British Journal of Pharmacology最新文献

{"title":"Tert-butylhydroquinone promotes skin flap survival by inhibiting oxidative stress mediated by the Nrf2/HO-1 signalling pathway","authors":"Kaitao Wang,&nbsp;An Wang,&nbsp;Jiapeng Deng,&nbsp;Jialong Yang,&nbsp;Guodong Chen,&nbsp;Qingyu Chen,&nbsp;Minle Ye,&nbsp;Dingsheng Lin","doi":"10.1111/bph.17321","DOIUrl":"10.1111/bph.17321","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Skin flaps are among the most important means of wound repair in clinical settings. However, partial or even total distal necrosis may occur after a flap operation, with severe consequences for both patients and doctors. This study investigated whether <i>tert</i>-butylhydroquinone (TBHQ), a known agonist of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), and an antioxidant, could promote skin flap survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>McFarlane skin flap models were established in male Sprague–Dawley rats and then randomly divided into control, low-dose TBHQ, and high-dose TBHQ treatment groups. On postoperative day 7, the survival and blood flow of the skin flaps were assessed. Using flap tissue samples, angiogenesis, inflammation, apoptosis, autophagy, and Nrf2/haem oxygenase 1 (HO-1) signalling pathway activity were measured with immunohistochemical techniques and western blotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>TBHQ dose-dependently stimulated the Nrf2/HO-1 signalling pathway, inducing autophagy through the up-regulation of LC3B and beclin 1 and concurrently suppressing p62 expression. Additionally, TBHQ hindered apoptosis by enhancing Bcl-2 expression while inhibiting the expression of Bax. It suppressed inflammation by inhibiting the expression of interleukin 1β, interleukin 6, and tumour necrosis factor-α and enhanced angiogenesis by promoting the expression of vascular endothelial growth factor.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>In summary, TBHQ promoted flap survival in rats by up-regulating the Nrf2/HO-1 signalling pathway. As TBHQ is already widely used as a food additive, it could offer an acceptable means of improving clinical outcomes following skin flap surgery in patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4845-4858"},"PeriodicalIF":6.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131898","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":"Advancing the field of viroporins—Structure, function and pharmacology: IUPHAR Review 39","authors":"Kira Devantier,&nbsp;Viktoria M. S. Kjær,&nbsp;Stephen Griffin,&nbsp;Birthe B. Kragelund,&nbsp;Mette M. Rosenkilde","doi":"10.1111/bph.17317","DOIUrl":"10.1111/bph.17317","url":null,"abstract":"<p>Viroporins possess important potential as antiviral targets due to their critical roles during virus life cycles, spanning from virus entry to egress. Although the antiviral amantadine targets the M2 viroporin of influenza A virus, successful progression of other viroporin inhibitors into clinical use remains challenging. These challenges relate in varying proportions to a lack of reliable full-length 3D-structures, difficulties in functionally characterising individual viroporins, and absence of verifiable direct binding between inhibitor and viroporin. This review offers perspectives to help overcome these challenges. We provide a comprehensive overview of the viroporin family, including their structural and functional features, highlighting the moldability of their energy landscapes and actions. To advance the field, we suggest a list of best practices to aspire towards unambiguous viroporin identification and characterisation, along with considerations of potential pitfalls. Finally, we present current and future scenarios of, and prospects for, viroporin targeting drugs.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 22","pages":"4450-4490"},"PeriodicalIF":6.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17317","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119022","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":"Targeting RNA with small molecules, from RNA structures to precision medicines: IUPHAR review: 40","authors":"Yuquan Tong,&nbsp;Jessica L. Childs-Disney,&nbsp;Matthew D. Disney","doi":"10.1111/bph.17308","DOIUrl":"10.1111/bph.17308","url":null,"abstract":"<p>RNA plays important roles in regulating both health and disease biology in all kingdoms of life. Notably, RNA can form intricate three-dimensional structures, and their biological functions are dependent on these structures. Targeting the structured regions of RNA with small molecules has gained increasing attention over the past decade, because it provides both chemical probes to study fundamental biology processes and lead medicines for diseases with unmet medical needs. Recent advances in RNA structure prediction and determination and RNA biology have accelerated the rational design and development of RNA-targeted small molecules to modulate disease pathology. However, challenges remain in advancing RNA-targeted small molecules towards clinical applications. This review summarizes strategies to study RNA structures, to identify small molecules recognizing these structures, and to augment the functionality of RNA-binding small molecules. We focus on recent advances in developing RNA-targeted small molecules as potential therapeutics in a variety of diseases, encompassing different modes of actions and targeting strategies. Furthermore, we present the current gaps between early-stage discovery of RNA-binding small molecules and their clinical applications, as well as a roadmap to overcome these challenges in the near future.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 21","pages":"4152-4173"},"PeriodicalIF":6.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119023","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 plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination","authors":"Yun Zhao,&nbsp;Guobin Zheng,&nbsp;Shu Yang,&nbsp;Shangjing Liu,&nbsp;Yifan Wu,&nbsp;Yaodong Miao,&nbsp;Zhen Liang,&nbsp;Yunqing Hua,&nbsp;Jing Zhang,&nbsp;Jia Shi,&nbsp;Dan Li,&nbsp;Yanfei Cheng,&nbsp;Yunsha Zhang,&nbsp;Yuanli Chen,&nbsp;Guanwei Fan,&nbsp;Chuanrui Ma","doi":"10.1111/bph.17311","DOIUrl":"10.1111/bph.17311","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and purpose</h3>\u0000 \u0000 <p>Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS (<i>Panax notoginseng saponins</i>), containing the main active ingredients of <i>Panax notoginseng</i>, exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE^−/− mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2^−/− macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2^−/− mice treated with high-fat diet (HFD) and AAV-PCSK9.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key results</h3>\u0000 \u0000 <p>PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and implications</h3>\u0000 \u0000 <p>PNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4822-4844"},"PeriodicalIF":6.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124879","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 novel inhibitor of class IIa histone deacetylases attenuates collagen-induced arthritis","authors":"Eunice K. Poon,&nbsp;Ligong Liu,&nbsp;Kai-Chen Wu,&nbsp;Junxian Lim,&nbsp;Matthew J. Sweet,&nbsp;Rink-Jan Lohman,&nbsp;Abishek Iyer,&nbsp;David P. Fairlie","doi":"10.1111/bph.17306","DOIUrl":"10.1111/bph.17306","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Most inhibitors of histone deacetylases (HDACs) are not selective and are cytotoxic. Some have anti-inflammatory activity in disease models, but cytotoxicity prevents long-term uses in non-fatal diseases. Inhibitors selective for class IIa HDACs are much less cytotoxic and may have applications in management of chronic inflammatory diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>LL87 is a novel HDAC inhibitor examined here for HDAC enzyme selectivity. It was also investigated in macrophages for cytotoxicity and for inhibition of lipopolysaccharide (LPS)-stimulated cytokine secretion. In a rat model of collagen-induced arthritis, LL87 was investigated for effects on joint inflammation in Dark Agouti rats. Histological, immunohistochemical, micro-computed tomography and molecular analyses characterise developing arthritis and anti-inflammatory efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>LL87 was significantly more inhibitory against class IIa than class I or IIb HDAC enzymes. In macrophages, LL87 was not cytotoxic and reduced both LPS-induced secretion of pro-inflammatory cytokines, and IL6-induced class IIa HDAC activity. In rats, LL87 attenuated paw swelling and clinical signs of arthritis, reducing collagen loss and histological damage in ankle joints. LL87 decreased immune cell infiltration, especially pro-inflammatory macrophages and osteoclasts, into synovial joints and significantly reduced expression of pro-inflammatory cytokines and tissue-degrading proteases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>A novel inhibitor of class IIa HDACs has been shown to have an anti-inflammatory and anti-arthritic profile distinct from current therapies. It is efficacious in reducing macrophage infiltration and joint inflammation in a chronic model of rat arthritis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4804-4821"},"PeriodicalIF":6.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17306","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119021","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":"Discovery of natural product derivative triptolidiol as a direct NLRP3 inhibitor by reducing K63-specific ubiquitination.","authors":"Mo-Yu Ding, Chengqing Ning, Shao-Ru Chen, Hao-Ran Yin, Jing Xu, Ying Wang","doi":"10.1111/bph.17320","DOIUrl":"https://doi.org/10.1111/bph.17320","url":null,"abstract":"<p><strong>Background and purpose: </strong>NLRP3 is up-regulated in inflammatory and autoimmune diseases. The development of NLRP3 inhibitors is challenged by the identification of compounds with distinct mechanisms of action avoiding side effects and toxicity. Triptolide is a natural product with multiple anti-inflammatory activities, but a narrow therapeutic window.</p><p><strong>Experimental approach: </strong>Natural product triptolide derivatives were screened for NLRP3 inhibitors in human THP-1 and mouse bone marrow-derived macrophages. The efficacy of potent NLRP3 inhibitors was evaluated in LPS-induced acute lung injury and septic shock models.</p><p><strong>Key results: </strong>Triptolidiol was identified as a selective inhibitor of NLRP3 with high potency. Triptolidiol inactivated the NLRP3 inflammasome in human THP-1 and mouse primary macrophages primed with LPS. Triptolidiol specifically inhibited pro-caspase 1 cleavage downstream of NLRP3, but not AIM2 or NLRC4 inflammasomes. Based on the structure-activity relationship study, the C8-β-OH group was critical for its binding to NLRP3. Triptolidiol exhibited a submicromolar K_D for NLRP3, binding to residue C280. This binding prevented the interaction of NLRP3 with NEK7, the key regulator of NLRP3 inflammasome oligomerization and assembly, but not with the inflammasome adaptor protein ASC. Triptolidiol decreased the K63-specific ubiquitination of NLRP3, leading NLRP3 to a \"closed\" inactive conformation. Intraperitoneal administration of triptolidiol significantly attenuated LPS-induced acute lung injury and lethal septic shock.</p><p><strong>Conclusion and implications: </strong>Triptolidiol is a novel NLRP3 inhibitor that regulates inflammasome assembly and activation by decreasing K63-linked ubiquitination. Triptolidiol has novel structural features that make it distinct from reported NLRP3 inhibitors and represents a viable therapeutic lead for inflammatory diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104565","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 path to the G protein-coupled receptor structural landscape: Major milestones and future directions.","authors":"Małgorzata M Kogut-Günthel, Zeenat Zara, Alessandro Nicoli, Alexandra Steuer, Marta Lopez-Balastegui, Jana Selent, Sanjai Karanth, Melanie Koehler, Antonella Ciancetta, Layara Akemi Abiko, Franz Hagn, Antonella Di Pizio","doi":"10.1111/bph.17314","DOIUrl":"https://doi.org/10.1111/bph.17314","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) play a crucial role in cell function by transducing signals from the extracellular environment to the inside of the cell. They mediate the effects of various stimuli, including hormones, neurotransmitters, ions, photons, food tastants and odorants, and are renowned drug targets. Advancements in structural biology techniques, including X-ray crystallography and cryo-electron microscopy (cryo-EM), have driven the elucidation of an increasing number of GPCR structures. These structures reveal novel features that shed light on receptor activation, dimerization and oligomerization, dichotomy between orthosteric and allosteric modulation, and the intricate interactions underlying signal transduction, providing insights into diverse ligand-binding modes and signalling pathways. However, a substantial portion of the GPCR repertoire and their activation states remain structurally unexplored. Future efforts should prioritize capturing the full structural diversity of GPCRs across multiple dimensions. To do so, the integration of structural biology with biophysical and computational techniques will be essential. We describe in this review the progress of nuclear magnetic resonance (NMR) to examine GPCR plasticity and conformational dynamics, of atomic force microscopy (AFM) to explore the spatial-temporal dynamics and kinetic aspects of GPCRs, and the recent breakthroughs in artificial intelligence for protein structure prediction to characterize the structures of the entire GPCRome. In summary, the journey through GPCR structural biology provided in this review illustrates how far we have come in decoding these essential proteins architecture and function. Looking ahead, integrating cutting-edge biophysics and computational tools offers a path to navigating the GPCR structural landscape, ultimately advancing GPCR-based applications.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104566","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":"Correction to “RTP801 is a critical factor in the neurodegeneration process of A53T a-synuclein in a mouse model of Parkinson's disease under chronic restraint stress”","authors":"","doi":"10.1111/bph.17323","DOIUrl":"10.1111/bph.17323","url":null,"abstract":"<p>\u0000 <span>Zhang, Z</span>, <span>Chu, SF</span>, <span>Wang, SS</span>, <span>Jiang, YN</span>, <span>Gao, Y</span>, <span>Yang, PF</span>, <span>Ai, QD</span>, <span>Chen, NH</span>. <span>RTP801 is a critical factor in the neurodegeneration process of A53T α-synuclein in a mouse model of Parkinson's disease under chronic restraint stress</span>. <i>Br J Pharmacol.</i> <span>2018</span> Feb; <span>175</span>(<span>4</span>): <span>590</span>–<span>605</span>, https://doi.org/10.1111/bph.14091</p><p>Accidental mistakes during article preparation led to wrong in Figure 8e. The images of A53T+RTP801 shRNA+CRS group in Figure 8e were incorrect. The corrected figure is provided below. All other data in Figure 8e remain unchanged, and this correction does not affect the interpretation of the results or the conclusions of the paper.</p><p>We apologise for this error.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 20","pages":"4085"},"PeriodicalIF":6.8,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17323","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104554","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":"The PARP inhibitor rucaparib blocks SARS-CoV-2 virus binding to cells and the immune reaction in models of COVID-19","authors":"Henrietta Papp,&nbsp;Emese Tóth,&nbsp;Judit Bóvári-Biri,&nbsp;Krisztina Bánfai,&nbsp;Péter Juhász,&nbsp;Mohamed Mahdi,&nbsp;Lilian Cristina Russo,&nbsp;Dávid Bajusz,&nbsp;Adrienn Sipos,&nbsp;László Petri,&nbsp;Tibor Viktor Szalai,&nbsp;Ágnes Kemény,&nbsp;Mónika Madai,&nbsp;Anett Kuczmog,&nbsp;Gyula Batta,&nbsp;Orsolya Mózner,&nbsp;Dorottya Vaskó,&nbsp;Edit Hirsch,&nbsp;Péter Bohus,&nbsp;Gábor Méhes,&nbsp;József Tőzsér,&nbsp;Nicola J. Curtin,&nbsp;Zsuzsanna Helyes,&nbsp;Attila Tóth,&nbsp;Nicolas C. Hoch,&nbsp;Ferenc Jakab,&nbsp;György M. Keserű,&nbsp;Judit E. Pongrácz,&nbsp;Péter Bai","doi":"10.1111/bph.17305","DOIUrl":"10.1111/bph.17305","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>To date, there are limited options for severe Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus. As ADP-ribosylation events are involved in regulating the life cycle of coronaviruses and the inflammatory reactions of the host; we have, here, assessed the repurposing of registered PARP inhibitors for the treatment of COVID-19.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>The effects of PARP inhibitors on virus uptake were assessed in cell-based experiments using multiple variants of SARS-CoV-2. The binding of rucaparib to spike protein was tested by molecular modelling and microcalorimetry. The anti-inflammatory properties of rucaparib were demonstrated in cell-based models upon challenging with recombinant spike protein or SARS-CoV-2 RNA vaccine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We detected high levels of oxidative stress and strong PARylation in all cell types in the lungs of COVID-19 patients, both of which negatively correlated with lymphocytopaenia. Interestingly, rucaparib, unlike other tested PARP inhibitors, reduced the SARS-CoV-2 infection rate through binding to the conserved 493–498 amino acid region located in the spike-ACE2 interface in the spike protein and prevented viruses from binding to ACE2. In addition, the spike protein and viral RNA-induced overexpression of cytokines was down-regulated by the inhibition of PARP1 by rucaparib at pharmacologically relevant concentrations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>These results point towards repurposing rucaparib for treating inflammatory responses in COVID-19.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4782-4803"},"PeriodicalIF":6.8,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17305","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079211","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":"PDE4B inhibition by nerandomilast: Effects on lung fibrosis and transcriptome in fibrotic rats and on biomarkers in human lung epithelial cells","authors":"Dennis Reininger,&nbsp;Katrin Fundel-Clemens,&nbsp;Christoph H. Mayr,&nbsp;Lutz Wollin,&nbsp;Baerbel Laemmle,&nbsp;Karsten Quast,&nbsp;Peter Nickolaus,&nbsp;Franziska Elena Herrmann","doi":"10.1111/bph.17303","DOIUrl":"10.1111/bph.17303","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The PDE4 family is considered a prime target for therapeutic intervention in several fibro-inflammatory diseases. We have investigated the molecular mechanisms of nerandomilast (BI 1015550), a preferential PDE4B inhibitor.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>In addition to clinically relevant parameters of idiopathic pulmonary fibrosis (IPF; lung function measurement/high-resolution computed tomography scan/AI-Ashcroft score), whole-lung homogenates from a therapeutic male Wistar rat model of pulmonary fibrosis were analysed by next-generation sequencing (NGS). Data were matched with public domain data derived from human IPF samples to investigate how well the rat model reflected human IPF. We scored the top counter-regulated genes following treatment with nerandomilast in human single cells and validated disease markers discovered in the rat model using a human disease-relevant in vitro assay of IPF.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Nerandomilast improved the decline of lung function parameters in bleomycin-treated animals. In the NGS study, most transcripts deregulated by bleomycin treatment were normalised by nerandomilast treatment. Most notably, a significant number of deregulated transcripts that were identified in human IPF disease were also found in the animal model and reversed by nerandomilast. Mapping to single-cell data revealed the strongest effects on mesenchymal, epithelial and endothelial cell populations. In a primary human epithelial cell culture system, several disease-related (bio)markers were inhibited by nerandomilast in a concentration-dependent manner.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>This study further supports the available knowledge about the anti-inflammatory/antifibrotic mechanisms of nerandomilast and provides novel insights into the mode of action and signalling pathways influenced by nerandomilast treatment of lung fibrosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4766-4781"},"PeriodicalIF":6.8,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17303","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054940","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}