British Journal of Pharmacology最新文献

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How ‘miracle’ weight-loss semaglutide promises to change medicine but can we afford the expense? “奇迹”减肥西马鲁肽如何承诺改变药物,但我们能负担得起这笔费用吗?
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-13 DOI: 10.1111/bph.70003
Ralf Weiskirchen, Amedeo Lonardo
{"title":"How ‘miracle’ weight-loss semaglutide promises to change medicine but can we afford the expense?","authors":"Ralf Weiskirchen,&nbsp;Amedeo Lonardo","doi":"10.1111/bph.70003","DOIUrl":"10.1111/bph.70003","url":null,"abstract":"<p>Obesity is a complex and growing global concern, affecting one in eight individuals and compromising health, quality of life and life expectancy. It carries significant metabolic, cardiovascular, oncological, hepatorenal, skeletal and psychiatric risks, imposing substantial costs on health-care systems. Traditional treatments have often been ineffective or have led to relapse after lifestyle changes. Whereas bariatric surgery is effective, it also involves risks such as mortality and hospitalisation. Semaglutide, licensed in 2018, is a synthetic analogue of glucagon-like peptide 1 which regulates glucose metabolism and gastrointestinal (GI) motility. Studies show that semaglutide, administered either weekly and subcutaneously, or daily orally, induces an average weight loss of −11.62 kg compared to placebo and reduces waist circumference by up to −9.4 cm. It also improves blood pressure, fasting glucose levels, C-reactive protein levels and lipid profiles. The most common adverse events are mild-to-moderate GI complaints occurring more frequently with daily administration than weekly doses; hypoglycaemia is more common without lifestyle intervention. Weight regain often follows semaglutide withdrawal. Furthermore, semaglutide offers cardiovascular benefits for patients with established atherosclerotic cardiovascular disease (CVD), lowers the risk of kidney outcomes and cardiovascular-related death, resolves nonalcoholic steatohepatitis in many cases, and positively impacts mental health and quality of life. In conclusion, semaglutide therapy could significantly benefit many adults regarding CVD and mortality if made widely accessible. Ethical and financial considerations must be addressed for personalised obesity treatment approaches.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 8","pages":"1651-1670"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1G93A amyotrophic lateral sclerosis (ALS) mice 新型FKBP脯氨酸异构酶1A (FKBP12)配体促进SOD1G93A肌萎缩性侧索硬化症(ALS)小鼠功能改善。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-13 DOI: 10.1111/bph.17448
Laura Moreno-Martinez, Núria Gaja-Capdevila, Laura Mosqueira-Martín, Mireia Herrando-Grabulosa, Laura Rodriguez-Gomez, Klaudia Gonzalez-Imaz, Ana C. Calvo, Maialen Sagartzazu-Aizpurua, Leticia Moreno-García, Jose Manuel Fuentes, Abraham Acevedo-Arozena, Jesús María Aizpurua, José Ignacio Miranda, Adolfo López de Munain, Ainara Vallejo-Illarramendi, Xavier Navarro, Rosario Osta, Francisco Javier Gil-Bea
{"title":"Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1G93A amyotrophic lateral sclerosis (ALS) mice","authors":"Laura Moreno-Martinez,&nbsp;Núria Gaja-Capdevila,&nbsp;Laura Mosqueira-Martín,&nbsp;Mireia Herrando-Grabulosa,&nbsp;Laura Rodriguez-Gomez,&nbsp;Klaudia Gonzalez-Imaz,&nbsp;Ana C. Calvo,&nbsp;Maialen Sagartzazu-Aizpurua,&nbsp;Leticia Moreno-García,&nbsp;Jose Manuel Fuentes,&nbsp;Abraham Acevedo-Arozena,&nbsp;Jesús María Aizpurua,&nbsp;José Ignacio Miranda,&nbsp;Adolfo López de Munain,&nbsp;Ainara Vallejo-Illarramendi,&nbsp;Xavier Navarro,&nbsp;Rosario Osta,&nbsp;Francisco Javier Gil-Bea","doi":"10.1111/bph.17448","DOIUrl":"10.1111/bph.17448","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons, characterized by dysregulated Ca<sup>2+</sup> influx and buffering in early ALS-affected motor neurones. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular Ca<sup>2+</sup>, as a therapeutic target.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the superoxide dismutase 1 (SOD1)<sup>G93A</sup> mouse model of ALS. Different outcomes were used to assess treatment efficacy, including electrophysiology, histopathology, neuromuscular function and survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Among the novel FKBP12 ligands, MP-010 was chosen for its central nervous system availability and favourable <i>in vitro</i> pharmaco-toxicological profile. Chronic administration of MP-010 to SOD1<sup>G93A</sup> mice produced preservation of motor nerve conduction, with the 61-mg·kg<sup>−1</sup> dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates and significant preservation of motor neurones in the spinal cord of treated mice. Notably, MP-010 treatment significantly extended lifespan by an average of 10 days compared to vehicle.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>FKBP12 ligands, particularly MP-010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 11","pages":"2466-2486"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17448","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Oral hyoscine butylbromide exerts spasmolytic effects in both gastrointestinal and urogenital tissues in rats 口服丁基溴海莨菪碱对大鼠胃肠道和泌尿生殖组织均有解痉作用。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-13 DOI: 10.1111/bph.17474
Sara Traserra, Terence Appelqvist, Robert Lange, Maura Corsetti, Marcel Jimenez
{"title":"Oral hyoscine butylbromide exerts spasmolytic effects in both gastrointestinal and urogenital tissues in rats","authors":"Sara Traserra,&nbsp;Terence Appelqvist,&nbsp;Robert Lange,&nbsp;Maura Corsetti,&nbsp;Marcel Jimenez","doi":"10.1111/bph.17474","DOIUrl":"10.1111/bph.17474","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Hyoscine butylbromide (HBB) has a low oral (PO) bioavailability. Further, limited data on its activity on non-gastrointestinal (GI) smooth muscle spasms after oral dosing are available, causing its effects beyond the GI tract to be questioned. This pharmacokinetic/pharmacodynamic (PK/PD) study, conducted using female rats, aimed to cover this gap.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>PK study: HBB and atropine (as a comparator agent) were administered PO and IV to rats, and concentrations in plasma and tissues (colon, uterus and urinary bladder; CUB) were measured. PD study 1: concentration–response curves of HBB and atropine (10<sup>−9</sup>–10<sup>−4</sup> M) were obtained for carbachol-induced (10<sup>−5</sup> M) pre-contracted tissues; PD study 2: CUB were pre-incubated with HBB and atropine at maximum concentrations (<i>C</i><sub>max</sub>) from PK studies and carbachol concentration–response curves (10<sup>−9</sup>–10<sup>−4</sup> M) were obtained; PD study 3: HBB and atropine were administered PO and IV to rats as for PK study, CUB tissues were collected at 0.5 h (IV) and 4 h (PO), and carbachol concentration–response curves (10<sup>−9</sup>–10<sup>−4</sup> M) obtained.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>PO HBB showed higher <i>C</i><sub>max</sub> in CUB tissues than in plasma. HBB and atropine reduced, concentration-dependently, carbachol-induced contractions in CUB tissues. PO HBB showed highest spasmolytic activity in colon (40%), followed by uterus (30%) and urinary bladder (10%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>This is the first comparison of PO and IV HBB and atropine in GI and non-GI tissues. Despite low bioavailability, PO HBB accumulated and exerted spasmolytic effects in tissues beyond the GI tract.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 11","pages":"2487-2502"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17474","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Vincamine ameliorates hepatic fibrosis via inhibiting S100A4-mediated farnesoid X receptor activation: based on liver microenvironment and enterohepatic circulation dependence 长春花胺通过抑制s100a4介导的法内甾体X受体激活改善肝纤维化:基于肝脏微环境和肠肝循环依赖性。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-12 DOI: 10.1111/bph.17471
Yu-Chen Jiang, Jia Guo, Sai-Hu Liu, Xu Dai, Chen-Yu Wang, Li-Hua Lian, Zhen-Yu Cui, Ji-Xing Nan, Yan-Ling Wu
{"title":"Vincamine ameliorates hepatic fibrosis via inhibiting S100A4-mediated farnesoid X receptor activation: based on liver microenvironment and enterohepatic circulation dependence","authors":"Yu-Chen Jiang,&nbsp;Jia Guo,&nbsp;Sai-Hu Liu,&nbsp;Xu Dai,&nbsp;Chen-Yu Wang,&nbsp;Li-Hua Lian,&nbsp;Zhen-Yu Cui,&nbsp;Ji-Xing Nan,&nbsp;Yan-Ling Wu","doi":"10.1111/bph.17471","DOIUrl":"10.1111/bph.17471","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Vincamine has extensive biological and pharmaceutical activity. We examined the hepatoprotective effects and mechanisms by which vincamine suppresses hepatic fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Hepatic stellate cells (HSCs), TGF-<i>β</i> stimulated, were cultured with either vincamine, farnesoid X receptor (NR1H4; FXR) agonist or antagonist. Further, C57BL/6 mice were given thioacetamide (TAA) to induce hepatic fibrosis and subsequently treated with vincamine or curcumin.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Vincamine regulated the deposition of extracellular matrix (ECM), inflammatory factors and S100A4, and up-regulated FXR and TGR5 (GPBA receptor) in activated HSCs, by activating FXR. FXR deficiency blocked vincamine effect on FXR, TGR5, <i>α</i>-smooth muscle actin (<i>α</i>-SMA) and IL1R1 in activated LX-2 cells. Vincamine corrected ECM imbalance, inflammatory secretion and FXR/TGR5 down-regulation in activated LX-2 cells with stimulating medium from LPS-primed THP-1 cells. S100A4 deficiency increased FXR and TGR5, and decreased IL-1β expression in activated THP-1. Further, S100A4 deficiency in activated macrophages could elevate FXR and TGR5 expression in activated LX-2, strengthening the impact of vincamine on <i>α</i>-SMA and IL-1β expression. Further, vincamine reduced serum ALT/AST levels, liver and intestinal histopathological changes, and caused ECM accumulation and protected the intestinal barrier in thioacetamide-induced hepatic fibrosis mice. Vincamine decreased inflammatory factors e.g. caspase 1 and IL-1β, and inhibited the S100A4-mediated FXR-TGR5 pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Vincamine significantly reverses hepatic fibrosis via inhibiting S100A4 involved in the crosstalk between macrophages and HSCs, and by activating the FXR-TGR5 pathway. Targeting the S100A4-mediated FXR dependence on modulating the liver environment may be the key target of vincamine in inhibiting hepatic fibrosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 11","pages":"2447-2465"},"PeriodicalIF":6.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
An optimised Bcl-3 inhibitor for melanoma treatment 一种用于黑色素瘤治疗的优化Bcl-3抑制剂。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-12 DOI: 10.1111/bph.17467
Karunakar Saamarthy, Renée Daams, Wondossen Sime, Cecilia Persson, Eduard Chygorin, Kristofer Ahlqvist, Susan Evans-Axelsson, Daniel Strand, Ramin Massoumi
{"title":"An optimised Bcl-3 inhibitor for melanoma treatment","authors":"Karunakar Saamarthy,&nbsp;Renée Daams,&nbsp;Wondossen Sime,&nbsp;Cecilia Persson,&nbsp;Eduard Chygorin,&nbsp;Kristofer Ahlqvist,&nbsp;Susan Evans-Axelsson,&nbsp;Daniel Strand,&nbsp;Ramin Massoumi","doi":"10.1111/bph.17467","DOIUrl":"10.1111/bph.17467","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Malignant melanoma is the most lethal form of skin cancer, characterised by a poor survival rate. One of the key factors driving the aggressive growth of melanoma cells is the elevated expression of the proto-oncogene Bcl-3. This study aims to optimise, evaluate and characterise a second-generation Bcl-3 inhibitor, using melanoma as a model to demonstrate its potential therapeutic efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We synthesised and screened a series of structural analogues and selected A27, the most promising candidate for further investigation. We assessed whether A27 disrupted the interaction between Bcl-3 and its binding partner, p50, and examined the subsequent effects on cyclin D1 expression. Additionally, we evaluated the impact of A27 on melanoma cell proliferation and migration in vitro, as well as its therapeutic efficacy in various in vivo melanoma models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Nuclear magnetic resonance (NMR) confirmed that A27 directly binds to Bcl-3, effectively inhibiting its function. By disrupting the Bcl-3/p50 interaction, A27 led to a significant down-regulation of cyclin D1 expression. In cellular assays, A27 markedly reduced proliferation and migration of melanoma cells. In vivo, treatment with A27 resulted in a substantial reduction in melanoma tumour growth, with no observed toxicity in treated animals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>At present, no other Bcl-3 inhibitors exist for clinical application in the field of oncology, and as a result, our novel findings provide a unique opportunity to develop a highly specific drug against malignant melanoma to meet an urgent clinical need.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 11","pages":"2426-2446"},"PeriodicalIF":6.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17467","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting FDX1 by trilobatin to inhibit cuproptosis in doxorubicin-induced cardiotoxicity 利用三叶铂靶向 FDX1,抑制多柔比星诱导的心脏毒性中的杯突症。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-11 DOI: 10.1111/bph.17468
Jiajia Wei, Guozhen Lan, Wenfang Zhang, Wang Ran, Yu Wei, Xin Liu, Yuandong Zhang, Qihai Gong, Haibo Li, Jianmei Gao
{"title":"Targeting FDX1 by trilobatin to inhibit cuproptosis in doxorubicin-induced cardiotoxicity","authors":"Jiajia Wei,&nbsp;Guozhen Lan,&nbsp;Wenfang Zhang,&nbsp;Wang Ran,&nbsp;Yu Wei,&nbsp;Xin Liu,&nbsp;Yuandong Zhang,&nbsp;Qihai Gong,&nbsp;Haibo Li,&nbsp;Jianmei Gao","doi":"10.1111/bph.17468","DOIUrl":"10.1111/bph.17468","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Doxorubicin (DOX), an anthracycline chemotherapeutic agent, whose use is limited owing to its dose-dependent cardiotoxicity. Mitochondrial oxidative stress plays a crucial role in the pathogenesis of DOX-induced cardiotoxicity (DIC). Trilobatin (TLB), a naturally occurring food additive, exhibits strong antioxidant properties, but its cardioprotective effects in DIC is unclear. This study investigates the cardioprotective effect of TLB on DIC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>DOX was used to generate an <i>in vivo</i> and <i>in vitro</i> model of cardiotoxicity. Echocardiography, enzyme-linked immunosorbent assay (ELISA) and haematoxylin and eosin (H&amp;E) staining were used to evaluate the cardiac function in these models. To identify the targets of TLB, RNA-sequence analysis, molecular dynamics simulations, surface plasmon resonance binding assays and protein immunoblotting techniques were used. Transmission electron microscopy, along with dihydroethidium and Mito-SOX staining, was conducted to examine the impact of trilobatin on mitochondrial oxidative stress. SiRNA transfection was performed to confirm the role of ferredoxin 1 (FDX1) in DIC development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>In DIC mice, TLB improved cardiac function in a dose-dependent manner and inhibited myocardial fibrosis in DIC mice. TLB also attenuated DOX-induced mitochondrial dysfunction and reduced cardiac mitochondrial oxidative stress. TLB was found to directly bind to FDX1 and suppresses cuproptosis after DOX treatment, causing significant inhibition of cuproptosis-related proteins.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>This is the first study to show that TLB strongly inhibits DIC by reducing mitochondrial oxidative stress and controlling DOX-mediated cuproptosis by targeting FDX1. Therefore, TLB is as a potential phytochemical cardioprotective candidate for ameliorating DIC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 11","pages":"2409-2425"},"PeriodicalIF":6.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Involvement of the somatosensory-autonomic reflex and muscarinic receptors in exacerbation of allergic pulmonary inflammation by electroacupuncture 电针诱发过敏性肺部炎症加重的躯体感觉-自主神经反射和毒蕈碱受体的参与。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-09 DOI: 10.1111/bph.17415
Shuyan Liu, Jiayi Ge, Weili Liu, Zhidi Zhuang, Shenbin Liu
{"title":"Involvement of the somatosensory-autonomic reflex and muscarinic receptors in exacerbation of allergic pulmonary inflammation by electroacupuncture","authors":"Shuyan Liu,&nbsp;Jiayi Ge,&nbsp;Weili Liu,&nbsp;Zhidi Zhuang,&nbsp;Shenbin Liu","doi":"10.1111/bph.17415","DOIUrl":"10.1111/bph.17415","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Emerging evidence suggests that electroacupuncture (EA) could cause autonomic reflexes to modulate visceral functions. However, the efficacy and underlying mechanisms for somatic stimulation on allergic pulmonary inflammation (API) remain elusive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Mice were administered intranasal Papain to induce API. Distinct current (0,0.1, 0.2 and 0.5 mA) of EA at the back BL13, hindlimb ST36 and forelimb LU5 acupoint were then carried out. The control group underwent the same procedure but without current stimulation. Changes in API was assessed using immunohistochemistry, flow cytometry and haematoxylin and eosin (H&amp;E) staining. Pharmacological approaches were used to investigate the underlying mechanisms of EA effects on API.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>EA at the back region but not limb regions, in a current intensity-dependent manner, exacerbated API, primarily causing a decrease in the survival rate and intensified inflammation in the lung, including the infiltration of lung type 2 innate lymphoid cells and eosinophils, and lung pathology scores. Blocking local thoracic sensory nerves with lidocaine or lung-innervated autonomic nerves with hexamethonium eliminates the EA-produced detrimental effects. Chemical pulmonary sympathectomy with 6-OHDA further enhanced lung pathology scores, but inhibiting the activity of pulmonary muscarinic receptors was sufficient to prevent the exacerbation of API induced by EA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Our findings suggest that BL13 EA induces a somatic-autonomic reflex involving the pulmonary muscarinic receptors, thereby exacerbating API. The selective and intensity-dependency activation of body thoracic regions in driving pulmonary autonomic pathways could help optimise stimulation parameters, enhancing both efficacy and safety in modulating API.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 11","pages":"2374-2391"},"PeriodicalIF":6.8,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Identification of new small molecules for selective inhibition of SERCA 1 in patient-derived metastatic papillary thyroid cancer 在患者源性转移性甲状腺乳头状癌中选择性抑制serca1的新小分子的鉴定。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-09 DOI: 10.1111/bph.17442
Seok-Mo Kim, Keunwan Park, Hyeok Jun Yun, Jung Min Kim, Kyung Hwa Choi, Ki Cheong Park
{"title":"Identification of new small molecules for selective inhibition of SERCA 1 in patient-derived metastatic papillary thyroid cancer","authors":"Seok-Mo Kim,&nbsp;Keunwan Park,&nbsp;Hyeok Jun Yun,&nbsp;Jung Min Kim,&nbsp;Kyung Hwa Choi,&nbsp;Ki Cheong Park","doi":"10.1111/bph.17442","DOIUrl":"10.1111/bph.17442","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Papillary thyroid cancer (PTC) is a general thyroid cancer subtype; however, PTC is associated with metastasis or recurrence via anti-cancer drug resistance, rendering it practically incurable. Therefore, effective and reliable clinical approaches are urgently required.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We demonstrated the coordinated up-regulation of sarco/endoplasmic reticulum (ER) calcium ATPase 1 (SERCA1) in metastatic PTC under treatment with sorafenib or lenvatinib. We screened novel drug candidates in a patient-derived lymph node metastatic PTC and compared outcomes with those in non-metastatic and main mass PTC in an in vitro and in vivo model to propose a new clinical strategy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>In the current study using patient-derived metastatic PTC cells, SERCA1 was considerably increased under sorafenib- or lenvatinib-treated conditions. SERCA is a critical component in cytosolic free calcium regulation and is regulated by calcium/calmodulin-dependent protein kinase 2 alpha (CaMK2α) via NFκB. However, cardiac dysfunction was inevitable in vivo because of non-specific inhibition of SERCA isoforms by conventional SERCA inhibitors. This study designed a therapeutic approach with decreased cardiac dysfunction via SERCA1 isoform–specific inhibition by novel small molecules, CKP1 and CKP2, under severe ER stress conditions in patient-derived metastatic PTC. These novel SERCA1-specific inhibitors remarkably increased tumour shrinkage in the patient-derived metastatic PTC xenograft tumour model without cardiac dysfunction when used in combination with sorafenib or lenvatinib.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>These outcomes suggest the potential efficacy of the novel combination strategy that uses targeted therapy to treat malignant cancer cells, such as sorafenib- or lenvatinib-resistant cancer cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 11","pages":"2392-2408"},"PeriodicalIF":6.8,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17442","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
System level network data and models attack cancer drug resistance. 系统级网络数据和模型攻击癌症耐药性。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-05 DOI: 10.1111/bph.17469
Márk Kerestély, Dávid Keresztes, Levente Szarka, Borbála M Kovács, Klára Schulc, Dániel V Veres, Peter Csermely
{"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}
引用次数: 0
Silencing drug transporters in human primary muscle cells modulates atorvastatin pharmacokinetics: A pilot study 沉默人原代肌细胞中的药物转运蛋白可调节阿托伐他汀的药代动力学:一项初步研究。
IF 6.8 2区 医学
British Journal of Pharmacology Pub Date : 2025-02-05 DOI: 10.1111/bph.17449
Emilia Hoste, Louise Deldicque, Giulio G. Muccioli, Nadtha Panin, Romano Terrasi, Adrien Paquot, Maxime Lingurski, Sébastien Pyr dit Ruys, Vincent Haufroid, Laure Elens
{"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}
引用次数: 0
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