British Journal of Pharmacology最新文献

{"title":"Artificial intelligence (AI)-enabled RNA therapeutic design: from molecular optimization to system-level evaluation.","authors":"Yongtian Wang, Jiaqi Wu","doi":"10.1111/bph.70712","DOIUrl":"https://doi.org/10.1111/bph.70712","url":null,"abstract":"<p><p>RNA therapeutics are increasingly moving from empirical screening towards rational, computation-guided design. Recent advances in RNA language models, generative models and structure-aware learning have improved sequence representation, candidate generation and structure-constrained optimization. However, favourable molecular properties do not necessarily translate into desirable biological performance, because therapeutic outcomes also depend on modality-specific mechanisms, delivery and exposure, molecular interactions, cellular state, immune responses and network-level adaptation. Here, we review AI-enabled RNA therapeutic design through the specific lens of the interface between molecular optimization and system-level evaluation. We compare the design constraints of siRNAs, antisense oligonucleotides, aptamers, mRNAs and translation-oriented circRNAs, and examine the capabilities and current limitations of sequence-, generative- and structure-based computational models. We further discuss the data resources and perturbation representations required to connect molecular candidates with broader cellular-response models. In this context, virtual cells are considered as approximate computational frameworks for candidate prioritization and risk-oriented system-level assessment rather than complete digital replicas of living cells. Finally, we outline a conceptual generation-simulation-feedback-optimization framework for integrating molecular design with progressively higher-level evaluation. This perspective emphasizes the need for better interfaces among RNA design, pharmacological context and cellular-response modelling, rather than relying on molecular optimization alone.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165573","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":"Targeting peroxynitrite production in a model of persistent temporomandibular disorder comorbid with migraine","authors":"Simon Akerman,&nbsp;Ana Belen Salinas-Abarca,&nbsp;Wei Guo,&nbsp;Daniela Salvemini,&nbsp;Marcela Romero-Reyes","doi":"10.1111/bph.70612","DOIUrl":"10.1111/bph.70612","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The persistence of temporomandibular disorders (TMDs), particularly myogenous, in a person with migraine can lead to exacerbated clinical outcomes and limited response to treatment. The pro-nociceptive reactive nitroxidative species, peroxynitrite, is involved in migraine mechanisms, but little is known of its role in this comorbidity. Here, we validate a model of persistent TMD comorbid with migraine in rats and dissect the role of peroxynitrite in its underlying nociceptive mechanisms, and as a novel therapeutic target.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>A combination of masseteric muscle injection of CFA and delayed CGRP infusion were used to model persistent myogenic-TMD comorbid with migraine, respectively. Using electrophysiological and behavioural methods, we assessed migraine-like neuronal outcomes and periorbital withdrawal thresholds to validate this approach. We measured 3-nitrotyrosine expression, as a marker of nitroxidative species, including peroxynitrite, and used the peroxynitrite decomposition catalyst, FeTPPS, and to determine the role of peroxynitrite in these comorbid mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Persistent myogenic-TMD exacerbated migraine-relevant neuronal outcomes in response to delayed CGRP, causing more prevalent and hypersensitive trigeminovascular neuronal responses to innocuous/noxious probing of dural and cutaneous-periorbital regions, demonstrating many of the signatures of ‘latent sensitization’. We also observed increased expression of 3-nitrotyrosine along the trigeminal pain pathway in TMD, migraine and comorbid models and confirm that targeting peroxynitrite breakdown prevents the development of this nociceptive neuronal phenotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Our persistent comorbid myogenic-TMD/migraine model translates to the exacerbated clinical phenotype, validating it as an approach to study mechanisms. Production of peroxynitrite along the trigeminal pain pathway contributes to the mechanisms underlying this phenotype and is a potentially novel monotherapy or combination approach.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 21","pages":"6371-6385"},"PeriodicalIF":7.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70612","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618483","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":"Behind the photographs: Close relations between German pharmacologists and the British Pharmacological Society in the 1930s observed through the diary of Wolfgang Heubner","authors":"Elizabeth Mary Burns,&nbsp;Claudia Engelmann,&nbsp;Nina Sophie Goebels,&nbsp;Hannes Schneider,&nbsp;Shelley McKeown,&nbsp;Frances Mary Platt,&nbsp;Roland Seifert","doi":"10.1111/bph.70654","DOIUrl":"10.1111/bph.70654","url":null,"abstract":"<p>In the 1930s, the British Pharmacological Society was founded and rapidly established itself, with Sir Henry Dale, Harold Burn and Ernest Verney playing leading roles. At the same time, with the rise of National Socialism in Germany, many pharmacologists were persecuted for their Jewish ethnicity or for political reasons, resulting in a substantial migration of scientists to the UK. Using recently discovered photographs found in the Department of Pharmacology at the University of Oxford, together with the detailed diary of German pharmacologist Wolfgang Heubner held at Hannover Medical School, this study reveals close relationships between British pharmacologists, German pharmacologists and persecuted pharmacologists. Members of these groups met informally in the UK on several occasions up to just 2 months before the outbreak of the Second World War. Within these settings, scientific ideas were exchanged freely and collaborative projects discussed. Photographs, diary entries and meeting records provide substantial evidence of strong personal and professional relationships formed through both scientific and social interactions. In these contexts, political differences do not appear to have overtly disrupted scientific exchange or social interaction. The photographs further suggest that genuine friendships existed between British pharmacologists, German colleagues associated with the National Socialist regime and persecuted German-Jewish scientists. Together, these findings demonstrate how long-standing collaborations, shared professional identities and common collective goals helped sustain relationships during a period of profound political division.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 21","pages":"6243-6260"},"PeriodicalIF":7.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70654","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900080","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":"Potentiation effects of the positive allosteric modulator PTC-174 on NMDA receptors in neonatal male rat substantia nigra dopaminergic neurons","authors":"Bangyuan Liu,&nbsp;Alasdair J. Gibb","doi":"10.1111/bph.70615","DOIUrl":"10.1111/bph.70615","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Positive allosteric modulators bind to secondary binding sites on the receptor and alter receptor conformation and activation, changing agonist potency and efficacy. PTC-174 is a novel NMDA receptor positive allosteric modulator that particularly enhances activity of receptors containing GluN2C or GluN2D subunits. We have investigated potentiation by PTC-174 of dopaminergic neuron NMDA responses, where receptors are likely to be GluN1/GluN2B/GluN2D triheteromeric receptors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Whole-cell and outside-out patch-clamp recordings from substantia nigra dopaminergic neurons in acute mid-brain slices from 6- to 8-day-old rats were used to investigate the effects of PTC-174 on NMDA responses and on NMDA receptor-mediated excitatory post-synaptic currents (EPSCs). A new ‘hypercube’ model with explicit receptor subunit-dependent binding steps for agonists and allosteric modulators was used to describe the effects of PTC-174.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>As expected, PTC-174 potentiated NMDA responses, with a &gt;1.7-fold increase at 200-μM NMDA. The effect was independent of inhibition by the GluN2B-selective NAM ifenprodil when the two drugs were co-applied. In outside-out patches, PTC-174 increased channel open probability without altering the unitary current amplitude. PTC-174 prolonged the decay of NMDA receptor-mediated EPSCs and increased EPSC charge transfer. The results were described by a two-binding site subunit-specific ‘hypercube’ model that suggests PTC-174 reduces agonist microscopic affinity but enhances channel-gating efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>The main implication of the results in this paper is that PAMs like PTC-174 have the potential to enhance NMDA receptor signalling at substantia nigra dopaminergic neurons in vivo and so could enhance basal ganglia dopamine signalling.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 21","pages":"6481-6500"},"PeriodicalIF":7.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70615","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700872","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":"Subregion-specific perineuronal net remodelling in the dorsal hippocampus drives vulnerability and resilience to chronic stress: The role of venlafaxine treatment","authors":"Paola Brivio,&nbsp;Arianna Palumbo,&nbsp;Maria Teresa Gallo,&nbsp;Filippo Umberto Tancredi Veronesi,&nbsp;Giorgia Cortinovis,&nbsp;Piotr Gruca,&nbsp;Magdalena Lason,&nbsp;Ewa Litwa,&nbsp;Dominika Biala,&nbsp;Fabio Fumagalli,&nbsp;Mariusz Papp,&nbsp;Francesca Calabrese","doi":"10.1111/bph.70594","DOIUrl":"10.1111/bph.70594","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Neuronal plasticity enables the brain to adapt to internal and external demands by dynamically regulating synaptic connectivity and emotional circuitry. Impaired neuroplasticity represents a core pathophysiological framework of major depressive disorder, one of the leading causes of disability worldwide. Chronic stress is a major determinant of vulnerability, with individuals displaying either maladaptive responses or resilient coping strategies.</p>\u0000 \u0000 <p>Emerging evidence links dysfunctional plasticity to alterations in extracellular matrix components, particularly perineuronal nets (PNNs), specialized structures that predominantly enwrap parvalbumin-positive interneurons and regulate synaptic stability and cortical inhibition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We employed the chronic mild stress (CMS) model for 6 weeks to distinguish vulnerable and resilient rats based on the hedonic behaviour, and we investigated whether differential susceptibility to chronic stress was associated with region-specific alterations in PNN organization. Furthermore, we studied whether treatment with venlafaxine (VLX; 10 mg·kg⁻¹) administered during CMS could restore stress-induced impairments in plasticity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We found that vulnerable animals showed increased PNNs enwrapping PV+ interneurons specifically in the CA3 and an impairment in the BDNF–TRKB pathway, reflecting a less permissive plastic environment, whereas resilient rats appeared to induce PNNs remodelling via MMP9 to face with stress. Notably, chronic VLX administration seemed to restore resilience to CMS by normalizing PNNs composition, PNNs surrounding PV+ interneurons in CA3 and by regulating MMP9 expression, supporting a role for the antidepressant in promoting a more adaptive hippocampal landscape.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and implications</h3>\u0000 \u0000 <p>Our findings identify PNN remodelling as a potential mechanism underlying stress susceptibility and suggest that VLX promotes resilience by selectively modulating PNN composition possibly via MMP9 regulation in the rat dorsal hippocampus.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 21","pages":"6291-6305"},"PeriodicalIF":7.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70594","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599469","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":"LEI-101 produces broad-spectrum analgesia in preclinical pain models","authors":"Muhammed Yusuf,&nbsp;Ayfer Busra Benkli,&nbsp;Ramiz Yusuf","doi":"10.1111/bph.70607","DOIUrl":"10.1111/bph.70607","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>A promising method for managing pain without the negative effects on the central nervous system linked to CB₁ receptor activation or opioid analgesics is the selective activation of the cannabinoid CB₂ receptor. Nevertheless, the pharmacological profiles of the available CB₂ agonists vary and in certain instances they depend on endogenous opioid signalling. We investigated the pharmacology of the selective CB₂ receptor agonist LEI-101 <i>in vitro</i> and <i>in vivo</i> in rodent pain models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Radioligand binding, cAMP inhibition and calcium mobilization at cannabinoid receptors in humans and rats were employed to characterize LEI-101. Rat models of osteoarthritis, neuropathic, postoperative and chronic inflammatory pain were used to assess analgesic efficacy. Selective CB₁, CB₂ and <i>μ</i>-opioid antagonists were used to measure receptor selectivity. To evaluate potential central nervous system side effects, locomotor activity was measured.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>With significant selectivity over CB₁ receptors, LEI-101 had high affinity and functional agonist efficacy at human and rat CB₂ receptors. Systemic administration of LEI-101 produced dose-dependent antihyperalgesic and antiallodynic effects across all pain models. These effects were abolished by CB₂-selective antagonists but not by CB₁ or <i>μ</i> antagonists. LEI-101 did not impair locomotor activity at analgesic doses and showed no evidence of opioid-like tolerance following repeated administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>These findings demonstrate that selective CB₂ receptor activation by LEI-101 produces robust analgesia across diverse pain states, with a predominantly CB_2-dependent and opioid-independent pharmacological profile. CB₂-selective agonists such as LEI-101 represent a promising non-opioid therapeutic strategy for the treatment of chronic pain.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 21","pages":"6352-6370"},"PeriodicalIF":7.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618498","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":"Histone deacetylase inhibitors as venetoclax-sensitising partners in acute myeloid leukaemia: Mechanisms, pharmacology and translational perspectives","authors":"Jaebok Lee,&nbsp;Marc Diederich","doi":"10.1111/bph.70641","DOIUrl":"10.1111/bph.70641","url":null,"abstract":"<p>Venetoclax combined with hypomethylating agents has improved treatment for older or unfit patients with acute myeloid leukaemia (AML), but resistance and relapse remain common. This review analyses the rationale for combining venetoclax with inhibitors of histone deacetylase (HDAC). Class I histone deacetylase 1/2/3-dependent suppression of myeloid cell leukaemia 1 and de-repression of pro-apoptotic BCL-2 homology domain 3 (BH3)-only genes provide the strongest mechanistic basis, whereas HDAC6/heat shock protein 90, autophagy, immune-modulatory and super-enhancer mechanisms remain context-dependent and incompletely validated in primary AML under venetoclax exposure. Effects of HDAC inhibition must also be interpreted in the context of tumour protein 53 status. Early HDAC inhibitor-containing composite regimens, particularly chidamide-based CACAG-VEN (chidamide, venetoclax, azacitidine, low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor), report high response rates, including overall response rate of 76.5–98.0%, complete remission/complete remission with incomplete count recovery or composite complete remission of 73.5–93.3%, and measurable residual disease negativity of 44–61%. This six-component regimen does not isolate the contribution of HDAC inhibition. Future development should prioritise biomarker-selected trials that hold non-HDAC components constant, incorporate pharmacodynamic HDAC engagement and BH3 profiling, and account for cytochrome P450 3A-mediated drug interactions. HDAC inhibitor–venetoclax combinations are mechanistically rational, but standard-of-care positioning requires randomised or pharmacodynamic validation.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 21","pages":"6261-6290"},"PeriodicalIF":7.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70641","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757980","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":"Tyrosine-protein phosphatase non-receptor type 2 deficiency in macrophages diminishes the anti-inflammatory and cardioprotective effects of gabapentin after myocardial infarction","authors":"Zhenjun Li,&nbsp;Guo Dong,&nbsp;Gaojun Shan,&nbsp;Ying Liu,&nbsp;Tianyi Lu,&nbsp;Ziguang Song,&nbsp;Zhuo Wang,&nbsp;Boxu Dou,&nbsp;Xiaofeng Cai,&nbsp;Mengjiao Pu,&nbsp;Jiyi Zhao","doi":"10.1111/bph.70609","DOIUrl":"10.1111/bph.70609","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Our previous study has highlighted the anti-inflammatory properties of gabapentin (GBP) after myocardial infarction (MI) by suppressing M1 macrophage polarization. In this study, we further dissected the important molecules involved.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Ligation of the left anterior descending coronary artery was used to construct the MI mouse model. Tyrosine-protein phosphatase non-receptor type 2 (PTPN2) expression in mouse myocardial tissue macrophages was evaluated using Western blot and dual-labelling immunofluorescence. An MI mouse model with macrophage-specific knockdown of PTPN2 was constructed and treated with GBP. M1 polarization was induced by lipopolysaccharide (LPS) and IFN-<i>γ</i> in mouse RAW264.7 cells and bone marrow-derived macrophages. Substrates of PTPN2 were predicted and verified using co-IP and amino acid mutations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>GBP alleviated cardiac dysfunction and reduced myocardial injury and macrophage M1 polarization in mice. PTPN2 expression was increased in macrophages of mice induced with MI in response to the inflammatory response, and GBP further up-regulated PTPN2. Macrophage depletion impaired the efficacy of GBP. PTPN2 knockdown enhanced M1 polarization of macrophages and exacerbated cardiac dysfunction in mice. The binding of PTPN2 to 7-dehydrocholesterol reductase (DHCR7) inhibited Y378 phosphorylation of DHCR7 and reduced the cholesterol synthesis catalysed by DHCR7. DHCR7 knockdown in macrophages reversed macrophage pro-inflammatory activation induced by PTPN2 knockdown, alleviated myocardial injury in mice and restored the efficacy of GBP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>GBP enhances PTPN2 expression to inhibit tyrosine phosphorylation of DHCR7 and blocks cholesterol metabolism to limit macrophage M1 polarization and alleviate MI-induced injury.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 21","pages":"6306-6328"},"PeriodicalIF":7.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599414","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 bile acid receptor TGR5 promotes functional recovery after spinal cord injury by rescuing mitochondrial dysfunction and suppressing AIM2-mediated pyroptosis","authors":"Yikang Wang,&nbsp;Yige Chen,&nbsp;Nongtao Fang,&nbsp;Jiawei Xu,&nbsp;Yangyi Xie,&nbsp;Xiangji Xia,&nbsp;Bing Liu,&nbsp;Haihong Jiang,&nbsp;Yaosen Wu,&nbsp;Yao Li","doi":"10.1111/bph.70619","DOIUrl":"10.1111/bph.70619","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Previous studies have highlighted the significance of the bile acid receptor TGR5 (also known as Takeda G protein-coupled receptor 5) in regulating inflammation and mitochondrial homeostasis in various diseases, whereas the specific involvement of TGR5 in spinal cord injury (SCI) remains unclear. This study aimed to elucidate the effects of TGR5 on SCI, as well as the underlying mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>The TGR5 agonist INT-777 was used to activate TGR5 in a mouse model of SCI, induced by contusion injury to T9-T10 vertebrae, and cultured cells. To determine the mechanism of TGR5 activation after SCI, public dataset analysis, behaviour assessment, histology and biochemical analysis relating to inflammation, pyroptosis and mitochondrial function were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>TGR5 levels were increased in a mouse model of spinal cord injury (SCI), and in primary microglia and BV2 cells treated with tert-butyl hydroperoxide. Furthermore, TGR5 activation by INT-777 improved functional recovery and tissue repair in SCI mice. Mechanistically, INT-777-mediated TGR5 activation exerted a neuroprotective effect by regulating cAMP/AMPK signalling, resulted in suppression of mitochondrial dysfunction and mitochondrial DNA (mtDNA) release, which inhibited absent in melanoma 2 (AIM2)-driven pyroptosis and the inflammatory response. Notably, AIM2 overexpression partly blocked the neuroprotective effects of TGR5 activation in SCI mice. Additionally, AMPK inhibition by dorsomorphin aggravated neural injury and inflammation was alleviated in AIM2 deletion mice following SCI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>INT-777 exerts anti-inflammatory and neuroprotective effects in the injured spinal cord by activating the TGR5/cAMP/AMPK pathway, thereby maintaining mitochondrial homeostasis and suppressing AIM2-mediated pyroptosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 21","pages":"6458-6480"},"PeriodicalIF":7.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668003","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":"Repurposing tirbanibulin as an orally active E2-targeting entry inhibitor against Chikungunya virus","authors":"Jing-wen Gu,&nbsp;Yan-hua He,&nbsp;Yu-qing Ma,&nbsp;Wan-da Tang,&nbsp;Shu-dan Luo,&nbsp;Hai-lin Tang,&nbsp;Yan-yong Yang,&nbsp;Fu Gao,&nbsp;Ping Zhao","doi":"10.1111/bph.70642","DOIUrl":"10.1111/bph.70642","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and purpose</h3>\u0000 \u0000 <p>Chikungunya virus (CHIKV) causes severe acute and chronic disease, yet no approved specific antiviral treatment exists. To rapidly identify potential treatments, we aimed to screen an FDA-approved drug library for inhibitors of CHIKV infection. Tirbanibulin, a dual-microtubule polymerization and Src kinase inhibitor, was assessed for its potential anti-CHIKV activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a high-throughput screen of an FDA-approved drug library. Mechanism-of-action studies included entry-step analysis, surface plasmon resonance (SPR) binding assays and molecular docking. <i>In vivo</i> efficacy was evaluated in lethal murine neuroinfection and CHIKV-induced arthritis models following oral administration of the candidate compound.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>Tirbanibulin exhibited nanomolar to low-micromolar antiviral activity (EC₅₀ range: 0.035–75.64 μM) across multiple cell lines, with high selective indices in key target HT22 and Huh7 cells. It acted at a post-attachment entry step, inhibiting clathrin-mediated endocytosis and potentially viral fusion. Surface plasmon resonance confirmed direct, high-affinity binding to the CHIKV E1 and E2 glycoprotein complex (K_D = 73 nM). In the lethal neuroinfection model, oral tirbanibulin significantly improved survival and reduced brain viral loads; in the arthritis model, it markedly attenuated footpad swelling and inflammatory pathology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and implications</h3>\u0000 \u0000 <p>Tirbanibulin is a novel, orally bioavailable entry-stage inhibitor that directly targets the E2 glycoprotein. Multiple preclinical and clinical studies have confirmed its favourable oral bioavailability and safety. Given its established clinical safety profile, it represents a promising repurposing candidate for clinical evaluation against Chikungunya fever.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"183 21","pages":"6519-6533"},"PeriodicalIF":7.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700904","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}