British Journal of Pharmacology最新文献

{"title":"TLR2 activates AP-1 to facilitate CTGF transcription and stimulate doxorubicin-induced myocardial injury.","authors":"Lang Hong, Xinyong Cai, Yuliang Zhan, Songtao Liu, Pengtao Zou, Yanmei Chen, Liang Shao","doi":"10.1111/bph.17423","DOIUrl":"https://doi.org/10.1111/bph.17423","url":null,"abstract":"<p><strong>Background and purpose: </strong>Our study aimed to explore the mechanistic network of toll-like receptor 2 (TLR2)/activator protein-1 (AP-1) combined with SOX10 activation of the mitogen-activated protein kinase (MAPK) pathway via connective tissue growth factor (CTGF) in doxorubicin (Dox)-induced myocardial injury.</p><p><strong>Experimental approach: </strong>Rats with Dox-induced myocardial injury were treated with a TLR2 inhibitor or CTGF silencing lentiviral vector. H9c2 cells were treated with genetic vectors or MAPK pathway activators. Cardiac function was tested using echocardiography and serum markers. H&E, Sirius red and TUNEL staining were used to detect myocardial pathological changes, collagen accumulation and apoptosis. Western blot was used to detect proteins related to cardiac hypertrophy, fibrosis, apoptosis and the MAPK pathway. H9c2 cell injury was assessed by testing cell viability, lactate dehydrogenase (LDH) release and mitochondrial membrane potential.</p><p><strong>Key results: </strong>TLR2 and CTGF were highly expressed in patients with heart failure, and Dox treatment further increased their expression. Inhibiting TLR2 or silencing CTGF improved cardiac function and reduced myocardial fibrosis and apoptosis in Dox-treated rats. Silencing of TLR2 alleviated Dox-induced H9c2 cell injury, which was nullified by CTGF overexpression. TLR2 activated AP-1, which cooperated with SOX10 to promote CTGF transcription. MAPK activation aggravated H9c2 cells against Dox-induced injury.</p><p><strong>Conclusions and implications: </strong>TLR2 activates AP-1 which cooperates with SOX10 to promote CTGF transcription and subsequently activate the MAPK pathway, thereby stimulating Dox-induced myocardial injury.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647319","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":"Rescue of loss-of-function long QT syndrome-associated mutations in K_V7.1/KCNE1 by the endocannabinoid N-arachidonoyl-L-serine (ARA-S).","authors":"Irene Hiniesto-Iñigo, Akshay Sridhar, Julien Louradour, Alicia De la Cruz, Siri Lundholm, Amaia Jauregi-Miguel, Federica Giannetti, Luca Sala, Katja E Odening, H Peter Larsson, Nina E Ottosson, Sara I Liin","doi":"10.1111/bph.70008","DOIUrl":"10.1111/bph.70008","url":null,"abstract":"<p><strong>Background and purpose: </strong>Congenital long QT syndrome (LQTS) involves genetic mutations affecting ion channels, leading to a prolonged QT interval and increased risk of potentially lethal ventricular arrhythmias. Mutations in the genes encoding K_V7.1/KCNE1 are the most frequent, with channel loss-of-function contributing to LQTS. The endocannabinoid N-arachidonoyl-L-serine (ARA-S) has been shown to facilitate activation of wild type K_V7.1/KCNE1 channels and to counteract a prolonged QT interval in isolated guinea pig hearts. In this study, we examine the ability of ARA-S to facilitate activation of LQTS-associated mutations, in various regions of the channel, and hence to counteract loss-of-function.</p><p><strong>Experimental approach: </strong>The two-electrode voltage clamp technique on Xenopus oocytes expressing human K_V7.1/KCNE1 channels was used to investigate the effects of ARA-S in 20 LQTS type 1-associated mutations distributed across the channel. Thereafter, different electrophysiology was used to assess ARA-S effects in mammalian cells.</p><p><strong>Key results: </strong>ARA-S enhanced the function of all mutated channels by shifting V₅₀ and increasing current amplitude. However, the magnitude of effect varied, related to whether mutations were in one of the two putative ARA-S binding sites on the channel as suggested by molecular dynamics simulations. ARA-S displayed translational potential by facilitating channel opening in mammalian cells and shortening the action potential duration in cardiomyocytes.</p><p><strong>Conclusions and implications: </strong>This study demonstrates the rescuing capability of ARA-S on a diverse set of LQTS mutants. These insights may aid in developing drug compounds using ARA-S sites and mechanisms and guide interpretation of which LQTS mutants respond well to such compounds.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623670","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":"Drug-likeness evaluation and inhibitory mechanism of the emodin derivative on cardiac fibrosis based on metastasis-associated protein 3.","authors":"Heng Liu, Runze Li, Zhixia Wang, Weina Han, Xiuxiu Sun, Xinxin Dong, Han Lou, Run Xu, Ange Hu, Denis Baranenko, Xue Bai, Dan Xiao, Weihong Lu","doi":"10.1111/bph.70012","DOIUrl":"https://doi.org/10.1111/bph.70012","url":null,"abstract":"<p><strong>Background and purpose: </strong>Emodin inhibits cardiac fibrosis through metastasis-associated protein 3 (MTA3), but its limited bioavailability hinders clinical application. To enhance emodin's clinical potential, a new derivative, emodin succinyl ethyl ester, was synthesised by modifying the 3'-OH position. This study assessed its drug-likeness, anti-fibrotic properties and molecular mechanisms involving MTA3.</p><p><strong>Experimental approach: </strong>Drug-likeness properties of the emodin derivative were evaluated using computational-aided drug design (CADD). Transverse aortic constriction (TAC)-induced cardiac fibrosis and Angiotensin II (Ang II)-stimulated cardiac fibroblasts were used in vivo and ex vivo, respectively, to determine the effects of the emodin derivative on cardiac fibrosis and fibroblast transdifferentiation. Bioinformatics analysis, CADD, chromatin immunoprecipitation (ChIP), luciferase reporter assays and functional experiments were employed to predict, identify and validate the relationship between MTA3 and its upstream transcription factors.</p><p><strong>Key results: </strong>The emodin derivative exhibited superior drug-likeness and anti-fibrotic effects compared to emodin by effectively inhibiting cardiac fibroblast transdifferentiation and restored MTA3 expression. E2F1 was identified and validated as a transcriptional regulator, promoting α-SMA and COL1A2 expression, and directly reducing MTA3 expression in cardiac fibroblasts. The emodin derivative demonstrated stronger binding to the E2F1 transcription site than emodin, reducing E2F1 expression and enhancing anti-fibrotic action.</p><p><strong>Conclusions and implications: </strong>The emodin derivative shows improved drug-likeness and potent inhibition of cardiac fibrosis by targeting E2F1, disrupting its pro-fibrotic function, restoring MTA3 expression and halting fibrosis progression. This advances emodin derivative's potential as a clinical therapy for cardiac fibrosis and provides insights into its anti-fibrotic mechanisms.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623669","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":"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}