British Journal of Pharmacology最新文献

{"title":"System level network data and models attack cancer drug resistance.","authors":"Márk Kerestély, Dávid Keresztes, Levente Szarka, Borbála M Kovács, Klára Schulc, Dániel V Veres, Peter Csermely","doi":"10.1111/bph.17469","DOIUrl":"https://doi.org/10.1111/bph.17469","url":null,"abstract":"<p><p>Drug resistance is responsible for >90% of cancer related deaths. Cancer drug resistance is a system level network phenomenon covering the entire cell. Small-scale interactomes and signalling network models of drug resistance guide directed drug development. Recently, proteome-wide human interactome and signalling network data have become available, which have been extended by drug-target interactions, drug resistance-inducing mutations, as well as by several cancer and drug resistance-related multi-omics datasets. System level signalling network models have become available examining therapy resistance, performing in silico clinical trials, and conducting large, in silico drug combination screens. Drug resistance network data and models have become interoperable and reliable. These advances paved the road for building proteome-wide drug resistance models.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254924","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":"Silencing drug transporters in human primary muscle cells modulates atorvastatin pharmacokinetics: A pilot study","authors":"Emilia Hoste,&nbsp;Louise Deldicque,&nbsp;Giulio G. Muccioli,&nbsp;Nadtha Panin,&nbsp;Romano Terrasi,&nbsp;Adrien Paquot,&nbsp;Maxime Lingurski,&nbsp;Sébastien Pyr dit Ruys,&nbsp;Vincent Haufroid,&nbsp;Laure Elens","doi":"10.1111/bph.17449","DOIUrl":"10.1111/bph.17449","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Non-adherence to atorvastatin treatment is relatively common and partly due to statin-related myotoxicities (SRMs). The risk of developing SRM is dose- and concentration-dependent, highlighting the importance of atorvastatin pharmacokinetics. This study explored the inter-individual variabilities in expression of the atorvastatin transporter gene contributing to modulation of atorvastatin within the muscle cell.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>mRNA levels of efflux and influx transporters were measured and modulated with siRNAs to evaluate effects on intracellular accumulation of atorvastatin in primary cultures of differentiated myotubes from 12 human volunteers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>All genes assessed were expressed with a high inter-individual variability. In differentiated myotubes, efflux transporters were expressed at higher levels than the influx carriers. When considering efflux and influx transporters separately, <i>ABCC1</i> and <i>SLCO2B1</i> are the most highly expressed efflux and influx transporters. Suppression of <i>ABCC1</i>, <i>ABCC4</i> and/or <i>ABCG2</i> mRNA levels with siRNA significantly increased intracellular accumulation of atorvastatin in differentiated myotubes. Interestingly, the siRNA targeting <i>ABCG2</i> had a moderate effect on intracellular accumulation of atorvastatin in a volunteer expressing the <i>ABCG2</i> variant rs2231142 (c.421C&gt;A, p.Gln141Lys). This hypothesis was further validated in a HEK recombinant model overexpressing ABCG2 either wild-type (421C) or variant (421A). Reduction of <i>SLCO1B1</i> and <i>SLCO2B1</i> mRNA levels significantly modified intracellular accumulation of atorvastatin in only some volunteers, depending on the expression levels of transporters.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Silencing <i>ABCC1</i>, <i>ABCC4</i> or <i>ABCG2</i> expression alters accumulation of atorvastatin in myotubes, whereas the effect of silencing influx transporters depends on the expression of these transporters.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 9","pages":"2049-2066"},"PeriodicalIF":6.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254922","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":"Advances in Bruton tyrosine kinase (Btk) inhibition are steered by Bruton tyrosine kinase phylogeny","authors":"Giorgio Minotti,&nbsp;Massimiliano Camilli,&nbsp;Emanuela Salvatorelli,&nbsp;Pierantonio Menna","doi":"10.1111/bph.17466","DOIUrl":"10.1111/bph.17466","url":null,"abstract":"<p>Bruton tyrosine kinase (Btk) has long been known to play a key role in chronic lymphatic leukaemia, Waldenström macroglobulinaemia and other B-cell proliferative disorders. An impressive programme of drug discovery and clinical development led to the approval of covalent and non-covalent Btk inhibitors that became pillars of treatment of such malignancies. However, both a risk of cardiovascular events and the emergence of an elusive mutational landscape seem to complicate the clinical use of each Btk inhibitor. In this plain language mini-review, we show that the search for better Btk inhibitors is challenged by the ancestral origin of Btk, its homology with innocent kinases in cardiovascular system and unique phylogenetic-like modalities with which Btk can mutate upon exposure to one inhibitor or another. Whereas basic and clinical pharmacology is already at work to explore new avenues of Btk inhibition, phylogeny remains behind the curtain to steer achievements and failures in this field.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1446-1451"},"PeriodicalIF":6.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17466","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188369","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":"Smooth muscle cell Piezo1 is essential for phenotypic switch and neointimal hyperplasia","authors":"Fei-Ran Zhang,&nbsp;Jie Tang,&nbsp;Ying Lai,&nbsp;Shi-Qi Mo,&nbsp;Zhuo-Miao Lin,&nbsp;Qing-Qing Lei,&nbsp;Cong-Cong Han,&nbsp;An-Dong Zhou,&nbsp;Xiao-Fei Lv,&nbsp;Cheng Wang,&nbsp;Jing-Song Ou,&nbsp;Jia-Guo Zhou,&nbsp;Rui-Ping Pang","doi":"10.1111/bph.17436","DOIUrl":"10.1111/bph.17436","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Disturbed blood flow is a critical factor in activation of vascular smooth muscle cells (VSMCs) and initiation of neointimal hyperplasia. The Piezo1 channel is a recent yet well-characterised mechanosensor that plays a vital role in vascular development and homeostasis. However, the role of VSMC Piezo1 in neointima development remains largely unknown. The purpose of this study is to investigate the functional role of Piezo1 channel in neointimal hyperplasia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We measured the expression of Piezo1 in VSMC-rich neointima from human coronary artery samples and two mouse neointimal hyperplasia models which were induced by cast implantation or guidewire injury. We utilised VSMC-specific Piezo1 knockout mice to explore its function and the underlying mechanism of neointimal hyperplasia, both in vivo and in vitro.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>In human and mouse neointima samples, we observed a significant up-regulation of Piezo1 expression in the VSMC-rich neointima compared to the medial layer. VSMC-specific knockout of Piezo1 significantly reduced neointimal hyperplasia in both animal models. Activation of Piezo1 facilitates, whereas Piezo1 deficiency inhibits disturbed flow-induced cell proliferation, migration and synthetic phenotype switch. Mechanistic studies suggest that Piezo1 activates YAP and TAZ through Ca²⁺ and its downstream effectors calmodulin kinase II and calcineurin, which in turn drive VSMC proliferation and migration, thereby facilitating neointimal hyperplasia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>These findings demonstrate a critical role of mechanosensitive Piezo1 channel in neointimal hyperplasia via modulating VSMC phenotype. Piezo1 channels may represent a novel therapeutic target for maladaptive vascular remodelling and occlusive vascular diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 9","pages":"2031-2048"},"PeriodicalIF":6.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122169","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":"Characterisation of neurogenic lipolytic responses in white adipose tissue ex vivo","authors":"Kayleigh E. Goddard,&nbsp;Samuel J. Fountain","doi":"10.1111/bph.17445","DOIUrl":"10.1111/bph.17445","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Dysfunction of the autonomic nervous system is associated with cardiovascular dysfunction, including metabolic syndrome and obesity. Understanding mechanisms of neurogenic control of white adipose tissue is key to understanding adipose physiology and pathophysiology, though there is limited research exploring this in adipose tissue using pharmacological tools, as opposed to genetic knockout models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Inguinal white adipose tissue from C57BL/6J mice was used in this study. We used immunocytochemistry to determine tissue innervation and glycerol release assays to quantify lipolysis in adipose tissue and isolated adipocytes. The voltage-gated Na⁺ channel opener veratridine was used to stimulate nervous activity in tissue ex vivo. The role of neurotransmitters and receptors mediating veratridine-evoked lipolysis in adipose tissue was pharmacologically characterised.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Veratridine evoked glycerol release in white adipose tissue but not from isolated adipocytes. This release was abolished by tetrodotoxin and propranolol. Veratridine also induced noradrenaline release from white adipose tissue. Veratridine- and noradrenaline-evoked glycerol release was blocked by the β₂-adrenoceptor antagonist ICI-118551 but not by the β₁-adrenoceptor antagonist CGP 20712A. Purported β₃-adrenoceptor antagonists L-748337 and SR59230A stimulated glycerol release from tissue and from isolated adipocytes. Neither L-748337 or SR59230A antagonised veratridine-evoked glycerol release but SR59230A antagonised noradrenaline-evoked glycerol release. We exclude contributions of sensory neuropeptides and the autonomic neurotransmitters neuropeptide Y and ATP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Neurogenic lipolytic responses can be measured in white adipose tissue ex vivo using veratridine to stimulate nerve activity. The lipolytic responses are mediated by β₂-adrenoceptor activation. This study provides the first evidence of neurogenic lipolysis in tissue ex vivo.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 9","pages":"1975-1988"},"PeriodicalIF":6.8,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17445","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078630","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":"Sex differences in the effects of maternal voluntary oral Cannabis consumption on the metabolic outcomes of high-fat diet in adult offspring.","authors":"Nada A Sallam, Colleen S Peterson, Samaa S Kamar, Camila Saenz, Frank Visser, Stephanie L Borgland","doi":"10.1111/bph.17447","DOIUrl":"10.1111/bph.17447","url":null,"abstract":"<p><strong>Background and purpose: </strong>Given the recent rise in Cannabis legalisation, accessibility to Cannabis and consumption have increased during pregnancy. Therefore, there could be unintended developmental consequences. The endocannabinoid system plays a key role in fetal development and later-life energy homeostasis. We explored the long-term effects of maternal voluntary Cannabis consumption on the metabolic outcomes of a high-fat diet (HFD) in adult offspring.</p><p><strong>Experimental approach: </strong>Pregnant mice voluntarily consumed Cannabis extract equivalent to 5 mg kg^-1 day^-1 Δ9-tetrahydrocannabinol (THC) from gestational day 1.5 until postnatal day (PD) 10. Pregnancy and pup outcomes and active maternal behaviour were recorded. Male and female offspring (PD49) were placed on a 12-week HFD or control diet; their weight gain, adiposity, glucose tolerance, insulin sensitivity, circulating hormones and pancreatic structure were measured.</p><p><strong>Key results: </strong>Perinatal Cannabis exposure (PCE) pup weight was initially reduced but restored by PD16. PCE did not influence weight gain or metabolic characteristics of male mice on a HFD. PCE female but not male offspring on a HFD had reduced accumulation of adipose tissue and lower insulin, leptin and resistin independent of body weight. PCE females on control diet also showed altered basal insulin sensitivity likely because of increased glucagon levels in parallel with reduced islets of Langerhans size and enhanced gene expression of cannabinoid 2 receptors in white adipose tissue.</p><p><strong>Conclusion and implications: </strong>PCE adversely affected glycaemic control in female offspring on control diet while it mitigated HFD-induced metabolic dysfunction. This raises concerns about the long-term effects of PCE on the metabolic health of offspring.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078570","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":"Fatty acid binding protein 3 activates endothelial adhesion of circulating monocytes and impairs endothelial angiogenesis","authors":"Yen-Wen Wu,&nbsp;Jaw-Wen Chen,&nbsp;Hao-Yuan Tsai,&nbsp;Hsin-Bang Leu,&nbsp;Chia-Chi Chang,&nbsp;Ting-Ting Chang","doi":"10.1111/bph.17451","DOIUrl":"10.1111/bph.17451","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Vascular inflammation and endothelial dysfunction cause the development of atherosclerotic cardiovascular diseases including coronary artery disease (CAD). While elevated fatty acid binding protein 3 (FABP3) may be associated with the presence of cardiovascular diseases, its mechanistic effects remain unclear. This study aimed to investigate the role of FABP3 in impaired angiogenesis and the development of atherosclerosis in CAD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>In total, 1104 patients were enrolled in a clinical observational study and the correlation between serum FABP3 and cardiovascular events were analysed. Another group of CAD patients and non-CAD subjects were enrolled, and their plasma FABP3 concentrations were measured. Primary cultured mononuclear cells endothelial progenitor cells and human coronary artery endothelial cells were used <i>in vitro</i>. Matrigel plug neovascularisation assay and the aortic ring assay were used in wild-type and apolipoprotein E-knockout mice <i>in vivo</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Circulating FABP3 was up-regulated in the cardiovascular event-positive group and in the CAD patients. Mononuclear cells from the CAD patients presented increased expression of FABP3. FABP3 enhanced the expression of adhesion molecules, including integrin β2, integrin α4 and PSGL1 in mononuclear cells. FABP3 caused endothelial cell dysfunction through the ERK/p38/STAT1/VEGF signalling pathway. Moreover, oxLDL or TNF-α stimulations impaired endothelial cell function through FABP3-dependent signalling pathways. FABP3 also impaired <i>in vivo</i> angiogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>This study elucidates the clinical and pathological impact of FABP3 on atherosclerotic CAD. Future research may be necessary to evaluate whether FABP3 could be a therapeutic target, especially with regard to stable CAD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 9","pages":"1989-2013"},"PeriodicalIF":6.8,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078634","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":"Involvement of Piezo 1 in inhibition of shear-induced platelet activation and arterial thrombosis by ginsenoside Rb1","authors":"Yilin Wang,&nbsp;Lu Liu,&nbsp;Jia Li,&nbsp;Yue You,&nbsp;Shunli Xiao,&nbsp;Jiantao Feng,&nbsp;Xiaojie Yin,&nbsp;Fulong Liao,&nbsp;Yun You","doi":"10.1111/bph.17434","DOIUrl":"10.1111/bph.17434","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Shear-induced platelet activation and aggregation (SIPA) play crucial roles in arterial thrombosis. Piezo1 is a mechanosensitive calcium channel that promotes platelet hyperactivation under pathological high-shear conditions. This study explores the function of platelet Piezo1 in SIPA and arterial thrombosis, and the inhibitory effects and mechanisms of ginsenoside Rb1 on these processes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Transgenic mice with platelet-specific Piezo1 deficiency (Piezo1^<i>ΔPlt</i>) were used to elucidate the role of platelet Piezo1 in SIPA and arterial thrombosis. A microfluidic channel system was employed to assess platelet aggregation, calcium influx, calpain activity, talin cleavage, integrin αIIbβ3 activation and P-selectin expression under shear flow. Cellular thermal shift assay was used to determine binding between Rb1 and Piezo1. Folts-like model in mice was used to evaluate antithrombotic effects of Rb1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Piezo1 deficiency in platelets reduced platelet activation and aggregation induced by a high shear rate of 4000 s⁻¹ and attenuated arterial thrombosis induced by Folts-like mouse model. Rb1 inhibited SIPA with an IC₅₀ of 10.8 μM. Rb1 inhibited shear-induced Ca²⁺-dependent platelet activation and aggregation, as well as thrombus formation in Folts-like model in Piezo1^<i>fl/fl</i> mice. Rb1 significantly improved thermal stability of Piezo1 in platelets by binding to Piezo1. Treatment of Piezo1^<i>ΔPlt</i> mice with Rb1 did not exhibit further inhibitory effects on SIPA and thrombosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Platelet Piezo1 is essential for SIPA and arterial thrombosis induced by high shear. Rb1 exerted anti-platelet and anti-thrombotic effects at high shear rates via Piezo1 channels, providing a potential candidate as antiplatelet therapeutic agent.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 9","pages":"1957-1974"},"PeriodicalIF":6.8,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17434","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078568","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":"Assessment of Spinster homologue 2 (Spns2)-dependent transport of sphingosine-1-phosphate as a therapeutic target","authors":"Yugesh Kharel,&nbsp;Tao Huang,&nbsp;Kyle Dunnavant,&nbsp;Daniel Foster,&nbsp;George M. P. R. Souza,&nbsp;Katherine E. Nimchuk,&nbsp;Andrea R. Merchak,&nbsp;Caitlin M. Pavelec,&nbsp;Zuzanna J. Juskiewicz,&nbsp;Simon S. Alexander,&nbsp;Alban Gaultier,&nbsp;Stephen B. G. Abbott,&nbsp;Jung-Bum Shin,&nbsp;Brant E. Isakson,&nbsp;Wehao Xu,&nbsp;Norbert Leitinger,&nbsp;Webster L. Santos,&nbsp;Kevin R. Lynch","doi":"10.1111/bph.17456","DOIUrl":"10.1111/bph.17456","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Sphingosine-1-phosphate (S1P) receptor modulator (SRM) drugs suppress immune system function by disrupting lymphocyte trafficking, but SRMs are broadly immunosuppressive with on-target liabilities. Another strategy to modulate the immune system is to block S1P transport. This study tests the hypothesis that blockers of S1P transport (STBs) mediated by Spinster homologue 2 (Spns2) approximate the efficacy of SRMs without their adverse events.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We have discovered and optimized STBs to enable investigations of S1P biology and to determine whether S1P transport is a valid drug target. The STB SLF80821178 was administered to rodents to assess its efficacy in a multiple sclerosis model and to test for toxicities associated with SRMs or Spns2-deficient mice. Further, potential biomarkers of STBs, absolute lymphocyte counts (ALCs) in blood and S1P concentrations in plasma and lymph, were measured.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>SLF80821178 resembles SRMs in that it is efficacious in a standard multiple sclerosis model but does not evoke bradycardia or lung leakage, common to the SRM drug class. Also, chronic SLF80821178 administration does not affect auditory responses in adult mice despite the neurosensorial hearing defect observed in Spns2-null mice. While both SRM and STB administration decrease ALCs, the maximal effect is less with an STB (45% vs. 90%). STBs have minimal effects on S1P concentration in plasma or thoracic duct lymph.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>We found nothing to invalidate Spns2-dependent S1P transport as a drug target. Indeed, STBs could be superior to SRMs as a therapy to modulate immune system function.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 9","pages":"2014-2030"},"PeriodicalIF":6.8,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17456","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078546","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":"MC16 promotes mitochondrial biogenesis and ameliorates acute and diabetic nephropathy","authors":"Austin D. Thompson,&nbsp;Kevin A. Hurtado,&nbsp;Jaroslav Janda,&nbsp;Natalie E. Scholpa,&nbsp;Baerbel Rohrer,&nbsp;Rick G. Schnellmann","doi":"10.1111/bph.17440","DOIUrl":"10.1111/bph.17440","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Kidney disease (KD) is a leading cause of mortality worldwide, affecting 〉10% of the global population. Two of the most common causes of KD are diabetes and acute kidney injury (AKI), both of which induce mitochondrial dysfunction resulting in renal proximal tubular damage/necrosis. Thus, pharmacological induction of mitochondrial biogenesis (MB) may provide a therapeutic strategy to block the onset/progression of KD. Here, we evaluated the pharmacological and potential therapeutic effects of a novel MB-inducing oxindole agent, <b>MC16</b>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Primary cultures of rabbit renal proximal tubule cells (RPTCs) were used to evaluate the cellular signalling and MB-inducing effects of <b>MC16</b>. Mice were used to determine the MB-inducing effects of <b>MC16</b> in vivo, and the metabolic effects of <b>MC16</b> on the renal cortical metabolome. Mouse models of AKI and diabetic kidney disease (DKD) were used to demonstrate the therapeutic potential of <b>MC16</b> to ameliorate acute and diabetic nephropathy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p><b>MC16</b> activated the PI3K-AKT-eNOS-FOXO1 axis and induced MB in RPTCs. <b>MC16</b> induced MB and altered the renal cortical metabolome of mice. <b>MC16</b> accelerated renal recovery, reduced vascular permeability, and diminished mitochondrial dysfunction following AKI. <b>MC16</b> decreased diabetes-induced renal swelling, improved renal and mitochondrial function, and diminished interstitial fibrosis in DKD mouse models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p><b>MC16</b> is a novel compound that induces MB and ameliorates acute and diabetic nephropathy in mice. This study underscores that targeting MB following the onset of renal/metabolic insults may provide a therapeutic strategy to mitigate the onset and/or progression of KD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 9","pages":"1912-1929"},"PeriodicalIF":6.8,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063916","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}