British Journal of Pharmacology最新文献

筛选
英文 中文
miR-210 as a therapeutic target in diabetes-associated endothelial dysfunction. miR-210 作为糖尿病相关内皮功能障碍的治疗靶点。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2024-10-14 DOI: 10.1111/bph.17329
Aida Collado, Tong Jiao, Eftychia Kontidou, Lucas Rannier Ribeiro Antonino Carvalho, Ekaterina Chernogubova, Jiangning Yang, Germana Zaccagnini, Allan Zhao, John Tengbom, Xiaowei Zheng, Bence Rethi, Michael Alvarsson, Sergiu-Bogdan Catrina, Ali Mahdi, Mattias Carlström, Fabio Martelli, John Pernow, Zhichao Zhou
{"title":"miR-210 as a therapeutic target in diabetes-associated endothelial dysfunction.","authors":"Aida Collado, Tong Jiao, Eftychia Kontidou, Lucas Rannier Ribeiro Antonino Carvalho, Ekaterina Chernogubova, Jiangning Yang, Germana Zaccagnini, Allan Zhao, John Tengbom, Xiaowei Zheng, Bence Rethi, Michael Alvarsson, Sergiu-Bogdan Catrina, Ali Mahdi, Mattias Carlström, Fabio Martelli, John Pernow, Zhichao Zhou","doi":"10.1111/bph.17329","DOIUrl":"https://doi.org/10.1111/bph.17329","url":null,"abstract":"<p><strong>Background and purpose: </strong>MicroRNA (miR)-210 function in endothelial cells and its role in diabetes-associated endothelial dysfunction are not fully understood. We aimed to characterize the miR-210 function in endothelial cells and study its therapeutic potential in diabetes.</p><p><strong>Experimental approach: </strong>Two different diabetic mouse models (db/db and Western diet-induced), miR-210 knockout and transgenic mice, isolated vessels and human endothelial cells were used.</p><p><strong>Key results: </strong>miR-210 levels were lower in aortas isolated from db/db than in control mice. Endothelium-dependent relaxation (EDR) was impaired in aortas from miR-210 knockout mice, and this was restored by inhibiting miR-210 downstream protein tyrosine phosphatase 1B (PTP1B), mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2), and mitochondrial oxidative stress. Inhibition of these pathways also improved EDR in both diabetic mouse models. High glucose reduced miR-210 levels in endothelial cells and impaired EDR in mouse aortas, effects that were reversed by overexpressing miR-210. However, plasma miR-210 levels were not affected in individuals with type 2 diabetes (T2D) following improved glycaemic status. Of note, genetic overexpression using miR-210 transgenic mice and pharmacological overexpression using miR-210 mimic in vivo ameliorated endothelial dysfunction in both diabetic mouse models by decreasing PTP1B, GPD2 and oxidative stress. Genetic overexpression of miR-210 altered the aortic transcriptome, decreasing genes in pathways involved in oxidative stress. miR-210 mimic restored decreased nitric oxide production by high glucose in endothelial cells.</p><p><strong>Conclusion and implications: </strong>This study unravels the mechanisms by which down-regulated miR-210 by high glucose induces endothelial dysfunction in T2D and demonstrates that miR-210 serves as a novel therapeutic target.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458475","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}
引用次数: 0
Pharmacology of PIEZO1 channels PIEZO1 通道的药理学。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2024-10-14 DOI: 10.1111/bph.17351
Jacob A. Kinsella, Marjolaine Debant, Gregory Parsonage, Lara C. Morley, Muath Bajarwan, Charlotte Revill, Richard Foster, David J. Beech
{"title":"Pharmacology of PIEZO1 channels","authors":"Jacob A. Kinsella,&nbsp;Marjolaine Debant,&nbsp;Gregory Parsonage,&nbsp;Lara C. Morley,&nbsp;Muath Bajarwan,&nbsp;Charlotte Revill,&nbsp;Richard Foster,&nbsp;David J. Beech","doi":"10.1111/bph.17351","DOIUrl":"10.1111/bph.17351","url":null,"abstract":"<p>PIEZO1 is a eukaryotic membrane protein that assembles as trimers to form calcium-permeable, non-selective cation channels with exquisite capabilities for mechanical force sensing and transduction of force into effect in diverse cell types that include blood cells, endothelial cells, epithelial cells, fibroblasts and stem cells and diverse systems that include bone, lymphatics and muscle. The channel has wide-ranging roles and is considered as a target for novel therapeutics in ailments spanning cancers and cardiovascular, dental, gastrointestinal, hepatobiliary, infectious, musculoskeletal, nervous system, ocular, pregnancy, renal, respiratory and urological disorders. The identification of PIEZO1 modulators is in its infancy but useful experimental tools emerged for activating, and to a lesser extent inhibiting, the channels. Elementary structure–activity relationships are known for the Yoda series of small molecule agonists, which show the potential for diverse physicochemical and pharmacological properties. Intriguing effects of Yoda1 include the stimulated removal of excess cerebrospinal fluid. Despite PIEZO1's broad expression, opportunities are suggested for selective positive or negative modulation without intolerable adverse effects. Here we provide a focused, non-systematic, narrative review of progress with this pharmacology and discuss potential future directions for research in the area.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17351","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458476","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}
引用次数: 0
A pH-sensitive opioid does not exhibit analgesic tolerance in a mouse model of colonic inflammation. 一种对 pH 值敏感的阿片类药物在小鼠结肠炎症模型中不会表现出镇痛耐受性。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2024-10-13 DOI: 10.1111/bph.17363
Claudius E Degro, Nestor Nivardo Jiménez-Vargas, Mabel Guzman-Rodriguez, Hailey Schincariol, Quentin Tsang, David E Reed, Alan E Lomax, Nigel W Bunnett, Christoph Stein, Stephen J Vanner
{"title":"A pH-sensitive opioid does not exhibit analgesic tolerance in a mouse model of colonic inflammation.","authors":"Claudius E Degro, Nestor Nivardo Jiménez-Vargas, Mabel Guzman-Rodriguez, Hailey Schincariol, Quentin Tsang, David E Reed, Alan E Lomax, Nigel W Bunnett, Christoph Stein, Stephen J Vanner","doi":"10.1111/bph.17363","DOIUrl":"https://doi.org/10.1111/bph.17363","url":null,"abstract":"<p><strong>Background and purpose: </strong>Tolerance to the analgesic effects of opioids and resultant dose escalation is associated with worsening of side effects and greater addiction risk. Here, we compare the development of tolerance to the conventional opioid fentanyl with a novel pH-sensitive μ-opioid receptor (MOR) agonist, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP) that is active only in acidic inflammatory microenvironments.</p><p><strong>Experimental approach: </strong>An opioid tolerance model was developed in male C57BL/6 mice, with and without dextran sulphate sodium colitis, using increasing doses of either fentanyl or NFEPP over 5 days. Visceral nociception was assessed in vivo by measuring visceromotor responses (VMRs) to noxious colorectal distensions and in vitro measuring colonic afferent nerve activity of mesenteric nerves and performing patch-clamp recordings from isolated dorsal root ganglia neurons. Somatic thermal nociception was tested using a tail immersion assay. Cardiorespiratory effects were analysed by pulse oximeter experiments.</p><p><strong>Key results: </strong>VMRs and tail immersion tests demonstrated tolerance to fentanyl, but not to NFEPP in colitis mice. Cross-tolerance also occurred to fentanyl, but not to NFEPP. The MOR agonist DAMGO inhibited colonic afferent nerve activity in colitis mice exposed to chronic NFEPP, but not those from fentanyl-treated mice. Similarly, in patch-clamp recordings from isolated dorsal root ganglia neurons, DAMGO inhibited neurons from NFEPP-, but not fentanyl-treated mice.</p><p><strong>Conclusion and implications: </strong>NFEPP did not exhibit tolerance in an inflammatory pain model, unlike fentanyl. Consequently, dose escalation to maintain analgesia during an evolving inflammation could be avoided, mitigating the potential risk of side effects.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458530","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}
引用次数: 0
Breaking the barriers: Overcoming cancer resistance by targeting the NLRP3 inflammasome. 打破障碍:通过靶向 NLRP3 炎症小体克服癌症抗药性。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2024-10-12 DOI: 10.1111/bph.17352
Nazanin Pazhouhesh Far, Mahsa Hajiheidari Varnousafaderani, Ferdos Faghihkhorasani, Sareh Etemad, Al-Hasnawi Rasool Riyadh Abdulwahid, Negar Bakhtiarinia, Afsaneh Mousaei, Elahe Dortaj, Soroush Karimi, Nasim Ebrahimi, Amir Reza Aref
{"title":"Breaking the barriers: Overcoming cancer resistance by targeting the NLRP3 inflammasome.","authors":"Nazanin Pazhouhesh Far, Mahsa Hajiheidari Varnousafaderani, Ferdos Faghihkhorasani, Sareh Etemad, Al-Hasnawi Rasool Riyadh Abdulwahid, Negar Bakhtiarinia, Afsaneh Mousaei, Elahe Dortaj, Soroush Karimi, Nasim Ebrahimi, Amir Reza Aref","doi":"10.1111/bph.17352","DOIUrl":"https://doi.org/10.1111/bph.17352","url":null,"abstract":"<p><p>Inflammation has a pivotal role in the initiation and progression of various cancers, contributing to crucial processes such as metastasis, angiogenesis, cell proliferation and invasion. Moreover, the release of cytokines mediated by inflammation within the tumour microenvironment (TME) has a crucial role in orchestrating these events. The activation of inflammatory caspases, facilitated by the recruitment of caspase-1, is initiated by the activation of pattern recognition receptors on the immune cell membrane. This activation results in the production of proinflammatory cytokines, including IL-1β and IL-18, and participates in diverse biological processes with significant implications. The NOD-Like Receptor Protein 3 (NLRP3) inflammasome holds a central role in innate immunity and regulates inflammation through releasing IL-1β and IL-18. Moreover, it interacts with various cellular compartments. Recently, the mechanisms underlying NLRP3 inflammasome activation have garnered considerable attention. Disruption in NLRP3 inflammasome activation has been associated with a spectrum of inflammatory diseases, encompassing diabetes, enteritis, neurodegenerative diseases, obesity and tumours. The NLRP3 impact on tumorigenesis varies across different cancer types, with contrasting roles observed. For example, colorectal cancer associated with colitis can be suppressed by NLRP3, whereas gastric and skin cancers may be promoted by its activity. This review provides comprehensive insights into the structure, biological characteristics and mechanisms of the NLRP3 inflammasome, with a specific focus on the relationship between NLRP3 and tumour-related immune responses, and TME. Furthermore, the review explores potential strategies for targeting cancers via NLRP3 inflammasome modulation. This encompasses innovative approaches, including NLRP3-based nanoparticles, gene-targeted therapy and immune checkpoint inhibitors.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458531","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}
引用次数: 0
Early transtympanic administration of rhBDNF exerts a multifaceted neuroprotective effect against cisplatin-induced hearing loss. 早期经鼓膜给药 rhBDNF 对顺铂诱导的听力损失具有多方面的神经保护作用。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bph.17359
Anna Pisani, Rolando Rolesi, Veronica Mohamed-Hizam, Raffaele Montuoro, Gaetano Paludetti, Cristina Giorgio, Pasquale Cocchiaro, Laura Brandolini, Nicola Detta, Anna Sirico, Pier Giorgio Amendola, Rubina Novelli, Andrea Aramini, Marcello Allegretti, Fabiola Paciello, Claudio Grassi, Anna Rita Fetoni
{"title":"Early transtympanic administration of rhBDNF exerts a multifaceted neuroprotective effect against cisplatin-induced hearing loss.","authors":"Anna Pisani, Rolando Rolesi, Veronica Mohamed-Hizam, Raffaele Montuoro, Gaetano Paludetti, Cristina Giorgio, Pasquale Cocchiaro, Laura Brandolini, Nicola Detta, Anna Sirico, Pier Giorgio Amendola, Rubina Novelli, Andrea Aramini, Marcello Allegretti, Fabiola Paciello, Claudio Grassi, Anna Rita Fetoni","doi":"10.1111/bph.17359","DOIUrl":"https://doi.org/10.1111/bph.17359","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cisplatin-induced sensorineural hearing loss is a significant clinical challenge. Although the potential effects of brain-derived neurotrophic factor (BDNF) have previously been investigated in some ototoxicity models, its efficacy in cisplatin-induced hearing loss remains uncertain. This study aimed to investigate the therapeutic potential of recombinant human BDNF (rhBDNF) in protecting cells against cisplatin-induced ototoxicity.</p><p><strong>Experimental approach: </strong>Using an in vivo model of cisplatin-induced hearing loss, we investigated the beneficial effects of transtympanic administration of rhBDNF in a thermogel solution on hearing function and cochlear injury, using electrophysiological, morphological, immunofluorescence and molecular analyses.</p><p><strong>Key results: </strong>Our data showed that local rhBDNF treatment counteracted hearing loss in rats receiving cisplatin by preserving synaptic connections in the cochlear epithelium and protecting hair cells (HCs) and spiral ganglion neurons (SGNs) against cisplatin-induced cell death. Specifically, rhBDNF maintains the balance of its receptor levels (pTrkB and p75), boosting TrkB-CREB pro-survival signalling and reducing caspase 3-dependent apoptosis in the cochlea. Additionally, it activates antioxidant mechanisms while inhibiting inflammation and promoting vascular repair.</p><p><strong>Conclusion and implications: </strong>Collectively, we demonstrated that early transtympanic treatment with rhBDNF plays a multifaceted protective role against cisplatin-induced ototoxicity, thus holding promise as a novel potential approach to preserve hearing in adult and paediatric patients undergoing cisplatin-based chemotherapy.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399464","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}
引用次数: 0
A systematic assessment of robustness in CNS safety pharmacology. 系统评估中枢神经系统安全药理学的稳健性。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bph.17358
Maria Reiber, Helen Stirling, Tim P Ahuis, Washington Arias, Katharina Aulehner, Ute Dreßler, Martien J H Kas, Johanna Kela, Kimberly Kerker, Tarja Kuosmanen, Helga Lorenz, Alexander T Pennington, Eva-Lotta von Rüden, Heike Schauerte, Isabel Seiffert, Steven R Talbot, Christina Torturo, Sami Virtanen, Ann-Marie Waldron, Sylvie Ramboz, Heidrun Potschka
{"title":"A systematic assessment of robustness in CNS safety pharmacology.","authors":"Maria Reiber, Helen Stirling, Tim P Ahuis, Washington Arias, Katharina Aulehner, Ute Dreßler, Martien J H Kas, Johanna Kela, Kimberly Kerker, Tarja Kuosmanen, Helga Lorenz, Alexander T Pennington, Eva-Lotta von Rüden, Heike Schauerte, Isabel Seiffert, Steven R Talbot, Christina Torturo, Sami Virtanen, Ann-Marie Waldron, Sylvie Ramboz, Heidrun Potschka","doi":"10.1111/bph.17358","DOIUrl":"https://doi.org/10.1111/bph.17358","url":null,"abstract":"<p><strong>Background and purpose: </strong>Irwin tests are key preclinical study elements for characterising drug-induced neurological side effects. This multicentre study aimed to assess the robustness of Irwin tests across multinational sites during three stages of protocol harmonisation. The projects were part of the Enhanced Quality in Preclinical Data framework, aiming to increase success rates in transition from preclinical testing to clinical application.</p><p><strong>Experimental approach: </strong>Female and male NMRI mice were assigned to one of three groups (vehicle, MK-801 0.1 and 0.3 mg kg<sup>-1</sup>). Irwin scores were assessed at baseline and multiple times following intraperitoneal injection of MK-801 using local protocols (Stage 1), shared protocols with harmonised environmental design (Stage 2) and fully harmonised Irwin scoring protocols (Stage 3).</p><p><strong>Key results: </strong>The analysis based on the four functional domains (motor, autonomic, sedation and excitation) revealed substantial data variability in Stages 1 and 2. Although there was still marked overall heterogeneity between sites in Stage 3 after complete harmonisation of the Irwin scoring scheme, heterogeneity was only moderate within functional domains. When comparing treatment groups versus vehicle, we found large effect sizes in the motor domain and subtle to moderate effects in the excitation-related and autonomic domains.</p><p><strong>Conclusion and implications: </strong>The pronounced interlaboratory variability in Irwin datasets for the CNS-active compound MK-801 needs to be carefully considered when making decisions during drug development. While environmental and general study design had a minor impact, the study suggests that harmonisation of parameters and their scoring can limit variability and increase robustness.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399463","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}
引用次数: 0
Excitation-contraction coupling inhibitors potentiate the actions of botulinum neurotoxin type A at the neuromuscular junction. 兴奋-收缩耦联抑制剂可增强 A 型肉毒杆菌神经毒素在神经肌肉接头处的作用。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bph.17367
Mickaël Machicoane, Marika Tonellato, Marica Zainotto, Paul Onillon, Marco Stazi, Mattia Dal Corso, Aram Megighian, Ornella Rossetto, Jean-Marc Le Doussal, Marco Pirazzini
{"title":"Excitation-contraction coupling inhibitors potentiate the actions of botulinum neurotoxin type A at the neuromuscular junction.","authors":"Mickaël Machicoane, Marika Tonellato, Marica Zainotto, Paul Onillon, Marco Stazi, Mattia Dal Corso, Aram Megighian, Ornella Rossetto, Jean-Marc Le Doussal, Marco Pirazzini","doi":"10.1111/bph.17367","DOIUrl":"https://doi.org/10.1111/bph.17367","url":null,"abstract":"<p><strong>Background and purpose: </strong>Botulinum neurotoxin type A1 (BoNT/A) is one of the most potent neurotoxins known. At the same time, it is also one of the safest therapeutic agents used for the treatment of several human disorders and in aesthetic medicine. Notwithstanding great effectiveness, strategies to accelerate the onset and prolong BoNT/A action would significantly ameliorate its pharmacological effects with beneficial outcomes for clinical use.</p><p><strong>Experimental approach: </strong>Here, we combined BoNT/A with two fast-acting inhibitors of excitation-contraction coupling inhibitors (ECCI), either the μ-conotoxin CnIIIC or dantrolene, and tested the effect of their co-injection on a model of hind-limb paralysis in rodents using behavioural, biochemical, imaging and electrophysiological assays.</p><p><strong>Key results: </strong>The BoNT/A-ECCI combinations accelerated the onset of muscle relaxation. Surprisingly, they also potentiated the peak effect and extended the duration of the three BoNT/A commercial preparations OnabotulinumtoxinA, AbobotulinumtoxinA and IncobotulinumtoxinA. ECCI co-injection increased the number of BoNT/A molecules entering motoneuron terminals, which induced a faster and greater cleavage of SNAP-25 during the onset and peak phases, and prolonged the attenuation of nerve-muscle neurotransmission during the recovery phase. We estimate that ECCI co-injection yields a threefold potentiation in BoNT/A pharmacological activity.</p><p><strong>Conclusions and implications: </strong>Overall, our results show that the pharmacological activity of BoNT/A can be combined and synergized with other bioactive molecules and uncover a novel strategy to enhance the neuromuscular effects of BoNT/A without altering the neurotoxin moiety or intrinsic activity, thus maintaining its exceptional safety profile.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399465","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}
引用次数: 0
Beneficial effects of CHF6467, a modified human nerve growth factor, in experimental neonatal hypoxic-ischaemic encephalopathy. 改良人神经生长因子 CHF6467 对实验性新生儿缺氧缺血性脑病的有益作用
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2024-10-08 DOI: 10.1111/bph.17353
Elisa Landucci, Dalila Mango, Silvia Carloni, Costanza Mazzantini, Domenico E Pellegrini-Giampietro, Amira Saidi, Walter Balduini, Elisa Schiavi, Laura Tigli, Barbara Pioselli, Bruno P Imbimbo, Fabrizio Facchinetti
{"title":"Beneficial effects of CHF6467, a modified human nerve growth factor, in experimental neonatal hypoxic-ischaemic encephalopathy.","authors":"Elisa Landucci, Dalila Mango, Silvia Carloni, Costanza Mazzantini, Domenico E Pellegrini-Giampietro, Amira Saidi, Walter Balduini, Elisa Schiavi, Laura Tigli, Barbara Pioselli, Bruno P Imbimbo, Fabrizio Facchinetti","doi":"10.1111/bph.17353","DOIUrl":"https://doi.org/10.1111/bph.17353","url":null,"abstract":"<p><strong>Background and purpose: </strong>Therapeutic hypothermia (TH) has become the standard care to reduce morbidity and mortality in neonates affected by moderate-to-severe hypoxic-ischaemic encephalopathy (HIE). Despite the use of TH for HIE, the incidence of mortality and disabilities remains high.</p><p><strong>Experimental approach: </strong>Nerve growth factor (NGF) is a potent neurotrophin, but clinical use is limited by its pain eliciting effects. CHF6467 is a recombinant modified form of human NGF devoid of algogenic activity (painless NGF).</p><p><strong>Key results: </strong>In rodent hippocampal slices exposed to oxygen and glucose deprivation, CHF6467 protected neurons from death and reverted neurotransmission impairment when combined with hypothermia. In a model of rat neonatal HIE, intranasal CHF6467 (20 μg kg<sup>-1</sup>) significantly reduced brain infarct volume versus vehicle when delivered 10 min or 3 h after the insult. CHF6467 (20 and 40 μg kg<sup>-1</sup>, i.n.), significantly decreased brain infarct volume to a similar extent to TH and when combined, showed a synergistic neuroprotective effect. CHF6467 (20 μg kg<sup>-1</sup>, i.n.) per se and in combination with hypothermia reversed locomotor coordination impairment (Rotarod test) and memory deficits (Y-maze and novel object recognition test) in the neonatal HIE rat model. Intranasal administration of CHF6467 resulted in meaningful concentrations in the brain, blunted HIE-induced mRNA elevation of brain neuroinflammatory markers and, when combined to TH, significantly counteracted the increase in plasma levels of neurofilament light chain, a peripheral marker of neuroaxonal damage.</p><p><strong>Conclusion and implications: </strong>CHF6467 administered intranasally is a promising therapy, in combination with TH, for the treatment of HIE.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388159","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}
引用次数: 0
Bruton's tyrosine kinase inhibition suppresses pathological retinal angiogenesis. 布鲁顿酪氨酸激酶抑制剂可抑制病理性视网膜血管生成。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2024-10-07 DOI: 10.1111/bph.17344
Siyue Chen, Yuming Liu, Yutian Zhang, Xu Guo, Tinghui Bai, Kai He, Yanfang Zhu, Yi Lei, Mei Du, Xiaohong Wang, Qiang Liu, Hua Yan
{"title":"Bruton's tyrosine kinase inhibition suppresses pathological retinal angiogenesis.","authors":"Siyue Chen, Yuming Liu, Yutian Zhang, Xu Guo, Tinghui Bai, Kai He, Yanfang Zhu, Yi Lei, Mei Du, Xiaohong Wang, Qiang Liu, Hua Yan","doi":"10.1111/bph.17344","DOIUrl":"https://doi.org/10.1111/bph.17344","url":null,"abstract":"<p><strong>Background and purpose: </strong>Pathological retinal angiogenesis is a typical manifestation of vision-threatening ocular diseases. Many patients exhibit poor response or resistance to anti-vascular endothelial growth factor (VEGF) agents. Bruton's tyrosine kinase (BTK) controls the proliferation and function of immune cells. Therefore, we examined the anti-inflammatory and anti-angiogenic effects of BTK inhibition on retinal angiogenesis.</p><p><strong>Experimental approach: </strong>Retinal neovascularisation and vascular leakage in oxygen-induced retinopathy in C57/BL6J mice were assessed by whole-mount retinal immunofluorescence. PLX5622 was used to deplete microglia and Rag1-knockout mice were used to test the contribution of lymphocytes to the effects of BTK inhibition. The cytokines, activation markers, inflammatory and immune-regulatory activities of retinal microglia/macrophages were detected using qRT-PCR and immunofluorescence. NLRP3 was detected by western blotting, and the effects of BTK inhibition on the co-culture of microglia and human retinal microvascular endothelial cells (HRMECs) were examined.</p><p><strong>Key results: </strong>BTK inhibition suppressed pathological angiogenesis and vascular leakage, and significantly reduced retinal inflammation, which involved microglia/macrophages but not lymphocytes. BTK inhibition increased anti-inflammatory factors and reduced pro-inflammatory cytokines that resulted from NLRP3 inflammasome activation. BTK inhibition suppressed the inflammatory activity of microglia/macrophages, and acted synergistically with anti-VEGF without retinal toxicity. Moreover, the supernatant of microglia incubated with BTK-inhibitor reduced the proliferation, tube formation and sprouting of HRMECs.</p><p><strong>Conclusion and implications: </strong>BTK inhibition suppressed retinal neovascularisation and vascular leakage by modulating the inflammatory activity of microglia and macrophages. Our study suggests BTK inhibition as a novel and promising approach for alleviating pathological retinal angiogenesis.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388160","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}
引用次数: 0
Inactivation induced by pathogenic Cav1.3 L-type Ca2+-channel variants enhances sensitivity for dihydropyridine Ca2+ channel blockers. 致病性 Cav1.3 L 型 Ca2+ 通道变体引起的失活会增强对二氢吡啶类 Ca2+ 通道阻滞剂的敏感性。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2024-10-07 DOI: 10.1111/bph.17357
Ferenc Török, Sarah Salamon, Nadine J Ortner, Monica L Fernández-Quintero, Jan Matthes, Jörg Striessnig
{"title":"Inactivation induced by pathogenic Ca<sub>v</sub>1.3 L-type Ca<sup>2+</sup>-channel variants enhances sensitivity for dihydropyridine Ca<sup>2+</sup> channel blockers.","authors":"Ferenc Török, Sarah Salamon, Nadine J Ortner, Monica L Fernández-Quintero, Jan Matthes, Jörg Striessnig","doi":"10.1111/bph.17357","DOIUrl":"https://doi.org/10.1111/bph.17357","url":null,"abstract":"<p><strong>Background and purpose: </strong>Pathogenic gain-of-function mutations in Ca<sub>v</sub>1.3 L-type voltage-gated Ca<sup>2+</sup>-channels (CACNA1D) cause neurodevelopmental disorders with or without endocrine symptoms. We aimed to confirm a pathogenic gain-of function phenotype of CACNA1D de novo missense mutations A749T and L271H, and investigated the molecular mechanism causing their enhanced sensitivity for the Ca<sup>2+</sup>-channel blocker isradipine, a potential therapeutic for affected patients.</p><p><strong>Experimental approach: </strong>Wildtype and mutant channels were expressed in tsA-201 cells and their gating analysed using whole-cell and single-channel patch-clamp recordings. The voltage-dependence of isradipine action was quantified using protocols inducing variable fractions of inactivated channels. The molecular basis for altered channel gating in the mutants was investigated using in silico modelling and molecular dynamics simulations.</p><p><strong>Key results: </strong>Both mutations were confirmed pathogenic due to characteristic shifts of voltage-dependent activation and inactivation towards negative potentials (~20 mV). At negative holding potentials both mutations showed significantly higher isradipine sensitivity compared to wildtype. The affinity for wildtype and mutant channels increased with channel inactivation as predicted by the modulated receptor hypothesis (30- to 40-fold). The IC<sub>50</sub> was indistinguishable for wildtype and mutants when >50% of channels were inactivated.</p><p><strong>Conclusions and implications: </strong>Mutations A749T and L271H induce pathogenic gating changes. Like wildtype, isradipine inhibition is strongly voltage-dependent. Our data explains their apparent higher drug sensitivity at a given negative voltage by the availability of more inactivated channels due to their more negative inactivation voltage range. Low nanomolar isradipine concentrations will only inhibit Ca<sub>v</sub>1.3 channels in neurons during prolonged depolarized states without selectivity for mutant channels.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380078","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}
引用次数: 0
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信