SERCA2a but not ryanodine receptor 2 (RyR2) on the sarcoplasmic reticulum (SR). The increased association of PDE4D isoforms with SERCA2a in HFD cardiomyocytes led to reduced local PKA activities and phosphorylation of phospholamban (PLB) but minimally effected the PKA activities and phosphorylation of RyR2. These changes correlate with slower calcium decay tau in the SR and attenuation of ECC in HFD cardiomyocytes. Selective inhibition of PDE4D3 or PDE4D9 restored PKA activities and phosphorylation of PLB at the SERCA2a complex, recovered calcium decay tau, and increased ECC in HFD cardiomyocytes. Therapies with PDE4 inhibitor roflumilast, PDE4D inhibitor BPN14770 or genetical deletion of PDE4D restored PKA phosphorylation of PLB and cardiac contractile function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>The current study identifies upregulation of specific PDE4D isoforms that selectively inhibit SERCA2a function in HFD-induced cardiomyopathy, indicating that this remodelling can be targeted to restore cardiac contractility in diabetic cardiomyopathy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1487-1507"},"PeriodicalIF":6.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17411","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812186","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":"Chronic stress induces behavioural changes through increased kynurenic acid by downregulation of kynurenine-3-monooxygenase with microglial decline","authors":"Masaya Hasegawa,&nbsp;Kazuo Kunisawa,&nbsp;Bolati Wulaer,&nbsp;Hisayoshi Kubota,&nbsp;Hitomi Kurahashi,&nbsp;Takatoshi Sakata,&nbsp;Honomi Ando,&nbsp;Suwako Fujigaki,&nbsp;Hidetsugu Fujigaki,&nbsp;Yasuko Yamamoto,&nbsp;Taku Nagai,&nbsp;Kuniaki Saito,&nbsp;Toshitaka Nabeshima,&nbsp;Akihiro Mouri","doi":"10.1111/bph.17407","DOIUrl":"10.1111/bph.17407","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Alterations in tryptophan-kynurenine (TRP-KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic–pituitary–adrenal (HPA) axis. We have shown that deficiency of kynurenine 3-monooxygenase (KMO) induces depression-like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP-KYN pathway in stress-induced behavioural changes and the regulation of the HPA axis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP-KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS-induced behavioural changes and an increase in serum corticosterone (CORT) concentration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. <i>Kmo</i>^+/− mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short-term CUMS. Nicotine attenuated CUMS-induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin-releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>CUMS-induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1466-1486"},"PeriodicalIF":6.8,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17407","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806372","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":"Antithrombotic but not anticoagulant activity of the thrombin-binding RNA aptamer Apta-1","authors":"Luiza Jedlina,&nbsp;Geena Paramel,&nbsp;Svetlana Soboleva,&nbsp;Oldriska Chutna Olin,&nbsp;Marianne Haug,&nbsp;Karin Fransén,&nbsp;Mikael Lindstam,&nbsp;Marta Brewinska-Olchowik,&nbsp;Katarzyna Piwocka,&nbsp;Magnus Grenegård","doi":"10.1111/bph.17382","DOIUrl":"10.1111/bph.17382","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Pharmacological intervention of thrombosis is challenging, requiring a fined tune balance between beneficial antithrombotic effect versus risk of major bleeding complications. In this investigation, we elucidated the antithrombotic capacity of the novel 90-mer RNA aptamer Apta-1 and its underlying mechanism of action.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We utilized three independent <i>in vivo</i> animal models to establish antithrombotic activity and bleeding risk of Apta-1. Several cellular and molecular techniques were utilized to extensively characterize the effects of Apta-1 on primary and secondary haemostasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Apta-1 significantly reduced thrombus weight in ferric chloride-induced carotid artery thrombosis. A consistent reduction in thrombus weight was also observed in arteriovenous shunt thrombosis in rats, whereas tail bleeding time was unaffected. Cellular and molecular analyses revealed that Apta-1 interacted with thrombin, resulting in significant inhibition of protease-activated receptor (PAR) signalling in platelets. On the other hand, Apta-1 shortened both thrombin generation and thrombin-induced clotting times.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Apta-1 targets the heparin-binding motif exosite II on thrombin leading to significant suppression of platelet PAR1 and PAR4 signalling. Intriguingly, Apta-1 produces substantial antithrombotic activity without anticoagulant or general antiplatelet properties. In fact, we found that Apta-1 accelerates the formation of blood clots and thus supports haemostasis without exhibiting typical anticoagulant properties. We suggest that Apta-1 may be a promising future drug candidate for treatment of thrombosis in diseases/conditions where there are significant risks of serious bleeding complications.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 6","pages":"1358-1376"},"PeriodicalIF":6.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17382","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799345","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":"Loss of AXIN1 regulates response to lenvatinib through a WNT/KDM5B/p15 signalling axis in hepatocellular carcinoma","authors":"Chengfang Tang,&nbsp;Chu Tang,&nbsp;Xuanchi Zhu,&nbsp;Simeng Wang,&nbsp;Yuan Yang,&nbsp;Yu Miao,&nbsp;Xiaoyao Zhao,&nbsp;Lina Jia,&nbsp;Jingyu Yang,&nbsp;Yang Su,&nbsp;Lihui Wang,&nbsp;Chunfu Wu","doi":"10.1111/bph.17413","DOIUrl":"10.1111/bph.17413","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>As a highly heterogeneous cancer, hepatocellular carcinoma (HCC) shows different response rates to the multi-kinase inhibitor lenvatinib. Thus, it is important to explore genetic biomarkers for precision lenvatinib therapy in HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>The effect and mechanism of AXIN1 mutation on HCC were revealed by cell proliferation assay, long-term clone formation assay, sphere formation assay and small molecule inhibitor library screening. A new therapeutic strategy targeting HCC with AXIN1 mutation was evaluated in humanized models (patient-derived xenograft [PDX] and patient-derived organoid [PDO]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Based on The Cancer Genome Atlas (TCGA) data, we screened 6 most frequently lost tumour suppressor genes in HCC (TP53, ARID1A, AXIN1, CDKN2A, ARID2 and PTEN) and identified AXIN1 as the most crucial gene for lenvatinib sensitivity. Further study showed that AXIN1-knockout HCC cells had a more malignant phenotype and lower sensitivity to lenvatinib <i>in vitro</i> and <i>in vivo</i>. Mechanistically, the WNT pathway and its target gene c-Myc were activated when AXIN1 was missing, and the expression of tumour suppressor p15 was inhibited by transcription co-repressors c-Myc and Miz-1, resulting in the exacerbation of the resistant phenotype. Screening of a library of epigenetic-related enzyme inhibitors showed that a KDM5B inhibitor up-regulated p15 expression, leading to increased sensitivity to lenvatinib <i>in vitro</i> and <i>in vivo</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 6","pages":"1394-1409"},"PeriodicalIF":6.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799484","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":"Memantine-induced functional rewiring of the glutamate synapse in the striatum of dopamine transporter knockout rats","authors":"Lucia Caffino,&nbsp;Giorgia Targa,&nbsp;Francesca Mottarlini,&nbsp;Sarah Thielens,&nbsp;Beatrice Rizzi,&nbsp;Agnes Villers,&nbsp;Laurence Ris,&nbsp;Raul R. Gainetdinov,&nbsp;Damiana Leo,&nbsp;Fabio Fumagalli","doi":"10.1111/bph.17403","DOIUrl":"10.1111/bph.17403","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Slow-acting biogenic amines, such as dopamine, are known to modulate fast neurotransmitters e.g. glutamate. In the striatum, dopamine (DA) interacts with glutamate, influencing neural excitability and promoting synaptic plasticity. The exact mechanism of such interaction is not fully understood. This study investigates, in detail, how dopamine overactivity in dopamine transporter knockout (DAT^−/−) rats, alters the homeostasis of the striatal glutamate synapse from a molecular, behavioural and functional point of view.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>The expression, localisation, retention and electrophysiological properties of N-methyl-D-aspartate (NMDA) receptors as well as dendritic spine density and morphology were investigated in the striatum of DAT^−/− rats, at baseline and after treatment with the non-competitive NMDA receptor antagonist memantine (30 mg kg⁻¹).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Dopamine overactivity dramatically reorganises the striatal glutamate synapse, redistributing NMDA receptors in the synapse as typified by reduced synaptic availability and reduced expression of NMDA scaffolding proteins, as well as by increased GluN2B-containing NMDA receptors in the extra synapse. Such changes are accompanied by reduced spine density, suggesting dopamine-induced structural rearrangements. These results converge into a compromised plasticity, as shown by the impaired ability to promote long-term depression (LTD) in the striatum of DAT^−/−rats. Notably, memantine counteracts hyperlocomotion, reverses spine alterations and abolishes the extrasynaptic movements of NMDA receptors in the striatum of DAT^−/− rats, thus restoring functional LTD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>A hyperdopaminergic condition seems to alter striatal homeostasis by increasing extrasynaptic NMDA receptors. These findings may be relevant to manipulate disorders characterised by elevated dopaminergic activity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 6","pages":"1377-1393"},"PeriodicalIF":6.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17403","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799485","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":"DysRegNet: Patient-specific and confounder-aware dysregulated network inference towards precision therapeutics.","authors":"Johannes Kersting, Olga Lazareva, Zakaria Louadi, Jan Baumbach, David B Blumenthal, Markus List","doi":"10.1111/bph.17395","DOIUrl":"https://doi.org/10.1111/bph.17395","url":null,"abstract":"<p><strong>Background and purpose: </strong>Gene regulation is frequently altered in diseases in unique and patient-specific ways. Hence, personalised strategies have been proposed to infer patient-specific gene-regulatory networks. However, existing methods do not scale well because they often require recomputing the entire network per sample. Moreover, they do not account for clinically important confounding factors such as age, sex or treatment history. Finally, a user-friendly implementation for the analysis and interpretation of such networks is missing.</p><p><strong>Experimental approach: </strong>We present DysRegNet, a method for inferring patient-specific regulatory alterations (dysregulations) from bulk gene expression profiles. We compared DysRegNet to the well-known SSN method, considering patient clustering, promoter methylation, mutations and cancer-stage data.</p><p><strong>Key results: </strong>We demonstrate that both SSN and DysRegNet produce interpretable and biologically meaningful networks across various cancer types. In contrast to SSN, DysRegNet can scale to arbitrary sample numbers and highlights the importance of confounders in network inference, revealing an age-specific bias in gene regulation in breast cancer. DysRegNet is available as a Python package (https://github.com/biomedbigdata/DysRegNet_package), and analysis results for 11 TCGA cancer types are available through an interactive web interface (https://exbio.wzw.tum.de/dysregnet).</p><p><strong>Conclusion and implications: </strong>DysRegNet introduces a novel bioinformatics tool enabling confounder-aware and patient-specific network analysis to unravel regulatory alteration in complex diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779529","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 paracetamol metabolite N-acetyl-4-benzoquinoneimine (NAPQI) prevents modulation of KV7 channels via G-protein coupled receptors by interference with PIP2 and Ca2+ sensitivity","authors":"Thomas Losgott,&nbsp;Oliver Kudlacek,&nbsp;Jae-Won Yang,&nbsp;Klaus W. Schicker,&nbsp;Stefan Boehm,&nbsp;Isabella Salzer","doi":"10.1111/bph.17419","DOIUrl":"10.1111/bph.17419","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Paracetamol has been found to alleviate inflammatory pain by modulating K_V7 channels. Its metabolite N-acetyl-4-benzoquinoneimine (NAPQI) increases currents through these channels via a stretch of three cysteine residues in the channel S2–S3 linker. Through this effect, the excitability of neurons in the pain pathway is dampened. Inflammatory mediators, in turn, enhance the excitability of sensory neurons by inhibiting K_V7 channels. Here, a specific interaction between NAPQI and the so-called inflammatory soup was investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Currents through K_V7 channels were measured in sensory neurons and after heterologous expression in tsA201 cells. In addition, changes in cytosolic Ca²⁺ and in the distribution of PIP₂ (PI(4,5)P₂) between membrane and cytosol were determined by fluorescence microscopy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>NAPQI abolished Ca²⁺-mediated inhibitory effects of an ‘inflammatory soup’ containing ADP, ATP, bradykinin, histamine, 5-hydroxytryptamine, prostaglandin E₂, substance P and a PAR2 agonist on K_V7 channel currents in sensory neurons. Moreover, the increase of K_V7.2 channel currents by quenching of cytosolic Ca²⁺ as well as the current decrease by depletion of membrane PIP₂ was impaired by NAPQI. These effects were lost in mutant channels lacking the three cysteines in the S2–S3 linker.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implication</h3>\u0000 \u0000 <p>NAPQI targets the three-cysteine motif in the S2–S3 linker of K_V7.2 channels to counteract the signalling cascades employed by inflammatory mediators that inhibit these channels. In sensory neurons, this abolishes the closure of K_V7 channels by the inflammatory soup. This mechanism is likely involved in the alleviation of inflammatory pain by paracetamol.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 6","pages":"1341-1357"},"PeriodicalIF":6.8,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17419","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766464","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":"V-domain immunoglobulin suppressor of T-cell activation and programmed death receptor 1 dual checkpoint blockade enhances antitumour immunity and survival in glioblastoma","authors":"Shasha Jin,&nbsp;Tao Li,&nbsp;Liu Liu,&nbsp;Ting Gao,&nbsp;Tingting Zhang,&nbsp;Dingyi Yuan,&nbsp;Jianwen Di,&nbsp;Zhanying Guo,&nbsp;Zhijie Luo,&nbsp;Haoliang Yuan,&nbsp;Jun Liu","doi":"10.1111/bph.17404","DOIUrl":"10.1111/bph.17404","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The current therapy cannot meet the needs of glioblastoma (GBM). V-domain immunoglobulin suppressor of T-cell activation (VISTA) is significantly up-regulated in GBM patients; however, its therapeutic potential in GBM is still unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Flow cytometry was used to detect the expression of VISTA and the co-expression pattern of VISTA and programmed death receptor 1 (PD-1) on brain infiltrating lymphocytes of GBM mice. Monoclonal antibody therapy was used to evaluate the therapeutic effect of <i>α</i>-VISTA monotherapy and <i>α</i>-VISTA combined with <i>α</i>-PD-1 on GBM mice. Transcriptome analysis, flow cytometry, and immunofluorescence were used to detect changes of immune microenvironment in mouse brain tumours. Immunofluorescence and TCGA data analysis were used to further validate the combined treatment strategy on patient data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Compared with normal mice, the frequency of VISTA expression and co-expression of VISTA and PD-1 on tumour-infiltrating lymphocytes (TILs) in tumour-bearing mice was increased. Anti-VISTA monotherapy significantly up-regulated multiple immune stimulation-related pathways and moderately prolonged mouse survival time. Blocking the immune checkpoint VISTA and PD-1 significantly prolonged the survival time of mice and cured about 80% of the mice; CD8⁺ T cells played an important role in this process. In addition, we found that the expression of VISTA and PD-1 was significantly up-regulated in GBM patients by immunofluorescence, and patients with high expression of VISTA and PD-1 were associated with poor overall survival. This combination of blocking the immune checkpoint VISTA and PD-1 may achieve clinical transformation in GBM.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 6","pages":"1306-1323"},"PeriodicalIF":6.8,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766466","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}