Pulmonary pharmacology & therapeutics最新文献_第3页

A novel macrolide, EP395, with reduced antibacterial activity and an enhancing effect on respiratory epithelial barrier 一种新型大环内酯EP395，具有降低抗菌活性和增强呼吸道上皮屏障的作用

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-06-03 DOI: 10.1016/j.pupt.2025.102363

Thorarinn Gudjonsson , Jon Petur Joelsson , Ari Jon Arason , Arni Asbjarnarson , Fridrik Runar Gardarsson , Fredrik Lehmann , Peter Teodorovic , Saevar Ingthorsson , Snaevar Sigurdsson , Bryndis Valdimarsdottir , Michael John Parnham , Clive Page , Jennifer Ann Kricker

Epithelial barrier failure, a feature of several inflammatory lung diseases, contributes to exacerbations and disease progression. Acute exacerbations are often treated with macrolides, including azithromycin (AZM). In part, this is due to both primary antimicrobial and additional immunomodulatory actions, complemented by recently reported enhanced integrity of respiratory epithelial barriers. However, long-term “off label” use of macrolides is associated with increased bacterial resistance. We now introduce a new class of compounds, “Barriolides” that are analogues of AZM promoting airway epithelial barrier integrity in vitro, with negligible antibacterial activity. The lead compound is EP395 which does not affect cell viability up to 100 μM in VA10 bronchial epithelial cells. Treatment with EP395 for three weeks enhanced epithelial barrier integrity, measured by increased transepithelial electrical resistance, reduced paracellular flux in air-liquid interface culture and increased expression of tight junction proteins. EP395 also induced epidermal differentiation and formation of lamellar bodies, complemented by a relevant genetic footprint. In mice exposed to sulphur dioxide, pre-treatment with EP395 reduced extravasation of human serum albumin into the bronchoalveolar lavage fluid. These data demonstrate epithelial barrier-protecting effects of EP395, a promising candidate for treatment of chronic respiratory diseases without risk of bacterial resistance.

上皮屏障功能障碍是几种炎症性肺病的一个特征，可导致病情恶化和疾病进展。急性加重通常用大环内酯类药物治疗，包括阿奇霉素（AZM）。在某种程度上，这是由于主要的抗菌和额外的免疫调节作用，以及最近报道的呼吸上皮屏障完整性增强的补充。然而，长期“标签外”使用大环内酯类药物与细菌耐药性增加有关。我们现在介绍了一类新的化合物，“Barriolides”，它是AZM的类似物，在体外促进气道上皮屏障的完整性，抗菌活性可以忽略不计。先导化合物EP395在100 μM范围内对VA10支气管上皮细胞的活性无影响。用EP395治疗三周后，上皮屏障的完整性增强，测量方法是增加上皮间电阻，减少气液界面培养中的细胞旁通量，增加紧密连接蛋白的表达。EP395还能诱导表皮分化和板层体的形成，并伴有相关的遗传足迹。在暴露于二氧化硫的小鼠中，EP395预处理减少了人血清白蛋白向支气管肺泡灌洗液的外渗。这些数据证明EP395具有上皮屏障保护作用，EP395是治疗慢性呼吸道疾病的有希望的候选药物，没有细菌耐药性的风险。

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引用次数: 0

A disproportionality analysis of diabetes mellitus in patients treated with biologics for asthma and related conditions using FAERS data 使用FAERS数据对使用生物制剂治疗哮喘及相关疾病的患者中糖尿病的歧化分析

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-07-02 DOI: 10.1016/j.pupt.2025.102377

Maria Gabriella Matera , Luigino Calzetta , Alfredo De Biase , Davide Lauro , Paola Rogliani , Mario Cazzola

Background

Biologics for asthma and related conditions target distinct immunologic pathways but may have differential effects on glucose metabolism. Emerging real-world evidence suggests a need to evaluate potential associations with diabetes mellitus (DM) and related metabolic adverse events (AEs).

Objective

To assess the disproportionality of DM and other metabolic AEs associated with six biologics approved for asthma and related conditions using data from the FDA Adverse Event Reporting System (FAERS).

Methods

Reported odds ratios (RORs) were calculated for metabolic events and DM for omalizumab, mepolizumab, benralizumab, reslizumab, dupilumab, and tezepelumab, comparing drug-specific AE profiles against the FAERS background.

Results

Omalizumab (ROR: 6.10) and benralizumab (ROR: 4.88) exhibited significant disproportionality regarding diabetes AEs, with mepolizumab also demonstrating an elevated ROR (2.80). For metabolic AEs, mepolizumab (ROR: 3.57) and omalizumab (ROR: 2.94) had the highest signals. Dupilumab showed the lowest RORs for both diabetes (0.10) and metabolic AEs (0.21).

Conclusion

This FAERS-based analysis identified a potential pharmacovigilance signal for DM associated with several biologics used to treat asthma and related conditions, most notably omalizumab and benralizumab. Similar patterns were observed for metabolic AEs, which reinforces the need for post-marketing studies and clinical awareness in patients with or at risk for metabolic disorders.

治疗哮喘和相关疾病的生物制剂针对不同的免疫途径，但可能对葡萄糖代谢有不同的影响。越来越多的现实证据表明，有必要评估其与糖尿病（DM）和相关代谢不良事件（ae）的潜在关联。目的利用FDA不良事件报告系统（FAERS）的数据，评估6种批准用于哮喘及相关疾病的生物制剂相关的糖尿病和其他代谢不良事件的不成比例。方法计算omalizumab， mepolizumab, benralizumab, reslizumab， dupilumab和tezepelumab的代谢事件和DM的报告优势比（RORs），将药物特异性AE与FAERS背景进行比较。结果somalizumab （ROR: 6.10）和benralizumab （ROR: 4.88）在糖尿病ae方面表现出显著的歧化，mepolizumab也显示出升高的ROR（2.80）。对于代谢性不良反应，美泊珠单抗（ROR: 3.57）和奥玛珠单抗（ROR: 2.94）的信号最高。Dupilumab在糖尿病（0.10）和代谢ae（0.21）方面均显示最低的RORs。结论：基于faers的分析确定了几种用于治疗哮喘和相关疾病的生物制剂与糖尿病相关的潜在药物警戒信号，最明显的是omalizumab和benralizumab。在代谢性不良反应中也观察到类似的模式，这加强了对代谢性疾病患者或有代谢性疾病风险的患者进行上市后研究和临床意识的必要性。

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引用次数: 0

Exploring the role of β2- and β3-adrenergic receptors in cystic fibrosis 探讨β2-和β3肾上腺素能受体在囊性纤维化中的作用

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-08-18 DOI: 10.1016/j.pupt.2025.102385

Alessandro Cannavo , Marika Comegna , Alice Castaldo , Caterina Vinciguerra , Anna Lauritano , Giulia Renata Franco , Giovanna Casoria , Graziamaria Corbi , Giuseppe Rengo , Giuseppe Castaldo

Cystic fibrosis (CF) is an autosomal recessive disorder that affects multiple organs, with clinical manifestations, disease progression, and response to therapy varying among individuals. This effect is mainly caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel.

In recent decades, other genes and their allelic variants, beyond CFTR mutations, have been proposed as genetic modifiers of CF phenotype. For instance, different polymorphic β2-adrenergic receptor (β2AR) polymorphic variants have been reported in CF individuals and appear to influence correct receptor function. β2AR belongs to the βAR family, which includes three subtypes: β1AR, β2AR, and β3AR. These receptors are crucial G protein-coupled receptors (GPCRs) expressed in various cell types and serve as key modulators of cAMP production, making their function particularly relevant in CF pathophysiology. β2AR is abundantly expressed in airway epithelial and smooth muscle cells, and studies revealed that it plays a crucial role in modulating CFTR activity and smooth muscle contractility through cAMP signaling. For these reasons, β2-agonists are widely used in clinical healthcare to treat patients with obstructive airway disorders, including CF.

Emerging evidence has also supported a role for β3AR, which is expressed in the canine and human bronchial epithelium and have been reported to enhance ciliary motility and regulate CFTR function, making it a potential therapeutic target in CF.

囊性纤维化（CF）是一种常染色体隐性遗传病，可影响多个器官，其临床表现、疾病进展和对治疗的反应因人而异。这种影响主要是由编码CF跨膜电导调节器（CFTR）的基因突变引起的，CFTR是camp调节的氯离子通道。近几十年来，除了CFTR突变外，其他基因及其等位变异也被认为是CF表型的遗传修饰因子。例如，在CF个体中已经报道了不同的多态β2-肾上腺素能受体（β2AR）多态变异，并且似乎影响了正确的受体功能。β2AR属于βAR家族，包括β1AR、β2AR和β3AR三个亚型。这些受体是关键的G蛋白偶联受体（gpcr），在各种细胞类型中表达，并作为cAMP产生的关键调节剂，使其功能与CF病理生理特别相关。β2AR在气道上皮细胞和平滑肌细胞中大量表达，研究发现它通过cAMP信号通路在调节CFTR活性和平滑肌收缩力中起着至关重要的作用。由于这些原因，β2激动剂被广泛应用于临床医疗保健，用于治疗包括CF在内的阻塞性气道疾病。新的证据也支持β3AR的作用，β3AR在犬和人的支气管上皮中表达，据报道可增强纤毛运动性并调节CFTR功能，使其成为CF的潜在治疗靶点。

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引用次数: 0

PM2.5 augments cigarette smoke-induced lung inflammation in mice by driving a stronger immune response: Potential beneficial effects of oleanolic acid PM2.5通过驱动更强的免疫反应来增强香烟引起的小鼠肺部炎症：齐墩果酸的潜在有益作用。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-07-16 DOI: 10.1016/j.pupt.2025.102379

Jitender Chandel, Amarjit S. Naura

Though cigarette smoke (CS) is primary risk factor for Chronic obstructive pulmonary disease (COPD), rising air pollution and higher concentrations of particulate matter (PM_2.5) in ambient air contribute substantially to COPD cases, particularly in smokers. However, the pathogenesis of COPD upon dual exposure to CS and PM_2.5 is not entirely known. Therefore, the impact of combined exposure to CS (9 cigarettes/day for 4 days) and PM_2.5 (single dose of 50 μg) on COPD pathogenesis was examined using mouse model in order to understand the key players behind the process. The data suggest that single exposure to PM_2.5 in CS pre-exposed mice triggered a strong inflammatory response, marked by switch from macrophage to neutrophilic inflammation, leading to severe deterioration in lung function compared to single hits. Furthermore, combined exposure led to robust increase in the levels of pro-inflammatory cytokines (G-CSF/KC/MCP-1/TNF-α/IL-1β/IL-6) in BALF as compared to the respective individual exposure. Interestingly, Oleanolic acid (OA) treatment protects against CS + PM_2.5-induced COPD-like pulmonary inflammation potentially by exerting antioxidant properties as reflected by data on BALF inflammatory cells, particularly neutrophils and various oxidative stress markers such as ROS/LPO/GSH/SOD/Catalase in lung tissue. Suppressed inflammation was associated with downregulation of gene expression of pro-inflammatory factors namely IL-1β, TNF-α, MIP-2 and normalization of proteinase-antiproteinase balance by downregulating gene expression of MMP-9 with simultaneous upregulation of its inhibitor TIMP-1. Reduced inflammatory response upon OA treatment correlates well with improved lung function. Overall, PM_2.5 exposure flares up the CS-induced lung inflammation linked to COPD, which is effectively ameliorated by OA.

虽然吸烟（CS）是慢性阻塞性肺病的主要危险因素，但空气污染加剧和环境空气中颗粒物（PM2.5）浓度升高在很大程度上导致了慢性阻塞性肺病病例，特别是对吸烟者而言。然而，双重暴露于CS和PM2.5的COPD发病机制尚不完全清楚。因此，我们通过小鼠模型研究了CS（9支/天，持续4天）和PM2.5（单剂量50μg）联合暴露对COPD发病机制的影响，以了解这一过程背后的关键因素。数据表明，CS预暴露小鼠的PM2.5单次暴露引发了强烈的炎症反应，其特征是从巨噬细胞炎症转变为中性粒细胞炎症，与单次暴露相比，导致肺功能严重恶化。此外，与单独暴露相比，联合暴露导致BALF中促炎细胞因子（G-CSF/KC/MCP-1/TNF-α/IL-1β/IL-6）水平的显著增加。有趣的是，正如肺组织中BALF炎症细胞，特别是中性粒细胞和各种氧化应激标志物（如ROS/LPO/GSH/SOD/过氧化氢酶）的数据所反映的那样，OA治疗可能通过发挥抗氧化特性来保护抗CS+ pm2.5诱导的copd样肺部炎症。抑制炎症与下调促炎因子IL-1β、TNF-α、mmp -2基因表达及蛋白酶-抗蛋白酶平衡正常化有关，其途径是下调MMP-9基因表达，同时上调其抑制剂TIMP-1。OA治疗后炎症反应的减少与肺功能的改善密切相关。总体而言，PM2.5暴露会加剧cs诱导的与COPD相关的肺部炎症，而OA可以有效改善这种炎症。

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引用次数: 0

Functional interplay between bradykinin receptors and transient receptor potential vanilloid-1 in lipopolysaccharide-induced acute lung injury in mice 缓激肽受体与瞬时受体电位香草素-1在脂多糖诱导的小鼠急性肺损伤中的功能相互作用

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-08-10 DOI: 10.1016/j.pupt.2025.102384

Mayara Alves Amorim , Vitor Hélio Souza Oliveira , João B. Calixto , Eunice André

In this study, we investigated the functional interplay between bradykinin receptors and the transient receptor potential vanilloid-1 (TRPV1) channel in a mouse model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Lung and bronchoalveolar lavages were collected at 6 and 24 h after the induction of ALI and evaluated for changes in body weight, inflammatory marker levels, lung injury, and TRPV1 expression. Pretreatments with a TRPV1 antagonist (capsazepine) or B₁ and B₂ receptor antagonists, i.e., DALBK and HOE 140, respectively, were evaluated in this ALI mouse model. The histological score revealed higher levels of lung injury in mice treated with LPS (5 and 10 mg/kg), assessed at both 6 and 24 h, compared to the vehicle-treated group. A loss of body weight was observed within 24 h of ALI induction. Furthermore, collagen deposition, pulmonary oedema, leukocyte influx, and increased cytokine levels were also observed following LPS administration. Pretreatment with capsazepine, DALBK, or HOE 140 not only reversed all inflammatory parameters but also prevented the increased expression of TRPV1 observed in the lungs of mice subjected LPS-induced ALI. Our data suggest that, following LPS-induced ALI, bradykinin activates both B₁ and B₂ receptors associated with the subsequent activation of TRPV1. These findings suggest that bradykinin can activate both B₁ and B₂ receptors, which may contribute functionally to TRPV1 upregulation and activation during LPS-induced ALI. This novel pathway appears to sustain inflammation, offering a new therapeutic target for ALI and ARDS.

在本研究中，我们研究了缓激肽受体与瞬时受体电位香草素-1 （TRPV1）通道在脂多糖（LPS）诱导的急性肺损伤（ALI）小鼠模型中的功能相互作用。在ALI诱导后6和24小时收集肺和支气管肺泡灌洗液，评估体重、炎症标志物水平、肺损伤和TRPV1表达的变化。用TRPV1拮抗剂（辣椒平）或B1和B2受体拮抗剂（分别为DALBK和ho140）预处理ALI小鼠模型进行评估。组织学评分显示，LPS（5和10 mg/kg）处理的小鼠在6和24小时的肺损伤水平均高于给药组。在ALI诱导24小时内观察到体重下降。此外，胶原沉积、肺水肿、白细胞内流和细胞因子水平升高也在LPS处理后被观察到。用辣椒平、DALBK或ho140预处理不仅可以逆转所有炎症参数，还可以阻止lps诱导的ALI小鼠肺中TRPV1表达的增加。我们的数据表明，在lps诱导的ALI后，缓激肽激活了与随后激活TRPV1相关的B1和B2受体。这些发现表明，缓激素可以激活B1和B2受体，这可能在功能上有助于lps诱导的ALI中TRPV1的上调和激活。这种新途径似乎可以维持炎症，为ALI和ARDS提供新的治疗靶点。

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引用次数: 0

The era of multiple biologics: Is combination and switching an option in the management of severe asthma? 多种生物制剂的时代：联合和转换是治疗严重哮喘的一种选择吗？

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-06-19 DOI: 10.1016/j.pupt.2025.102375

Emmanuel Oshiogwe Okwuofu , Audrey Chee Hui Yong , Jonathan Chee Woei Lim , Johnson Stanslas

Background and objective

The introduction of biologics therapies targeting specific cytokines relevant to asthma pathophysiology has changed the landscape in the treatment of severe asthma in both adults and children. However, the availability of multiple agents, inclusion criteria for randomised control trials (RCTs), variation in national and international guidelines, instances of treatment failures, and the potential of switching or combining biologic therapies, highlight the need for real-world evidence. Data from real-world studies of biologics in severe asthma may complement efficacy data obtained from RCTs and provide important post-marketing safety information. Additionally, these studies may help inform the design of future clinical trials, characterise the natural history of the disease, and support important translational research. This review highlights current evidence for the combination and switching of biologics in severe asthma and comorbid diseases that may serve as pointers for optimal clinical outcomes.

Method

Pubmed, Scopus, and Web of Science were searched using specified search strategies.

Results

Available evidence suggests that patients with severe asthma who received combination or switched biologics (omalizumab, benralizumab, reslizumab, mepolizumab, dupilumab, and Tezepelumab) in real-world settings experienced significant improvement in asthma control, exacerbation, and lung function. Although combining biologics is not currently a common practice, there are cases where biologic therapies were combined, discontinued, or switched.

Conclusion

Patients may benefit from the early and systematic consideration of combination and switching of biologic therapies in severe asthma.

背景与目的：针对哮喘病理生理相关的特定细胞因子的生物制剂疗法的引入已经改变了成人和儿童重度哮喘治疗的格局。然而，多种药物的可用性、随机对照试验（rct）的纳入标准、国家和国际指南的变化、治疗失败的实例以及切换或联合生物治疗的潜力，都突出了对真实证据的需求。来自生物制剂治疗严重哮喘的实际研究数据可以补充随机对照试验获得的疗效数据，并提供重要的上市后安全性信息。此外，这些研究可能有助于为未来临床试验的设计提供信息，描述疾病的自然历史，并支持重要的转化研究。这篇综述强调了目前在严重哮喘和合并症疾病中联合和转换生物制剂的证据，这些证据可能作为最佳临床结果的指针。方法：采用指定的检索策略对Pubmed、Scopus和Web of Science进行检索。结果：现有证据表明，在现实环境中接受联合或转换生物制剂（omalizumab, benralizumab, reslizumab, mepolizumab， dupilumab和Tezepelumab）的严重哮喘患者在哮喘控制，恶化和肺功能方面有显着改善。虽然联合生物制剂目前还不是一种常见的做法，但也有联合、停止或切换生物疗法的情况。结论：在重症哮喘患者早期系统考虑联合和切换生物治疗可能会受益。

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引用次数: 0

Mitigating systemic corticosteroid risks in COPD: A call for earlier triple therapy initiation 减轻慢性阻塞性肺病的全身皮质类固醇风险：呼吁尽早开始三联治疗

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-06-03 DOI: 10.1016/j.pupt.2025.102360

Luis J. Nannini

Current GOLD guidelines recommend initial dual therapy with a LABA and LAMA for COPD patients with a high risk of exacerbations (at least two moderate or one severe exacerbation in the previous 12 months), with Inhaled Corticosteroids (ICS) added for specific phenotypes or continued exacerbations. Systemic corticosteroids (SCS) are advised for severe exacerbations, but cumulative SCS exposure is linked to significant adverse outcomes such as endocrine disorders and pneumonia. Studies suggest that after limited exacerbations, COPD patients may exhaust their “SCS credit,” increasing their risk of severe comorbidities. Earlier initiation of triple therapy in high-risk, symptomatic patients shows substantial benefits, including improved quality of life, compared to standard care. Like asthma management, SCS exposure in COPD should be minimised, and precision medicine should guide early triple therapy to preserve SCS use for future exacerbations.

目前的GOLD指南推荐对急性加重高风险（过去12个月内至少有两次中度或一次严重加重）的COPD患者进行LABA和LAMA的初始双重治疗，并针对特定表型或持续加重添加吸入皮质类固醇（ICS）。对于严重的恶化，建议使用全身性皮质类固醇（SCS），但累积的SCS暴露与内分泌紊乱和肺炎等重大不良后果有关。研究表明，在有限的加重后，COPD患者可能耗尽其“SCS信用”，增加其严重合并症的风险。与标准治疗相比，在高风险、有症状的患者中早期开始三联疗法显示出实质性的益处，包括改善生活质量。与哮喘治疗一样，慢性阻塞性肺病患者的SCS暴露应最小化，精准医学应指导早期三联治疗，以保留SCS在未来恶化时的使用。

引用次数: 0

Icaritin protects against airway inflammation by inhibiting the TLR4/NF-κB pathway in vivo and in vitro 在体内和体外实验中，淫羊藿苷通过抑制TLR4/NF-κB通路对气道炎症具有保护作用

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-07-29 DOI: 10.1016/j.pupt.2025.102380

Bo Xiao , Guiming Zhou , Lixia Hou , Lihong Yang , Zhimei Li , Yuchun Cai , Ailing Zhao , Biwen Mo , Dong Yao

Icaritin, a bioactive phytomolecule derived from Epimedium flavonoids (EFs), has been shown to have anti-inflammatory, anti-proliferative, and pro-apoptotic properties. However, its potential mechanisms in asthma airway inflammation have not been elucidated. In this study, Ovalbumin (OVA)-induced asthma mouse model and human bronchial epithelial cells (BEAS-2B) were used to illustrate the effects and mechanisms of Icaritin on airway inflammation. Specific airway resistance (sRAW) was used to detect the airway hyperresponsiveness (AHR). Hematoxylin-eosin (H&E) and periodic acid schiff (PAS) were used to detect the pathological changes. Bronchoalveolar lavage fluid (BALF) was used to detect the airway inflammatory cells. Serum and supernatants were used to detect the cytokines. Immunohistochemistry (IHC) and western blotting were used to detect the expression of TLR4, p-65, p-p65, IκBα, and p-IκBα. Cell Counting Kit-8 (CCK-8) was used to detect the cell viability. Icaritin suppressed AHR, attenuated eosinophilic infiltration and mucus hypersecretion, and significantly reduced the levels of OVA-specific cytokines in asthmatic mice. Moreover, Icaritin inhibited TLR4 expression, decreased phosphorylation of IκBα, and reduced NF-κB p65 activation in lung tissue of asthmatic mice. Further mechanistic studies showed that Icaritin reduces TLR4-induced inflammatory factor expression and blocks TLR4-activated NF-κB pathway in BEAS-2B cells. These findings demonstrate for the first time that Icaritin suppresses airway inflammation in asthma by inhibiting the TLR4/NF-κB pathway, suggesting its potential as a therapeutic agent for asthma.

淫羊藿黄酮类化合物淫羊藿苷（Icaritin）是淫羊藿黄酮类化合物中的一种生物活性植物分子，具有抗炎、抗增殖和促细胞凋亡的作用。然而，其在哮喘气道炎症中的潜在机制尚未阐明。本研究通过卵清蛋白（OVA）诱导的哮喘小鼠模型和人支气管上皮细胞（BEAS-2B），探讨了淫羊藿苷对气道炎症的影响及其机制。采用特异性气道阻力（sRAW）检测气道高反应性（AHR）。采用苏木精-伊红（H&；E）和周期性酸席夫（PAS）检测病理变化。支气管肺泡灌洗液（BALF）检测气道炎症细胞。血清和上清液检测细胞因子。采用免疫组化（IHC）和western blotting检测TLR4、p-65、p-p65、i - κ b α、p- i - κ b α的表达。细胞计数试剂盒-8 （CCK-8）检测细胞活力。icartin抑制哮喘小鼠AHR，减轻嗜酸性粒细胞浸润和粘液高分泌，显著降低ova特异性细胞因子水平。此外，淫羊藿苷抑制哮喘小鼠肺组织TLR4表达，降低i -κB α磷酸化，降低NF-κB p65活化。进一步的机制研究表明，Icaritin可降低BEAS-2B细胞中tlr4诱导的炎症因子表达，阻断tlr4激活的NF-κB通路。这些发现首次表明，icartin通过抑制TLR4/NF-κB通路抑制哮喘气道炎症，提示其作为哮喘治疗药物的潜力。

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引用次数: 0

Targeted inhibition of IDO1 by Kushenol A enhances radiosensitivity in non-small cell lung cancer 苦参酚A靶向抑制IDO1增强非小细胞肺癌的放射敏感性。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-06-03 DOI: 10.1016/j.pupt.2025.102362

Yingwei Zhu , Yunqian Chu , Hanjue Dai , Enci Lu , Qian Geng , Qingying Xian , Hua Jiang , Wenyu Zhu

Kushenol, a monomeric compound, was extracted from the roots of the medicinal plant Sophora flavescens. To explore the activity of Kushenol A in non-small cell lung cancer (NSCLC), CCK-8 assay, flow cytometry, and Western blot were performed. A xenograft mouse model was established. Our results demonstrated that Kushenol A treatment significantly enhanced the killing effect of radiation on NSCLC cells. Co-treatment with radiation and Kushenol A markedly reduced cell viability, increased intracellular ROS levels, and elevated the proportion of apoptotic cells compared to NSCLC cells treated with radiation alone. Animal experiments further confirmed that radiation therapy with simultaneous Kushenol A administration suppressed tumor growth and improved radiotherapy sensitivity compared to mice treated with radiation alone. Furthermore, Kushenol A did not produce significant toxic damage to the major organs of mice. Mechanistically, radiation therapy combined with Kushenol A treatment significantly upregulated protein levels of cleaved Caspase-3 and cleaved Caspase-9, leading to Bax translocation from the cytoplasm to mitochondria. Concurrently, Kushenol A treatment reduced NRF2 levels in the cytoplasm, thereby promoting an increase in ROS levels. Notably, Kushenol A enhanced tumor radiosensitivity by targeted inhibition of Indoleamine 2,3-dioxygenase 1 (IDO1). Taken together, our findings suggested that cotreatment with Kushenol A and radiation promoted the entry of Bax into mitochondria and activated the mitochondrial apoptotic pathway. Kushenol A exhibited targeted inhibition of IDO1, enhancing the sensitivity of non-small cell lung cancer to radiotherapy.

苦参酚是一种单体化合物，从药用植物苦参的根中提取。为探讨苦参酚A在非小细胞肺癌（NSCLC）中的活性，采用CCK-8测定、流式细胞术和Western blot检测。建立异种移植小鼠模型。我们的研究结果表明，Kushenol A处理显著增强了辐射对NSCLC细胞的杀伤作用。与单独放疗相比，放疗和Kushenol A联合治疗显著降低了细胞活力，增加了细胞内ROS水平，并增加了凋亡细胞的比例。动物实验进一步证实，与单独放疗小鼠相比，同时给予Kushenol A的放疗抑制了肿瘤生长，提高了放疗敏感性。此外，苦参酚A对小鼠主要器官没有产生明显的毒性损害。从机制上讲，放射治疗联合Kushenol A治疗可显著上调裂解型Caspase-3和裂解型Caspase-9的蛋白水平，导致Bax从细胞质转运到线粒体。同时，Kushenol A处理降低了细胞质中的NRF2水平，从而促进ROS水平的增加。值得注意的是，Kushenol A通过靶向抑制吲哚胺2,3-双加氧酶1 （IDO1）增强肿瘤放射敏感性。综上所述，我们的研究结果表明，Kushenol A和辐射共处理可促进Bax进入线粒体并激活线粒体凋亡途径。Kushenol A表现出对IDO1的靶向抑制，增强了非小细胞肺癌对放疗的敏感性。

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引用次数: 0

Drug repurposing tactics in the USA: Known active pharmaceutical ingredients in new indications 美国的药物再利用策略：新适应症中的已知活性药物成分。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-06-01 Epub Date: 2025-03-01 DOI: 10.1016/j.pupt.2025.102348

Thomas P. Dooley

引用次数: 0