British Journal of Pharmacology最新文献

{"title":"Ethosuximide: Subunit- and Gβγ-dependent blocker and reporter of allosteric changes in GIRK channels","authors":"Boris Shalomov,&nbsp;Theres Friesacher,&nbsp;Daniel Yakubovich,&nbsp;J. Carlo Combista,&nbsp;Haritha P. Reddy,&nbsp;Shoham Dabbah,&nbsp;Harald Bernsteiner,&nbsp;Eva-Maria Zangerl-Plessl,&nbsp;Anna Stary-Weinzinger,&nbsp;Nathan Dascal","doi":"10.1111/bph.17446","DOIUrl":"10.1111/bph.17446","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The antiepileptic drug ethosuximide (ETX) suppresses epileptiform activity in a mouse model of <i>GNB1</i> syndrome, caused by mutations in Gβ₁ protein, likely through the inhibition of G-protein gated K⁺ (GIRK) channels. Here, we investigated the mechanism of ETX inhibition (block) of different GIRKs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We studied ETX inhibition of GIRK channels expressed in <i>Xenopus</i> oocytes with or without their physiological activator, the G protein subunit dimer Gβγ. ETX binding site and mode of action were analysed using molecular dynamic (MD) simulations and kinetic modelling, and the predictions were tested by mutagenesis and functional testing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>We show that ETX is a subunit-selective, allosteric blocker of GIRKs. The potency of ETX block is increased by Gβγ, in parallel with channel activation. MD simulations and mutagenesis locate the ETX binding site in GIRK2 to a region associated with phosphatidylinositol-4,5-bisphosphate (PIP₂) regulation, and suggest that ETX acts by closing the helix bundle crossing (HBC) gate and altering channel's interaction with PIP₂. The apparent affinity of ETX block is highly sensitive to changes in channel gating caused by mutations in Gβ₁ or GIRK subunits.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>ETX block of GIRKs is allosteric, subunit-specific, and enhanced by Gβγ through an intricate network of allosteric interactions within the channel molecule. Our findings pose GIRK as a potential therapeutic target for ETX and ETX as a potent allosteric GIRK blocker and a tool for probing gating-related conformational changes in GIRK.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 8","pages":"1704-1718"},"PeriodicalIF":6.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17446","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000392","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":"Actions of dexmedetomidine in regulating NLRP3 in postoperative cognitive dysfunction in aged mice via the autophagy–lysosome pathway","authors":"Zhi Wang,&nbsp;Li-na Zhang,&nbsp;Ting Wu,&nbsp;Xu Pan,&nbsp;Le Li,&nbsp;Xin Yang,&nbsp;Miao Zhang,&nbsp;Ying Liu,&nbsp;Yong Liu","doi":"10.1111/bph.17378","DOIUrl":"10.1111/bph.17378","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and purpose</h3>\u0000 \u0000 <p>Autophagy–lysosomal pathway dysfunction leads to postoperative cognitive dysfunction (POCD). Dexmedetomidine (Dex) improves POCD, and we probed the effects of Dex on autophagy–lysosomal pathway dysfunction in a POCD model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>A POCD mouse model was established and intraperitoneally injected with Dex. Cognitive function was evaluated by Morris water maze/open field test/novel object recognition assay. Levels of neurotransmitters/inflammatory cytokines in hippocampus, and NLRP3/ASC/Cleaved Caspase-1 proteins were determined by ELISA/Western blot. NLRP3 inflammasome-mediated microglial activation/astrocyte A1 differentiation in the hippocampal CA1 region were assessed by immunofluorescence assay. BV-2 cells were treated with lipopolysaccharide (LPS) and Dex and/or the NLRP3 inflammasome activator Nigericin, and transfected with si-TFEB for co-culture with primary reactive astrocytes (RAs) to verify the function of Dex in vitro.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Dex alleviated cognitive dysfunction in POCD mice and repressed NLRP3 inflammasome-mediated microglial activation and astrocyte A1 differentiation. NLRP3 inflammasome activation partially reversed the protective effect of Dex on the POCD condition. In vitro experiments verified the inhibitory properties of Dex on microglial activation and astrocyte A1 differentiation. Dex induces TFEB nuclear translocation, microglial autophagy and lysosomal biogenesis. By activating the autophagy–lysosome pathway, Dex regulated NLRP3 inflammasome-mediated microglial activation, inhibited astrocyte A1 differentiation and alleviated POCD in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and implications</h3>\u0000 \u0000 <p>Dex regulates NLRP3 inflammasome-mediated hippocampal microglial activation by promoting TFEB nuclear translocation and activating the autophagy–lysosome pathway and inhibits astrocyte A1 differentiation, thereby alleviating POCD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 8","pages":"1683-1703"},"PeriodicalIF":6.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000389","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":"Activation of δ-opioid receptors blocks allodynia in a model of headache induced by PACAP","authors":"Elizaveta Mangutov,&nbsp;Isaac Dripps,&nbsp;Kendra Siegersma,&nbsp;Yanping Zhang,&nbsp;Rebecca Bocian,&nbsp;Sarah Asif,&nbsp;Timothy Halbesma,&nbsp;Wiktor Witkowski,&nbsp;Amynah A. Pradhan","doi":"10.1111/bph.17424","DOIUrl":"10.1111/bph.17424","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and purpose</h3>\u0000 \u0000 <p>Pituitary adenylate cyclase activating polypeptide (PACAP) is a human migraine trigger that is being targeted for migraine. The δ-opioid receptor (δ-receptor) is a novel target for the treatment of migraine, but its mechanism remains unclear. The goals of this study were to develop a mouse PACAP-headache model using clinically significant doses of PACAP; determine the effects of δ-receptor activation in this model; and investigate the co-expression of δ-receptors, PACAP and PACAP-PAC1 receptor.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>Cephalic allodynia to low doses of acute and chronic PACAP were tested. A triptan (sumatriptan) and a CGRP receptor antagonist (olcegepant) were tested in this model. The δ-receptor agonist SNC80 was tested in PACAP and CGRP-induced headache models. Expression of PACAP, PAC1, CRLR and δ-receptors was determined using in situ hybridisation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key results</h3>\u0000 \u0000 <p>Low doses of PACAP produced dose-dependent acute and chronic cephalic allodynia, blocked by sumatriptan but not by olcegepant. The PAC1 antagonist (M65) did not inhibit CGRP-induced allodynia. There was moderate co-expression of PAC1 and CRLR transcripts in migraine-related regions. SNC80 blocked PACAP- and CGRP-induced allodynia. There was low co-expression of PACAP and δ-receptors in brain regions measured. However, there was high co-expression of PAC1 and δ-receptors in somatosensory cortex, hippocampus and trigeminal nucleus caudalis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and implications</h3>\u0000 \u0000 <p>We developed a translationally significant model of PACAP-induced headache, which was mechanistically distinct from CGRP. Activation of δ-receptors blocked PACAP- and CGRP-induced allodynia, and δ-receptors were highly co-expressed with the PACAP-ergic system. Future studies will examine the functional relationship between δ-receptors and PAC1.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1630-1643"},"PeriodicalIF":6.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963888","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":"Carbonic anhydrase IX inhibition as a path to treat neuroblastoma","authors":"Agne Petrosiute,&nbsp;Audrius Zakšauskas,&nbsp;Asta Lučiūnaitė,&nbsp;Vytautas Petrauskas,&nbsp;Lina Baranauskienė,&nbsp;Agnė Kvietkauskaitė,&nbsp;Alvilė Ščerbavičienė,&nbsp;Marta Tamošiūnaitė,&nbsp;Justina Musvicaitė,&nbsp;Alberta Jankūnaitė,&nbsp;Gediminas Žvinys,&nbsp;Laimonas Stančaitis,&nbsp;Edita Čapkauskaitė,&nbsp;Aurelija Mickevičiūtė,&nbsp;Vaida Juozapaitienė,&nbsp;Virginija Dudutienė,&nbsp;Asta Zubrienė,&nbsp;Švitrigailė Grincevičienė,&nbsp;Virginija Bukelskienė,&nbsp;Helgi B. Schiöth,&nbsp;Jurgita Matulienė,&nbsp;Daumantas Matulis","doi":"10.1111/bph.17429","DOIUrl":"10.1111/bph.17429","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Tumour hypoxia frequently presents a major challenge in the treatment of neuroblastoma (NBL). The neuroblastoma cells produce carbonic anhydrase IX (CA IX), an enzyme crucial for the survival of cancer cells in low-oxygen environments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We designed and synthesised a novel high-affinity inhibitor of CA IX. The highest to-date. The affinities were determined for all human catalytically active CA isozymes showing significant selectivity for CA IX over other isozymes. The inhibitor effect on neuroblastoma cancer cell growth was determined <i>in vitro</i> and <i>in vivo</i> via a mice xenograft model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>The novel designed inhibitor effectively mitigated the acidification induced by CA IX and reduced spheroid growth under hypoxic conditions in the SK-N-AS cell line. It also diminished the secretion of pro-tumour chemokines IL-8 (CXCL2) and CCL2. When we combined this novel CA IX inhibitor with a compound that inhibits the chemokine receptor CCR2 protein activity, we observed a reduction in mouse tumour growth. The combined treatment also prompted tumours to exhibit adaptive resistance by producing higher levels of vascular endothelial growth factor receptors (VEGFR) and other compensatory signals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>This research underscores the pivotal role of CA IX in cancer and the potential of a novel CA IX inhibitor-based combination intervention therapy for neuroblastoma treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1610-1629"},"PeriodicalIF":6.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944964","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":"Agonists of the opioid δ-receptor improve irritable bowel syndrome-like symptoms via the central nervous system","authors":"Toshinori Yoshioka,&nbsp;Sayaka Kimiki,&nbsp;Mayuna Yamazaki,&nbsp;Takumi Hamano,&nbsp;Mizuki Ou,&nbsp;Yumi Ode,&nbsp;Rui Ehara,&nbsp;Keita Kajino,&nbsp;Satoka Kasai,&nbsp;Kazumi Yoshizawa,&nbsp;Tsuyoshi Saitoh,&nbsp;Daisuke Yamada,&nbsp;Hiroshi Nagase,&nbsp;Akiyoshi Saitoh","doi":"10.1111/bph.17428","DOIUrl":"10.1111/bph.17428","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Irritable bowel syndrome (IBS) is a common condition that is challenging to treat, and novel drugs are needed for this condition. Previously, a chronic vicarious social defeat stress (cVSDS) mouse model exhibits IBS-like symptoms. Also agonists of the opioid δ-receptor exert anti-stress effects in rodents with minimal adverse effects. Here, we evaluated the effects of δ-receptor agonists on the IBS-like symptoms in cVSDS mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>cVSDS mice (male C57BL/6J mice) were prepared following a 10-day exposure to witness of social defeat stress. Subsequently, intestinal peristaltic motility and abdominal hyperalgesia were evaluated using the charcoal meal test (CMT) and capsaicin-induced hyperalgesia test (CHT), respectively. Extracellular glutamate levels were measured using in vivo brain microdialysis. The drug was singly administrated 30 min before testing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>In cVSDS mice, systemic (10 mg kg⁻¹) and intracerebroventricular (30 nmol) administration of a δ-receptor agonist regulated intestinal peristalsis in the CMT and relieved abdominal pain in the CHT. Effects of systemic administration were blocked by intracerebroventricular injection of a δ-receptor inhibitor. Local infusion of the δ-receptor agonist (0.6 nmol) into the insular cortex improved cVSDS-induced intestinal hypermotility. The in vivo brain microdialysis study showed that re-exposure to VSDS elevated the extracellular glutamate levels in the IC, which was restored by the δ-receptor agonist.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>We propose that agonists of opioid δ-receptors are potential drugs for the radical treatment of IBS because they can ameliorate IBS-like symptoms via the CNS, specifically the insular cortex.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1599-1609"},"PeriodicalIF":6.8,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17428","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892428","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":"Hydroxyl chalcone derivative DK02 as a multi-target-directed ligand for Alzheimer's disease: A preclinical study in zebrafish","authors":"Balasubramanian Haridevamuthu,&nbsp;Ankit Kumar Bharti,&nbsp;Santosh Pushpa Ramya Ranjan Nayak,&nbsp;Dhaareeshwar Narayanan,&nbsp;Dhivya Loganathan Sumathi,&nbsp;Bharath Kumar Chagaleti,&nbsp;Venkatesan Saravanan,&nbsp;Rajakrishnan Rajagopal,&nbsp;Ahmed Alfarhan,&nbsp;Kathiravan Muthu Kumaradoss,&nbsp;Jesu Arockiaraj","doi":"10.1111/bph.17426","DOIUrl":"10.1111/bph.17426","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) is a widespread neurodegenerative condition characterized by amyloid-beta (Aβ) plaques and tau protein aggregates, leading to significant cognitive decline. Existing treatments primarily offer symptomatic relief, underscoring the urgent need for novel therapies that address multiple AD pathways. This study evaluates the efficacy of DK02, a hydroxyl chalcone derivative, in a scopolamine-induced dementia model in zebrafish, hypothesizing that it targets several neurodegenerative mechanisms simultaneously.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We employed a blend of experiments, including in silico docking, in vitro enzyme inhibition assays and in vivo zebrafish models, to assess therapeutic effects of DK02. Methods included molecular docking to forecast interaction sites, acetylcholinesterase (AChE) inhibition testing, and various behavioural and histopathological analyses to gauge DK02's cognitive and neuroprotective impacts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>DK02 emerged as a potent AChE inhibitor via virtual screening, and significantly enhanced cognitive functions in zebrafish, by improving memory retention and reducing anxiety-like behaviours. DK02 also displayed strong antioxidant properties, reducing oxidative stress-induced neuronal damage. Histopathological analysis confirmed its neuroprotective effects by showing decreased amyloid plaque burden and mitigated structural brain damage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>DK02 shows promise as a multi-target-directed ligand for AD, offering a new therapeutic path by simultaneously addressing cholinergic, oxidative and amyloid pathways. Its potential to enhance cognitive functions and curtail neurodegeneration suggests advantages over current symptomatic treatments. Further research into DK02 mechanisms and long-term impacts is essential for its development in AD therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1582-1598"},"PeriodicalIF":6.8,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876236","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":"Semaglutide protects against diabetes-associated cardiac inflammation via Sirt3-dependent RKIP pathway","authors":"Kaibin Lin,&nbsp;Ai Wang,&nbsp;Changlin Zhai,&nbsp;Yun Zhao,&nbsp;Huilin Hu,&nbsp;Dong Huang,&nbsp;Qiwei Zhai,&nbsp;Yan Yan,&nbsp;Junbo Ge","doi":"10.1111/bph.17327","DOIUrl":"10.1111/bph.17327","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert cardiovascular benefits in diabetic patients, but the underlying mechanisms remain incompletely understood. Semaglutide, a novel long-acting GLP-1RA, has shown a reduced risk of cardiovascular events. Based on these results, we investigated the therapeutic potential of semaglutide in diabetic cardiomyopathy and sought to elucidate the underlying mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Mice with diabetes induced by high-fat diet/streptozotocin were treated with semaglutide. The mechanisms underlying the cardioprotective effects of semaglutide were analysed using animal and cell experiments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>In diabetic mice, semaglutide alleviated metabolic disorders, ameliorated myocardial fibrosis, improved cardiac function, antagonized oxidative stress and suppressed cardiomyocyte apoptosis. More significantly, semaglutide attenuated cardiac inflammation through restoring Raf kinase inhibitor protein (RKIP) expression and inhibiting downstream TANK-binding kinase 1 (TBK1)-NF-κB pathway. Meanwhile, decreased RKIP expression and activated TBK1-NF-κB signalling pathway were also found in tissues from human diabetic hearts. RKIP deficiency exacerbated cardiac inflammation and offset the cardioprotective effect of semaglutide in diabetic mice. Moreover, semaglutide also restored the expression level of Sirtuin 3(Sirt3), which served as a modulator against cardiac inflammation by regulating RKIP-dependent pathway. In diabetic mice, RKIP deficiency abolished the cardioprotective benefits conferred by the Sirt3 activator honokiol. We also found that cAMP/PKA signalling, rather than glucose lowering, contributed to the anti-inflammatory effect of semaglutide through Sirt3-dependent RKIP pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Semaglutide exerted cardioprotective effects against diabetic heart failure by alleviating cardiac inflammation through Sirt3-dependent RKIP signalling pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1561-1581"},"PeriodicalIF":6.8,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876238","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 Australia story: Current status and future challenges for the clinical applications of psychedelics.","authors":"David J Nutt, Peter Hunt, Anne Katrin Schlag, Paul Fitzgerald","doi":"10.1111/bph.17398","DOIUrl":"https://doi.org/10.1111/bph.17398","url":null,"abstract":"<p><p>The past decade has seen a huge increase in clinical research with psychedelic drugs and 3,4-methylenedioxymethamphetamine (MDMA), which have revealed great potential for treating mental health conditions. Given this progress in research, as well as the current unmet clinical need of millions of patients, in 2023, the Australian Therapeutic Goods Administration (TGA) approved the use of psilocybin for treatment-resistant depression and MDMA for PTSD to take effect from 1 July 2023. The campaign for TGA approval was led by a coalition comprising the Australian charity Mind Medicine Australia with support from Professor David Nutt, Drug Science, Professor Arthur Christopolous, Professor Chris Langmead (both from Monash University) and from large numbers of clinical, academic and patient groups. Under the rescheduling, current prescribing rights are limited to psychiatrists who have become authorised prescribers under the TGA's Authorised Prescriber Scheme, and psilocybin can only be used for treatment resistant depression and MDMA can only be used for PTSD. This paper reviews the background for this decision, its implications for approvals in other jurisdictions, as well as for the development pathways for other psychedelic drugs.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863504","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":"EXPRESSION OF CONCERN: Dose-Dependent Biphasic Leptin-Induced Proliferation is Caused by Non-Specific IL-6/NF-κB Pathway Activation in Human Myometrial Cells","authors":"","doi":"10.1111/bph.17430","DOIUrl":"10.1111/bph.17430","url":null,"abstract":"<p><b>EXPRESSION OF CONCERN</b>: M. Barrichon, T. Hadi, M. Wendremaire, C. Ptasinski, R. Seigneuric, G. Marcion, M. Delignette, J. Marchet, M. Dumas, P. Sagot, M. Bardou, C. Garrido and F. Liruss, “Dose-Dependent Biphasic Leptin-Induced Proliferation is Caused by Non-Specific IL-6/NF-κB Pathway Activation in Human Myometrial Cells,” <i>British Journal of Pharmacology</i> 172, no. 12 (2015): 2974–2990, https://doi.org/10.1111/bph.13100.</p><p>This Expression of Concern is for the above article, published online on 05 February 2015 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Péter Ferdinandy; the British Pharmacological Society; and John Wiley and Sons Ltd. The Expression of Concern has been agreed following an investigation based on concerns raised by a third party. The investigation revealed duplication between the P-STAT3 bands presented in the two western blots in Figure S2A. The two blots represent different conditions. Furthermore, the control bands representing NF-κB at 4 minutes and 50 minutes in Figure 8A originate from a different gel than the other bands in the figure. The western blot was not delineated to indicate the splice sites. The authors provided an explanation and some raw data. However, this was not considered satisfactory to remove doubt. Therefore, the journal has decided to issue an Expression of Concern to inform and alert the readers.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 4","pages":"1121"},"PeriodicalIF":6.8,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17430","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833899","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":"Pharmacodynamics of the orexin type 1 (OX1) receptor in colon cancer cell models: A two-sided nature of antagonistic ligands resulting from partial dissociation of Gq","authors":"Valérie Gratio,&nbsp;Paulina Dragan,&nbsp;Laurine Garcia,&nbsp;Loredana Saveanu,&nbsp;Pascal Nicole,&nbsp;Thierry Voisin,&nbsp;Dorota Latek,&nbsp;Alain Couvineau","doi":"10.1111/bph.17422","DOIUrl":"10.1111/bph.17422","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Orexins have important biological effects on the central and peripheral nervous systems. Their primary ability is to regulate the sleep–wake cycle. Orexins and their antagonists, via OX₁ receptor have been shown to have proapoptotic and antitumor effects on various digestive cancers cell models. We investigated, (1) the ability of orexin-A and its antagonists to regulate OX₁ receptor expression at the cell surface and (2), how OX₁ antagonists induced proapoptotic effect in cancer cell<span>s</span> models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>The OX₁ receptor internalisation is determined by imaging flow cytometry in colon cancer cell models and the OX₁ receptor coupling to G proteins via bioluminescence resonance energy transfer and molecular dynamic simulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Orexin-A induced rapid receptor internalisation within 15 min via β-arrestin 2 recruitment, whereas antagonists had no effect. Furthermore, Gq is critical for receptor internalisation and signalling pathways, and no other G proteins appear to be recruited. Surprisingly, antagonists induced recruitment and conformational changes in Gq protein. Simulated molecular dynamics of agonists/orexin receptor/Gq complexes show that antagonists exhibits a similar binding mode, stable at the binding site and show conformational changes of ECL2, similar to that of the agonists.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>OX₁ receptor activation induced orexin/β-arrestin-dependent internalisation, which was independent of the apoptotic pathway induced by orexins and antagonists. In addition, antagonists activate the Gq protein, suggesting its putative partial dissociation. These results suggest that the development of OX₁ receptor targeting molecules, including orexin antagonists with antitumor properties, may pave the way for innovative cancer therapies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1528-1545"},"PeriodicalIF":6.8,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17422","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827406","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}