British Journal of Pharmacology最新文献

{"title":"GraphCPP: The new state-of-the-art method for cell-penetrating peptide prediction via graph neural networks","authors":"Attila Imre,&nbsp;Balázs Balogh,&nbsp;István Mándity","doi":"10.1111/bph.17388","DOIUrl":"10.1111/bph.17388","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Cell-penetrating peptides (CPPs) are short amino acid sequences that can penetrate cell membranes and deliver molecules into cells. Several models have been developed for their discovery, yet these models often face challenges in accurately predicting membrane penetration due to the complex nature of peptide–cell interactions. Hence, there is a need for innovative approaches that can enhance predictive performance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>In this study, we present the application GraphCPP, a novel graph neural network (GNN) for the prediction of membrane penetration capability of peptides.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>A new comprehensive dataset—dubbed CPP1708—was constructed resulting in the largest reliable database of CPPs to date. Comparative analyses with previous methods, such as MLCPP2, C2Pred, CellPPD and CellPPD-Mod, demonstrated the superior predictive performance of our model. Upon testing against other published methods, GraphCPP performs exceptionally, achieving 0.5787 Matthews correlation coefficient and 0.8459 area under the curve (AUC) values on one dataset. This means a 92.8% and 23.3% improvement in Matthews correlation coefficient and AUC measures respectively compared with the next best model. The capability of the model to effectively learn peptide representations was demonstrated through t-distributed stochastic neighbour embedding plots. Additionally, the uncertainty analysis revealed that GraphCPP maintains high confidence in predictions for peptides shorter than 40 amino acids. The source code is available at https://github.com/attilaimre99/GraphCPP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>These findings indicate the potential of GNN-based models to improve CPP penetration prediction and it may contribute towards the development of more efficient drug delivery systems.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 3","pages":"495-509"},"PeriodicalIF":6.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17388","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680736","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":"NaHS alters synaptic plasticity proteins and enhances dendritic arborization to improve cognitive and motor deficits after traumatic brain injury in mice","authors":"Farheen Nasir,&nbsp;Priyanka Yadav,&nbsp;Thamil Mani Sivanandam","doi":"10.1111/bph.17386","DOIUrl":"10.1111/bph.17386","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Traumatic brain injury (TBI) is a complex medical condition affecting people globally. Hydrogen sulfide (H₂S) is a recently discovered gaseous mediator and is dysregulated in the brain after TBI. Sodium hydrogen sulfide (NaHS), a known donor of H₂S, is beneficial in various biological processes involving aging and diseases, including injury. It is neuroprotective against oxidative stress, neuroinflammation, and other secondary injury processes. However, the NaHS-H₂S system has not been investigated as a regulator of injury-mediated synaptic plasticity proteins and the underlying mechanisms after TBI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>We developed a model of TBI in Swiss albino mice to study the effects of exogenous H₂S, administered as NaHS. We assessed cognitive function (Barnes maze and novel object recognition) and motor function (rotarod). Brain tissue was analysed with ELISA, qRT-PCR, immunoblotting, Golgi-cox staining, and immunofluorescence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key results</h3>\u0000 \u0000 <p>NaHS administration restored the injury-caused decline in H₂S levels. Injury-mediated oxidative stress parameters were improved following NaHS. It down-regulated TBI biomarkers, ameliorated the synaptic marker proteins, and improved cognitive and motor deficits. These changes were accompanied by enhanced dendritic arborization and spine number. Restoration of <i>N</i>-methyl D-aspartate receptor subunits and diminished glutamate and calcium levels, along with marked changes in microtubule-associated protein 2 A and calcium/calmodulin-dependent protein kinase II, formed the basis of the underlying mechanism(s).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Our findings suggest that NaHS could have therapeutic activity against TBI, as it ameliorated cognitive and motor deficits caused by changes in synaptic plasticity proteins and dendritic arborisation, in our model.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 5","pages":"1183-1205"},"PeriodicalIF":6.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675210","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 endocannabinoid anandamide mediates anti-inflammatory effects through activation of NR4A nuclear receptors","authors":"Tom Teichmann,&nbsp;Beatrice Pflüger-Müller,&nbsp;Virna Margarita Martín Giménez,&nbsp;Fiona Sailer,&nbsp;Henrik Dirks,&nbsp;Simonida Zehr,&nbsp;Timothy Warwick,&nbsp;Felix Brettner,&nbsp;Paola Munoz-Tello,&nbsp;Andreas Zimmer,&nbsp;Irmgard Tegeder,&nbsp;Dominique Thomas,&nbsp;Robert Gurke,&nbsp;Stefan Günther,&nbsp;Jan Heering,&nbsp;Ewgenij Proschak,&nbsp;Gerd Geisslinger,&nbsp;Iris-S. Bibli,&nbsp;Dagmar Meyer zu Heringdorf,&nbsp;Walter Manucha,&nbsp;Maike Windbergs,&nbsp;Stefan Knapp,&nbsp;Andreas Weigert,&nbsp;Matthias S. Leisegang,&nbsp;Douglas Kojetin,&nbsp;Ralf P. Brandes","doi":"10.1111/bph.17366","DOIUrl":"10.1111/bph.17366","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and purpose</h3>\u0000 \u0000 <p>Endocannabinoids are lipid mediators, which elicit complex biological effects that extend beyond the central nervous system. Tissue concentrations of endocannabinoids increase in atherosclerosis, and for the endocannabinoid N-arachidonoyl-ethanolamine (anandamide, AEA), this has been linked to an anti-inflammatory function. In this study, we set out to determine the anti-inflammatory mechanism of action of AEA, specifically focusing on vascular smooth muscle cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>RNA-sequencing, RT-qPCR, LC-MS/MS, NanoBit, ChIP, microscale thermophoresis, NMR structural footprinting, Gal4 reporter gene assays and loss of function approaches in cell and ex vivo organ culture were used.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key results</h3>\u0000 \u0000 <p>AEA pretreatment attenuated the cytokine-mediated induction of inflammatory gene expression such as CCL2. This effect was also observed in preparations obtained from cannabinoid receptor knockout mice and after pertussis toxin treatment. The anti-inflammatory effect of AEA required preincubation, suggesting an effect through gene induction. AEA increased the expression of the nuclear receptors NR4A1 and NR4A2. Knockdown and knockout of these receptors blocked the AEA-mediated anti-inflammatory effect in cell culture and aortic organ culture, respectively. Conversely, NR4A agonists (CsnB, C-DIM12) attenuated inflammatory gene expression. AEA binds to NR4A, and mutations in NR4A attenuated this effect. The interaction of AEA with NR4A caused recruitment of the nuclear corepressor NCoR1 to the CCL2 promoter, resulting in gene suppression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and implications</h3>\u0000 \u0000 <p>By binding to NR4A, AEA elicits an anti-inflammatory response in vascular smooth muscle cells. NR4A-binding by AEA analogues may represent novel anti-inflammatory agents.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 5","pages":"1164-1182"},"PeriodicalIF":6.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17366","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675211","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":"RETRACTION: Cloricromene, a Coumarine Derivative, Protects Against Collagen-induced Arthritis in Lewis Rats","authors":"","doi":"10.1111/bph.17417","DOIUrl":"10.1111/bph.17417","url":null,"abstract":"<p><b>RETRACTION</b>: S. Cuzzocrea, E. Mazzon, C. Bevilaqua, G. Costantino, D. Britti, G. Mazzullo, A. De Sarro, and A. P. Caputi, “Cloricromene, a Coumarine Derivative, Protects Against Collagen-induced Arthritis in Lewis Rats,” <i>British Journal of Pharmacology</i> 131, no. 7 (2000): 1399–1407, https://doi.org/10.1038/sj.bjp.0703695.</p><p>The above article, published online on 29 January 2009 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Péter Ferdinandy; the British Pharmacological Society; and John Wiley &amp; Sons Ltd. The retraction has been agreed due to concerns raised by third parties on the data presented in the article. Specifically, image elements of Figure 7 were found to have been published in a different article with at least one common author and in a different scientific context. Further investigation by the journal team revealed that also Figure 4B was published in the same article to represent a different treatment. Due to the significant time elapsed since publication, the authors were unable to retrieve the full set of original data, and the data provided was found insufficient to address the concerns. As the editors have lost trust in the accuracy and integrity of the overall body of data presented in the article and consider the conclusions invalid, the article must be retracted.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 1","pages":"198"},"PeriodicalIF":6.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17417","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646583","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":"RETRACTION: Pyrrolidine Dithiocarbamate Attenuates the Development of Acute and Chronic Inflammation","authors":"","doi":"10.1111/bph.17418","DOIUrl":"10.1111/bph.17418","url":null,"abstract":"<p><b>RETRACTION</b>: S. Cuzzocrea, P. K. Chatterjee, E. Mazzon, L. Dugo, I. Serraino, D. Britti, G. Mazzullo, A. P. Caputi, and C. Thiemermann, “Pyrrolidine Dithiocarbamate Attenuates the Development of Acute and Chronic Inflammation,” <i>British Journal of Pharmacology</i> 135, no. 2 (2002): 496–510, https://doi.org/10.1038/sj.bjp.0704463.</p><p>The above article, published online on 2 February 2009 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Péter Ferdinandy; the British Pharmacological Society; and John Wiley &amp; Sons Ltd. The retraction has been agreed due to concerns raised by third parties on the data presented in the article.</p><p>Specifically, the Western Blot presented in Figure 6 was found to have been presented in multiple previous publications with at least one common author and in a different scientific context. Furthermore, duplication has been detected within Figure 3. Due to the significant time elapsed since publication, the authors were unable to retrieve the full set of original data, and the data provided was found insufficient to address the concerns. As the editors have lost trust in the accuracy and integrity of the overall body of data presented in the article and consider the conclusions invalid, the article must be retracted.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 1","pages":"199"},"PeriodicalIF":6.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17418","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646596","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":"Combined therapy with pirfenidone and nintedanib counteracts fibrotic silicosis in mice","authors":"Lu Bai,&nbsp;Jiaxin Wang,&nbsp;Xue Wang,&nbsp;Jixin Wang,&nbsp;Wei Zeng,&nbsp;Junling Pang,&nbsp;Tiantian Zhang,&nbsp;Shengxi Li,&nbsp;Meiyue Song,&nbsp;Yiwei Shi,&nbsp;Jing Wang,&nbsp;Chen Wang","doi":"10.1111/bph.17390","DOIUrl":"10.1111/bph.17390","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Pneumoconiosis, especially silicosis, is a prevalent occupational disease with substantial global economic implications and lacks a definitive cure. Both pneumoconiosis and idiopathic pulmonary fibrosis (IPF) are interstitial lung diseases, which share many common physiological characteristics. Because pirfenidone and nintedanib are approved to treat IPF, their potential efficacy as antifibrotic agents in advanced silicosis deserves further exploration. Thus, we aimed to evaluate the individual and combined effects of pirfenidone and nintedanib in treating advanced silicosis mice and elucidate the underlying mechanisms of their therapeutic actions via multiomics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We administered monotherapy or combined therapy of pirfenidone and nintedanib, with low and high doses, in silicosis established after 6 weeks and evaluated lung function, inflammatory responses and fibrotic status. Additionally, we employed transcriptomic and metabolomic analyses to uncover the mechanisms underlying different therapeutic strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Both pirfenidone and nintedanib were effective in treating advanced silicosis, with superior outcomes observed in combination therapy. Transcriptomic and metabolomic analyses revealed that pirfenidone and nintedanib primarily exerted their therapeutic effects by modulating immune responses, signalling cascades and metabolic processes involving lipids, nucleotides and carbohydrates. Furthermore, we experimentally validated both monotherapy and combined therapy yielded therapeutic benefits through two common signalling pathways: steroid biosynthesis and purine metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>In conclusion, pirfenidone and nintedanib, either individually or in combination, demonstrate substantial potential in advanced silicosis. Furthermore, combined therapy outperformed monotherapy, even at low doses. These therapeutic benefits are attributed to their influence on diverse signalling pathways and metabolic processes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 5","pages":"1143-1163"},"PeriodicalIF":6.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17390","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638405","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":"Optical control of cardiac electrophysiology by the photochromic ligand azobupivacaine 2","authors":"Timm Fehrentz,&nbsp;Ehsan Amin,&nbsp;Nicole Görldt,&nbsp;Tobias Strasdeit,&nbsp;Seyed-Erfan Moussavi-Torshizi,&nbsp;Philipp Leippe,&nbsp;Dirk Trauner,&nbsp;Christian Meyer,&nbsp;Norbert Frey,&nbsp;Philipp Sasse,&nbsp;Nikolaj Klöcker","doi":"10.1111/bph.17394","DOIUrl":"10.1111/bph.17394","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Patients suffering from ischaemic heart disease and heart failure are at high risk of recurrent ventricular arrhythmias (VAs), eventually leading to sudden cardiac death. While high-voltage shocks delivered by an implantable defibrillator may prevent sudden cardiac death, these interventions themselves impair quality of life and raise both morbidity and mortality, which accentuates the need for developing novel defibrillation techniques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Photopharmacology allows for reversible control of biological processes by light. When relying on synthetic and externally applied chromophores, it renders genetic modification of target cells dispensable and may hence be advantageous over optogenetic approaches. Here, the photochromic ligand azobupivacaine 2 (AB2) was probed as a modulator of cardiac electrophysiology in an <i>ex vivo</i> intact mouse heart model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>By reversibly blocking voltage-gated Na⁺ and K⁺ channels, photoswitching of AB2 modulated both the ventricular effective refractory period and the conduction velocity in native heart tissue. Moreover, photoswitching of AB2 was able to convert VA into sinus rhythm.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>The present study provides the first proof of concept that AB2 enables gradual control of cardiac electrophysiology by light. AB2 may hence open the door to the development of an optical defibrillator based on photopharmacology.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 5","pages":"1125-1142"},"PeriodicalIF":6.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17394","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615165","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 expression of contextual fear conditioning involves the dorsal hippocampus TRPV1 receptor interacting with the NMDA/NO/cGMP signalling pathway","authors":"Gabriela L. Bertacchini,&nbsp;Andreza B. Sonego,&nbsp;Sabrina F. Lisboa,&nbsp;Davi C. Lagatta,&nbsp;Leonardo B. M. Resstel","doi":"10.1111/bph.17384","DOIUrl":"10.1111/bph.17384","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The dorsal hippocampus (dHIP) is pivotal for learning, memory, and defensive responses. Transient receptor potential vanilloid type 1 (TRPV1) receptors in the dHIP modulate contextual fear conditioning by triggering a cascade involving glutamate release, nitric oxide (NO) formation and cyclic guanosine monophosphate (cGMP) production. The present study investigated the involvement of dHIP TRPV1 receptors and their interaction with the glutamate/NO/cGMP signalling pathway in modulating the expression of contextual fear conditioning (CFC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Male Wistar rats were submitted to an aversive contextual conditioning session and, 48 h later, were re-introduced to the same aversive environment where the freezing response and autonomic activity (evidenced by increased arterial pressure and heart rate and a decrease in tail temperature) were measured.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>The results demonstrated that the TRPV1 antagonist 6-I-CPS in dHIP reduced the expression of CFC, whereas the agonist capsaicin had the opposite effect. Furthermore, dHIP pre-treatment with an NMDA receptor antagonist (AP7), neuronal NO synthase inhibitor (N-propyl-L-arginine), NO scavenger (c-PTIO) or guanylate cyclase inhibitor (ODQ) attenuated capsaicin-induced increases in CFC. Finally, we observed that re-exposure to the aversive chamber increased dHIP NO levels in conditioned animals compared with a non-conditioned group, which was prevented by the administration of the TRPV1 antagonist, 6-I-CPS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Our study revealed that TRPV1 receptors in the dHIP play a crucial role in modulating contextual fear expression by acting through the NMDA receptor/NO/cGMP signalling pathway, providing important insights into the underlying mechanisms and potential therapeutic avenues associated with these pathways.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 4","pages":"1107-1120"},"PeriodicalIF":6.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615166","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":"Compound 4a induces paraptosis in liver cancer through endoplasmic reticulum stress mediated by the calreticulin protein.","authors":"Chunmiao Wang, Dandan Liang, Xiaoyan Shen, Xuyang Chen, Linfang Lai, Huaxin Hou","doi":"10.1111/bph.17385","DOIUrl":"https://doi.org/10.1111/bph.17385","url":null,"abstract":"<p><strong>Background and purpose: </strong>Emerging evidence has highlighted that paraptosis may be an effective strategy for treating liver cancer. In our previous studies, Compound 4a induced paraptosis in cancer cells. Here, the characteristics of Compound 4a-induced paraptosis were further revealed and, for the first time, the target and related molecular mechanisms of Compound 4a-induced paraptosis in liver cancer were defined.</p><p><strong>Experimental approach: </strong>The effects and mechanism of Compound 4a in liver cancer cells were studied in in vitro and in vivo (BALB/c-nude xenograft model) experiments, and the targets of Compound 4a that trigger paraptosis were identified and confirmed via mass spectrometry-based drug affinity responsive target stability (DARTS) analyses, siRNA experiments and a cellular thermal shift assay (CETSA). The function and distribution of calreticulin (CRT) protein were detected via Cal-520 AM and immunofluorescence staining, respectively.</p><p><strong>Key results: </strong>Compound 4a effectively induced paraptosis-like cell death in liver cancer, both in vitro and in vivo, and its effect was comparable with the first-line anti-liver cancer drug oxaliplatin but with a higher safety profile. We identified the CRT protein as a target of Compound 4a, which caused cellular endoplasmic reticulum stress (ERS) and calcium overload. CRT knockdown weakened the anti-liver cancer activity of Compound 4a, which may be related to the inhibition of paraptosis.</p><p><strong>Conclusion: </strong>Compound 4a represents a potentially safe and effective agent for the treatment of liver cancer. The characteristics of Compound 4a-triggered paraptosis was clarified and a unique function of CRT in paraptosis was revealed.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615161","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":"Dual effects of DLG5 (disks large homolog 5 gene) modulation on chemotherapy-induced thrombocytopenia and nausea/vomiting via the hippo signalling pathway","authors":"Mingming Li,&nbsp;Rong Wang,&nbsp;Tao Yan,&nbsp;Xia Tao,&nbsp;Shouhong Gao,&nbsp;Zhipeng Wang,&nbsp;Yunsheng Chai,&nbsp;Shi Qiu,&nbsp;Wansheng Chen","doi":"10.1111/bph.17391","DOIUrl":"10.1111/bph.17391","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The CAPEOX (combination of oxaliplatin and capecitabine) chemotherapy protocol is widely used for colorectal cancer treatment, but it can lead to chemotherapy-induced adverse effects (CRAEs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>To uncover the mechanisms and potential biomarkers for CRAE susceptibility, we performed whole-genome sequencing on normal colorectal tissue (CRT) before adjuvant chemotherapy. This is followed by <i>in vivo</i> and <i>in vitro</i> verifications for selected gene and CRAE pair.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Our analysis revealed specific germline mutations linked to Grade 2 (or higher) chemotherapy-induced thrombocytopenia (CIT) and nausea/vomiting (CINV). Notably, both CRAEs were associated with mutations in the <i>DLG5</i> gene. We found that <i>DLG5</i> mutations related to CIT were associated with increased gene expression, while those associated with CINV were linked to suppressed gene expression, as indicated by the Genotype-Tissue Expression (GTEX) database. In megakaryocytes, overexpression of human DLG5 suppressed the hippo signalling pathway and induced YAP expression. In zebrafish, overexpression of human DLG5 not only reduced platelet production but also inhibited thrombus formation. Subsequent qPCR analysis revealed that <i>DLG5</i> overexpression affected genes involved in cytoskeleton formation and alpha-granule formation, which could impact the normal generation of proplatelets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>We identified a series of germline mutations associated with susceptibility to CIT and CINV. Of particular interest, we demonstrated that induced and suppressed <i>DLG5</i> expression is respectively related to CIT and CINV. These findings shed light on the involvement of the hippo signalling pathway and <i>DLG5</i> in the development of CRAEs, providing valuable insights into potential targets for therapeutic interventions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 4","pages":"1090-1106"},"PeriodicalIF":6.8,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615162","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}