British Journal of Pharmacology最新文献

{"title":"Paraoxonase-2 agonist vutiglabridin promotes autophagy activation and mitochondrial function to alleviate non-alcoholic steatohepatitis","authors":"Gu-Choul Shin,&nbsp;Hyeong Min Lee,&nbsp;Nayeon Kim,&nbsp;Jihyeon Hur,&nbsp;Sang-Ku Yoo,&nbsp;Yun Sun Park,&nbsp;Hyung Soon Park,&nbsp;Dongryeol Ryu,&nbsp;Min-Ho Park,&nbsp;Jung Hee Park,&nbsp;Sang-Uk Seo,&nbsp;Leo Sungwong Choi,&nbsp;Martin Rønn Madsen,&nbsp;Michael Feigh,&nbsp;Kwang Pyo Kim,&nbsp;Kyun-Hwan Kim","doi":"10.1111/bph.16438","DOIUrl":"10.1111/bph.16438","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Only limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH). Glabridin, a promising anti-obesity candidate, has only limited druggability due to its low <i>in vivo</i> chemical stability and bioavailability. Therefore, we developed vutiglabridin (VUTI), which is based on a glabridin backbone, and investigated its mechanism of action in treating NASH in animal models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Anti-NASH effects of VUTI were determined in <i>in vitro</i> fatty liver models, spheroids of primary human hepatocytes and L02 normal liver cell lines. To identify VUTI possible cellular target/s, biotin-labelled VUTI was synthesized and underwent chemical proteomic analysis. Further, the evaluation of VUTI therapeutic efficacy was carried out using an amylin-NASH and high-fat (HF) diet-induced obese (DIO) mouse models. This was carried out using transcriptomic, lipidomic and proteomic analyses of the livers from the amylin-NASH mouse model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>VUTI treatment markedly reduces hepatic steatosis, fibrosis and inflammation by promoting lipid catabolism, activating autophagy and improving mitochondrial dysfunction, all of which are hallmarks of effective NASH treatment. The cellular target of VUTI was identified as paraoxonase 2 (PON2), a newly proposed protein target for the treatment of NASH, VUTI enhanced PON2 activity. The results using PON2 knockdown cells demonstrated that PON2 is important for VUTI- activation of autophagy, promoting mitochondrial function, decreasing oxidative stress and alleviating lipid accumulation under lipotoxic condition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Our data demonstrated that VUTI is a promising therapeutic for NASH. Targeting PON2 may be important for improving liver function in various immune-metabolic diseases including NASH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16438","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295563","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":"Airway epithelial overexpressed cathepsin K induces airway remodelling through epithelial–mesenchymal trophic unit activation in asthma","authors":"Ling Qin,&nbsp;Ye Yao,&nbsp;Weijie Wang,&nbsp;Qingwu Qin,&nbsp;Jingjing Liu,&nbsp;Huijun Liu,&nbsp;Lin Yuan,&nbsp;Yunchang Yuan,&nbsp;Xizi Du,&nbsp;Bingrong Zhao,&nbsp;Xinyu Wu,&nbsp;Bei Qing,&nbsp;Leng Huang,&nbsp;Gang Wang,&nbsp;Yang Xiang,&nbsp;Xiangping Qu,&nbsp;Xuewei Zhang,&nbsp;Ming Yang,&nbsp;Zhenkun Xia,&nbsp;Chi Liu","doi":"10.1111/bph.16423","DOIUrl":"10.1111/bph.16423","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Airway epithelial cells (AECs) regulate the activation of epithelial–mesenchymal trophic units (EMTUs) during airway remodelling through secretion of signalling mediators. However, the major trigger and the intrinsic pathogenesis of airway remodelling is still obscure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>The differing expressed genes in airway epithelia related to airway remodelling were screened and verified by RNA-sequencing and signalling pathway analysis. Then, the effects of increased cathepsin K (CTSK) in airway epithelia on airway remodelling and EMTU activation were identified both in vitro and in vivo, and the molecular mechanism was elucidated in the EMTU model. The potential of CTSK as an an effective biomarker of airway remodelling was analysed in an asthma cohort of differing severity. Finally, an inhibitor of CTSK was administered for potential therapeutic intervention for airway remodelling in asthma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>The expression of CTSK in airway epithelia increased significantly along with the development of airway remodelling in a house dust mite (HDM)-stressed asthma model. Increased secretion of CTSK from airway epithelia induced the activation of EMTUs by activation of the PAR2-mediated pathway. Blockade of CTSK inhibited EMTU activation and alleviated airway remodelling as an effective intervention target of airway remodelling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Increased expression of CTSK in airway epithelia is involved in the development of airway remodelling in asthma through EMTU activation, mediated partly through the PAR2-mediated signalling pathway. CTSK is a potential biomarker for airway remodelling, and may also be a useful intervention target for airway remodelling in asthma patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295562","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":"Silibinin, a commonly used therapeutic agent for non-alcohol fatty liver disease, functions through upregulating intestinal expression of fibroblast growth factor 15/19","authors":"Yujie Bai,&nbsp;Jing Zhang,&nbsp;Jialin Li,&nbsp;Minghui Liao,&nbsp;Yajing Zhang,&nbsp;Yufeng Xia,&nbsp;Zhifeng Wei,&nbsp;Yue Dai","doi":"10.1111/bph.16431","DOIUrl":"10.1111/bph.16431","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Silibinin is used to treat non-alcohol fatty liver disease (NAFLD) despite having rapid liver metabolism. Therefore, we investigated the role of the intestine in silibinin mechanism of action.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>NAFLD mice model was established by feeding them with a high-fat diet (HFD). Liver pathological were examined using H&amp;E and oil red O staining. Tissue distribution of silibinin was detected by LC–MS/MS. SiRNA was employed for gene silencing and plasmid was used for gene overexpression. ChIP-qPCR assay was performed to detect the levels of histone acetylation. Recombinant adeno-associated virus 9-short hairpin-fibroblast growth factor (FGF)-15 and -farnesoid X receptor (FXR; NR1H4) were used to knockdown expression of FGF-15 and FXR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Oral silibinin significantly reversed NAFLD in mice, although liver concentration was insufficient for reduction of lipid accumulation in hepatocytes. Among endogenous factors capable of reversing NAFLD, the expression of Fgf-15 was selectively up-regulated by silibinin in ileum and colon of mice. When intestinal expression of Fgf-15 was knocked down, protection of silibinin against lipid accumulation and injury of livers nearly disappeared. Silibinin could reduce activity of histone deacetylase 2 (HDAC2), enhance histone acetylation in the promoter region of FXR and consequently increase intestinal expression of FGF-15/19.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Oral silibinin selectively promotes expression of FGF-15/19 in ileum by enhancing transcription of FXR via reduction of HDAC2 activity, and FGF-15/19 enters into circulation to exert anti-NAFLD action. As the site of action is the intestine this would explain the discrepancy between pharmacodynamics and pharmacokinetics of silibinin.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261041","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":"Difluorinated thromboxane A2 reveals crosstalk between platelet activatory and inhibitory pathways by targeting both the TP and IP receptors","authors":"Megan F. Allen,&nbsp;James L. Hutchinson,&nbsp;Michael Keith,&nbsp;Shahida Mallah,&nbsp;Robin A. Corey,&nbsp;Justin S. Trory,&nbsp;Changcheng Jing,&nbsp;Huaquan Fang,&nbsp;Liang Wei,&nbsp;Steven H. Bennett,&nbsp;Varinder K. Aggarwal,&nbsp;Stuart J. Mundell,&nbsp;Ingeborg Hers","doi":"10.1111/bph.16435","DOIUrl":"10.1111/bph.16435","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Thromboxane A₂ (TXA₂) is a prostanoid produced during platelet activaton, important in enhancing platelet reactivity by activation of TP receptors. However, due to the short half-life, studying TXA₂ signalling is challenging. To enhance our understanding of TP receptor-mediated platelet biology, we therefore synthesised mono and difluorinated TXA₂ analogues and explored their pharmacology on heterologous and endogenously expressed TP receptor function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Platelet functional and signalling responses were studied using aggregometry, Ca²⁺ mobilisation experiments and immunoblotting and compared with an analogue of the TXA₂ precursor prostaglandin H₂, U46619. Gα_q/Gα_s receptor signalling was determined using a bioluminescence resonance energy transfer (BRET) assay in a cell line overexpression system.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>BRET studies revealed that F-TXA₂ and F₂-TXA₂ promoted receptor-stimulated TP receptor G-protein activation similarly to U46619. Unexpectedly, F₂-TXA₂ caused reversible aggregation in platelets, whereas F-TXA₂ and U46619 induced sustained aggregation. Blocking the IP receptor switched F₂-TXA₂-mediated reversible aggregation into sustained aggregation. Further BRET studies confirmed F₂-TXA₂-mediated IP receptor activation. F₂-TXA₂ rapidly and potently stimulated platelet TP receptor-mediated protein kinase C/P-pleckstrin, whereas IP-mediated protein kinase A/P-vasodilator-stimulated phosphoprotein was more delayed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>F-TXA₂ is a close analogue to TXA₂ used as a selective tool for TP receptor platelet activation. In contrast, F₂-TXA₂ acts on both TP and IP receptors differently over time, resulting in an initial wave of TP receptor-mediated platelet aggregation followed by IP receptor-induced reversibility of aggregation. This study reveals the potential difference in the temporal aspects of stimulatory and inhibitory pathways involved in platelet activation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16435","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261034","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":"Positive allosteric modulation of the cannabinoid CB1 receptor potentiates endocannabinoid signalling and changes ERK1/2 phosphorylation kinetics","authors":"Hayley M. Green,&nbsp;Jamie J. Manning,&nbsp;Ian R. Greig,&nbsp;Ruth A. Ross,&nbsp;David B. Finlay,&nbsp;Michelle Glass","doi":"10.1111/bph.16433","DOIUrl":"10.1111/bph.16433","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Activation of CB₁ by exogenous agonists causes adverse effects in vivo. Positive allosteric modulation may offer improved therapeutic potential and a reduced on-target adverse effect profile compared with orthosteric agonists, due to reduced desensitisation/tolerance, but this has not been directly tested. This study investigated the ability of PAMs/ago-PAMs to induce receptor regulation pathways, including desensitisation and receptor internalisation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Bioluminescence resonance energy transfer (BRET) assays in HEK293 cells were performed to investigate G protein dissociation, ERK1/2 phosphorylation and β-arrestin 2 translocation, while immunocytochemistry was performed to measure internalisation of CB₁ in response to the PAMs ZCZ011, GAT229 and ABD1236 alone and in combination with the orthosteric agonists AEA, 2-AG, and AMB-FUBINACA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>ZCZ011, GAT229 and ABD1236 were allosteric agonists in all pathways tested. The ago-PAM ZCZ011 induced a biphasic ERK1/2 phosphorylation time course compared to transient activation by orthosteric agonists. In combination with 2-AG but not AEA or AMB-FUBINACA, ZCZ011 and ABD1236 caused the transient peak of ERK1/2 phosphorylation to become sustained. All PAMs increased the potency and efficacy of AEA-induced signalling in all pathways tested; however, no notable potentiation of 2-AG or AMB-FUBINACA was observed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Ago-PAMs can potentiate endocannabinoid CB₁ agonism by AEA to a larger extent compared with 2-AG. However, all compounds were found to be allosteric agonists and induce activation of CB₁ in the absence of endocannabinoid, including β-arrestin 2 recruitment and internalisation. Thus, the spatiotemporal signalling of endogenous cannabinoids will not be retained in vivo.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16433","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236915","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":"Circular RNA regulatory role in pathological cardiac remodelling.","authors":"Alessia Bibi, Monika Bartekova, Shrey Gandhi, Simona Greco, Alisia Madè, Moumita Sarkar, Victoria Stopa, Spyros Tastsoglou, David de Gonzalo-Calvo, Yvan Devaux, Costanza Emanueli, Artemis G Hatzigeorgiou, A Yaël Nossent, Zhichao Zhou, Fabio Martelli","doi":"10.1111/bph.16434","DOIUrl":"https://doi.org/10.1111/bph.16434","url":null,"abstract":"<p><p>Cardiac remodelling involves structural, cellular and molecular alterations in the heart after injury, resulting in progressive loss of heart function and ultimately leading to heart failure. Circular RNAs (circRNAs) are a recently rediscovered class of non-coding RNAs that play regulatory roles in the pathogenesis of cardiovascular diseases, including heart failure. Thus, a more comprehensive understanding of the role of circRNAs in the processes governing cardiac remodelling may set the ground for the development of circRNA-based diagnostic and therapeutic strategies. In this review, the current knowledge about circRNA origin, conservation, characteristics and function is summarized. Bioinformatics and wet-lab methods used in circRNA research are discussed. The regulatory function of circRNAs in cardiac remodelling mechanisms such as cell death, cardiomyocyte hypertrophy, inflammation, fibrosis and metabolism is highlighted. Finally, key challenges and opportunities in circRNA research are discussed, and orientations for future work to address the pharmacological potential of circRNAs in heart failure are proposed.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236913","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":"Trained immunity: A link between risk factors and cardiovascular disease.","authors":"Mingqi Chen, Xuya Kang, Yan Zhang, Yahan Liu","doi":"10.1111/bph.16472","DOIUrl":"https://doi.org/10.1111/bph.16472","url":null,"abstract":"<p><p>Cardiovascular diseases are significant contributors to human mortality, closely associated with inflammation. With the changing living conditions and the extension of human lifespan, greater attention has been directed towards understanding the impact of early, long-term events on the development of cardiovascular events. Lifestyle factors such as stress, unhealthy diet and physical inactivity can increase the risk of cardiovascular diseases. Interestingly, even if the risk factors are addressed later, their influence may persist. Recently, the concept of trained innate immunity (TRIM), defined as sustained alterations in the function of innate immunocyte that promote a more robust response to downstream stimuli, has been proposed to be involved in cardiovascular diseases. It is hypothesized that TRIM may serve as a mediator bridging the impacts of aforementioned risk factors. This review aims to elucidate the role of TRIM in cardiovascular diseases and highlight its significance in uncovering new mechanisms and therapeutic targets.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199613","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":"ERNEST COST action overview on the (patho)physiology of GPCRs and orphan GPCRs in the nervous system.","authors":"Necla Birgül Iyison, Clauda Abboud, Dayana Abboud, Abdulrasheed O Abdulrahman, Ana-Nicoleta Bondar, Julie Dam, Zafiroula Georgoussi, Jesús Giraldo, Anemari Horvat, Christos Karoussiotis, Alba Paz-Castro, Miriam Scarpa, Hannes Schihada, Nicole Scholz, Bilge Güvenc Tuna, Nina Vardjan","doi":"10.1111/bph.16389","DOIUrl":"https://doi.org/10.1111/bph.16389","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are a large family of cell surface receptors that play a critical role in nervous system function by transmitting signals between cells and their environment. They are involved in many, if not all, nervous system processes, and their dysfunction has been linked to various neurological disorders representing important drug targets. This overview emphasises the GPCRs of the nervous system, which are the research focus of the members of ERNEST COST action (CA18133) working group 'Biological roles of signal transduction'. First, the (patho)physiological role of the nervous system GPCRs in the modulation of synapse function is discussed. We then debate the (patho)physiology and pharmacology of opioid, acetylcholine, chemokine, melatonin and adhesion GPCRs in the nervous system. Finally, we address the orphan GPCRs, their implication in the nervous system function and disease, and the challenges that need to be addressed to deorphanize them.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199611","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":"Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms","authors":"Ryan J. Rakoczy,&nbsp;Grace N. Runge,&nbsp;Abhishek K. Sen,&nbsp;Oscar Sandoval,&nbsp;Hunter G. Wells,&nbsp;Quynh Nguyen,&nbsp;Brianna R. Roberts,&nbsp;Jon H. Sciortino,&nbsp;William J. Gibbons Jr,&nbsp;Lucas M. Friedberg,&nbsp;J. Andrew Jones,&nbsp;Matthew S. McMurray","doi":"10.1111/bph.16466","DOIUrl":"10.1111/bph.16466","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Demand for new antidepressants has resulted in a re-evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin-containing “magic” mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We compared baeocystin, norbaeocystin and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, similarly penetrate the blood–brain barrier, serve as ligands for similar receptors and modulate behaviour in rodents similarly. We also assessed the stability and optimal storage and handling conditions for each compound.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p><i>In vitro</i> enzyme kinetics assays found that all compounds had nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin crossed a blood–brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. The dephosphorylated form of norbaeocystin was found to activate the 5-HT_2A receptor with similar efficacy to psilocin and norpsilocin in <i>in vitro</i> cell imaging assays. Behaviourally, only psilocybin induced head twitch responses in rats, a marker of 5-HT_2A-mediated psychedelic effects and hallucinogenic potential. However, like psilocybin, norbaeocystin improved outcomes in the forced swim test. All compounds caused minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16466","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199612","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":"Pronociceptive role of spinal Cav2.3 (R-type) calcium channels in a mouse model of postoperative pain","authors":"Marcella de Amorim Ferreira,&nbsp;Debora Denardin Lückemeyer,&nbsp;Fernanda Martins,&nbsp;Roberta Giusti Schran,&nbsp;Ana Merian da Silva,&nbsp;Eder Gambeta,&nbsp;Gerald W. Zamponi,&nbsp;Juliano Ferreira","doi":"10.1111/bph.16407","DOIUrl":"10.1111/bph.16407","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>More than 80% of patients may experience acute pain after a surgical procedure, and this is often refractory to pharmacological intervention. The identification of new targets to treat postoperative pain is necessary. There is an association of polymorphisms in the Ca_v2.3 gene with postoperative pain and opioid consumption. Our study aimed to identify Ca_v2.3 as a potential target to treat postoperative pain and to reduce opioid-related side effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>A plantar incision model was established in adult male and female C57BL/6 mice. Ca_v2.3 expression was detected by qPCR and suppressed by siRNA treatment. The antinociceptive efficacy and safety of a Ca_v2.3 blocker—alone or together with morphine—was also assessed after surgery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Paw incision in female and male mice caused acute nociception and increased Ca_v2.3 mRNA expression in the spinal cord but not in the incised tissue. Intrathecal treatment with siRNA against Ca_v2.3, but not with a scrambled siRNA, prevented the development of surgery-induced nociception in both male and female mice, with female mice experiencing long-lasting effects. High doses of i.t. SNX-482, a Ca_v2.3 channel blocker, or morphine injected alone, reversed postoperative nociception but also induced side effects. A combination of lower doses of morphine and SNX-482 mediated a long-lasting reversal of postsurgical pain in female and male mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results demonstrate that Ca_v2.3 has a pronociceptive role in the induction of postoperative pain, indicating that it is a potential target for the development of therapeutic approaches for the treatment of postoperative pain.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174439","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}