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Exogenous MOTS-c mitigates myocardial ischemia-reperfusion injury: experimental and in silico evidence from rat heart models. 外源性MOTS-c减轻心肌缺血再灌注损伤:来自大鼠心脏模型的实验和计算机证据。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-28 DOI: 10.1007/s00210-026-05018-0
Saranya Sri Santhanam, Srijan Jayaraman, Gino A Kurian

The mitochondrial-derived peptide MOTS-c regulates metabolic and cellular stress responses, but its dose-response profile and direct cardioprotective mechanisms in myocardial ischemia-reperfusion injury (MIRI) remain undefined. This proof-of-concept study aimed to identify the optimal cardioprotective dose of exogenous MOTS-c and delineate its multi-pathway mechanisms using an ex vivo rat heart IR model with in silico support. Isolated Langendorff-perfused rat hearts underwent 30-min global ischemia and 60-min reperfusion with or without MOTS-c (0.25-0.7 mg/kg) delivered via Krebs-Henseleit buffer during the first 10 min of reperfusion. Hemodynamics, infarct size (TTC), oxidative stress markers, inflammation, and apoptotic gene expression were quantified. Peptide-protein interactions with survival pathways were predicted computationally. MOTS-c at 0.5 mg per kg conferred maximal protection, producing a 73% reduction in infarct size compared with ischemia-reperfusion alone, improving heart rate, left ventricular developed pressure, and rate-pressure product, and lowering end-diastolic pressure. Lactate dehydrogenase release decreased by 65%. Antioxidant defenses improved with increased superoxide dismutase, catalase, and glutathione redox ratio, along with reduced lipid peroxidation. Myeloperoxidase activity normalized, pro-apoptotic genes including caspase 3, caspase 7, caspase 9, BAX, and PARP were downregulated, while cytoprotective genes including BCL2, GPX4, and FOXO were increased. Molecular docking demonstrated high-affinity interactions of MOTS-c with MAPK, mTOR, AMPK, NRF2, PI3K, and caspase 3. This ex vivo study identifies 0.5 mg/kg as the optimal dose within the tested range, producing coordinated anti-apoptotic, antioxidant, and anti-inflammatory effects. Although the isolated heart model isolates direct myocardial actions, the lack of systemic influences and limited dose range necessitate broader dosing and pharmacokinetic studies before translational application.

线粒体来源的肽MOTS-c调节代谢和细胞应激反应,但其在心肌缺血再灌注损伤(MIRI)中的剂量-反应谱和直接心脏保护机制尚不清楚。这项概念验证研究旨在确定外源性MOTS-c的最佳心脏保护剂量,并通过体外大鼠心脏IR模型描述其多途径机制。langendorff灌注的离体大鼠心脏在再灌注前10分钟内,用或不加MOTS-c (0.25-0.7 mg/kg)通过Krebs-Henseleit缓冲液给药,进行30分钟全脑缺血和60分钟再灌注。量化血流动力学、梗死面积(TTC)、氧化应激标志物、炎症和凋亡基因表达。通过计算预测了肽-蛋白与生存途径的相互作用。0.5 mg / kg的MOTS-c具有最大的保护作用,与单独缺血-再灌注相比,可使梗死面积减少73%,提高心率、左室发达压和率压产物,降低舒张末期压。乳酸脱氢酶释放量减少65%。随着超氧化物歧化酶、过氧化氢酶和谷胱甘肽氧化还原比的增加,以及脂质过氧化的减少,抗氧化防御能力得到改善。髓过氧化物酶活性正常化,促凋亡基因caspase 3、caspase 7、caspase 9、BAX、PARP下调,细胞保护基因BCL2、GPX4、FOXO上调。分子对接表明,MOTS-c与MAPK、mTOR、AMPK、NRF2、PI3K和caspase 3具有高亲和力相互作用。体外研究确定0.5 mg/kg为试验范围内的最佳剂量,可协同产生抗凋亡、抗氧化和抗炎作用。虽然离体心脏模型分离了直接的心肌作用,但缺乏全身影响和有限的剂量范围需要在转化应用之前进行更广泛的剂量和药代动力学研究。
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引用次数: 0
Drug-associated deep vein thrombosis: a disproportionality analysis of the FDA adverse event reporting system (FAERS) database. 药物相关性深静脉血栓:FDA不良事件报告系统(FAERS)数据库的歧化分析。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-28 DOI: 10.1007/s00210-026-05024-2
Ying Liu, Jintuo Zhou, Lihuan Song, Peiguang Niu

Drug-associated deep vein thrombosis (DVT) poses a growing clinical concern, yet the thrombotic risk profiles of many medications are not fully established. This study aimed to systematically detect and characterize drug safety signals for DVT using real-world pharmacovigilance data. A disproportionality analysis was conducted using reports from the FDA adverse event reporting system (FAERS) spanning the first quarter of 2004 to the second quarter of 2025. After deduplication and filtering, 43,226 DVT cases linked to a primary suspect drug were analyzed. Four disproportionality metrics-the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS)-were applied to identify safety signals. Drugs were categorized using the anatomical therapeutic chemical (ATC) classification system. Time-to-onset (TTO) profiles were assessed via the Weibull distribution modeling and the Kaplan-Meier analysis. Among the included reports, 60.23% involved female patients, and 97.48% were classified as serious outcomes. Eighty-eight drugs met the predefined signal threshold. The ten highest-ranking agents by case count were drospirenone/ethinyl estradiol (ROR 69.09), ethinyl estradiol/etonogestrel (ROR 43.41), lenalidomide (ROR 4.89), testosterone (ROR 30.13), rofecoxib (ROR 5.41), ethinyl estradiol/norelgestromin (ROR 28.53), bevacizumab (ROR 3.53), thalidomide (ROR 9.26), pomalidomide (ROR 3.18), and celecoxib (ROR 3.90). These agents predominantly belonged to antineoplastic/immunomodulatory or genitourinary/hormonal therapeutic classes. The median TTO was 120 days (IQR 29-441), with 25.87% of events occurring within the first month of treatment. Early failure patterns were most frequent (52.6% of drugs), especially among hormonal contraceptives, immunomodulators, and chemotherapeutic agents. This large-scale pharmacovigilance analysis identifies robust DVT signals across multiple drug classes, notably hormonal therapies, immunomodulators, and targeted anticancer agents. The results highlight the importance of proactive thrombotic risk assessment and monitoring in clinical practice when using these medications.

药物相关性深静脉血栓形成(DVT)引起了越来越多的临床关注,但许多药物的血栓风险概况尚未完全确定。本研究旨在利用真实世界的药物警戒数据系统地检测和表征深静脉血栓形成的药物安全信号。使用FDA不良事件报告系统(FAERS)从2004年第一季度到2025年第二季度的报告进行了歧化分析。经过重复数据删除和过滤,43226例与主要可疑药物有关的DVT病例被分析。四种歧化指标——报告优势比(ROR)、比例报告比(PRR)、贝叶斯置信传播神经网络(BCPNN)和多项目伽玛泊松收缩器(MGPS)——被用于识别安全信号。采用解剖治疗化学(ATC)分类系统对药物进行分类。通过威布尔分布模型和Kaplan-Meier分析评估发作时间(TTO)概况。在纳入的报告中,女性患者占60.23%,97.48%归为严重结局。88种药物符合预定义的信号阈值。按病例数排名前十位的药物分别是:屈螺酮/炔雌醇(ROR 69.09)、炔雌醇/炔雌酮(ROR 43.41)、来那度胺(ROR 4.89)、睾酮(ROR 30.13)、罗非昔布(ROR 5.41)、炔雌醇/去瑞孕酮(ROR 28.53)、贝伐单抗(ROR 3.53)、沙利度胺(ROR 9.26)、泊马度胺(ROR 3.18)和塞来昔布(ROR 3.90)。这些药物主要属于抗肿瘤/免疫调节或泌尿生殖系统/激素治疗类。中位TTO为120天(IQR 29-441), 25.87%的事件发生在治疗的第一个月内。早期失败模式最为常见(52.6%的药物),尤其是激素避孕药、免疫调节剂和化疗药物。这种大规模的药物警戒分析确定了多种药物类别中强大的DVT信号,特别是激素治疗、免疫调节剂和靶向抗癌药物。结果强调了在临床实践中使用这些药物时主动血栓风险评估和监测的重要性。
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引用次数: 0
β-Carboline alkaloid harmaline alleviates hyperuricemia-mediated renal inflammation by suppressing oxidative stress. β-碳碱生物碱碱通过抑制氧化应激减轻高尿酸血症介导的肾脏炎症。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-28 DOI: 10.1007/s00210-026-04987-6
Ayush Kattna, Lovedeep Singh, Mohd Nazam Ansari, Abdulaziz S Saeedan, Sara Abdulrahman Aldossary

Hyperuricemia is a metabolic disorder marked by elevated serum uric acid levels and is closely linked to the development of gout and progressive renal dysfunction. It is increasingly recognized as a major public health concern due to its association with chronic kidney disease and cardiovascular complications. Hyperuricemia induces kidney impairment through a complex interplay of oxidative and inflammatory stress. Harmaline, a β-carboline alkaloid primarily found in Peganum harmala, exhibits antioxidant and anti-inflammatory activities. Considering the roles of oxidative and inflammatory stress in renal dysfunction and the modulatory potential of harmaline, this study aimed to evaluate harmaline against potassium oxonate-induced hyperuricemia and renal impairment in mice. In this study, 25 Swiss albino mice were divided into five groups (n = 5). Hyperuricemia was induced by intraperitoneal administration of potassium oxonate (300 mg/kg) for 7 days. Harmaline (2.5 and 5 mg/kg, i.p.) and allopurinol (10 mg/kg, i.p.) were administered 1-h after potassium oxonate treatment. On day 8, serum was collected to measure uric acid, creatinine, and blood urea nitrogen (BUN), and thereafter, the kidneys were harvested for biochemical analyses. Potassium oxonate administration resulted in hyperuricemia-associated renal dysfunction, as evidenced by increased serum uric acid, creatinine, BUN, thiobarbituric acid (TBARS), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), along with decreased renal glutathione (GSH) and interleukin-10 (IL-10) levels. Treatment with harmaline significantly attenuated these potassium oxonate-induced biochemical and inflammatory alterations. Notably, the higher dose of harmaline exhibited the prominent effect. Overall, the results suggest that harmaline, particularly at 5 mg/kg, effectively alleviates potassium oxonate-induced hyperuricemia and renal dysfunction in mice.

高尿酸血症是一种以血清尿酸水平升高为特征的代谢性疾病,与痛风和进行性肾功能障碍的发展密切相关。由于它与慢性肾脏疾病和心血管并发症有关,它越来越被认为是一个主要的公共卫生问题。高尿酸血症通过氧化应激和炎症应激的复杂相互作用诱导肾损害。榛果碱是一种主要在榛果中发现的β-碳碱生物碱,具有抗氧化和抗炎活性。考虑到氧化应激和炎症应激在肾功能障碍中的作用以及盐碱的调节潜力,本研究旨在评估盐碱对氧酸钾诱导的小鼠高尿酸血症和肾损害的影响。本研究将25只瑞士白化病小鼠分为5组(n = 5)。腹腔注射氧酸钾(300 mg/kg) 7 d诱导高尿酸血症。在氧酸钾处理1 h后,分别给药Harmaline(2.5和5 mg/kg, i.p.)和别嘌呤醇(10 mg/kg, i.p.)。第8天采集血清测定尿酸、肌酐和血尿素氮(BUN),随后取肾进行生化分析。氧酸钾给药导致高尿酸血症相关性肾功能障碍,其证据是血清尿酸、肌酐、BUN、硫代巴比妥酸(TBARS)、肿瘤坏死因子α (TNF-α)和白细胞介素6 (IL-6)升高,同时肾谷胱甘肽(GSH)和白细胞介素10 (IL-10)水平降低。用正阳碱治疗可显著减轻氧膦酸钾引起的生化和炎症改变。值得注意的是,高剂量的正邪碱表现出显著的效果。综上所述,研究结果表明,小虫碱,特别是5 mg/kg剂量,可有效缓解氧酸钾诱导的小鼠高尿酸血症和肾功能障碍。
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引用次数: 0
Comparison of pharmacokinetics, pharmacodynamics, safety, and immunogenicity of a candidate biosimilar INTP23.1 with EU and US‑approved denosumab reference products in healthy adult men. 在健康成年男性中,候选生物仿制药INTP23.1与欧盟和美国批准的denosumab参考产品的药代动力学、药效学、安全性和免疫原性的比较
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-28 DOI: 10.1007/s00210-025-04964-5
Steve Fenwick, Vidhi Parekh, Naman Shah, Ronak Patel, Prashant Kale, Shrikrishna Kolte

Purpose: This Phase 1 study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of INTP23.1, a proposed denosumab biosimilar, compared with US- and EU-licensed reference denosumab (Xgeva®) in healthy male volunteers.

Methods: This randomized, double-blind, three-arm, 36 week, parallel-group trial (CTRI/2020/09/027619), assessed a single 35 mg subcutaneous dose of INTP23.1, Xgeva (US), or Xgeva (EU), administered in the upper arm. PK endpoints were statistically compared using geometric least-squares means (LSM) and 90% confidence intervals (CIs). PD markers were evaluated, immunogenicity and safety were assessed through validated assays, and adverse events (AEs) were monitored.

Results: A total of 234 healthy male volunteers were enrolled. Baseline demographics were similar across the three treatment sequence groups. PK equivalence was demonstrated, with all geometric LSM ratios and 90% CIs for maximum serum concentration, area under the concentration-time curve (AUC) from time zero to the last measurable concentration, and AUC from time zero to infinity falling within the predefined bioequivalence range of 80.00% to 125.00%. PD responses showed comparable suppression of C-terminal telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) across treatment groups. Immunogenicity profiles were similar, with low anti-drug antibody incidence and no neutralizing antibodies detected. AEs were generally mild or moderate in intensity, and no unexpected safety signals were observed.

Conclusions: INTP23.1 demonstrated comparable PK, PD, immunogenicity, and safety to US- and EU-licensed denosumab reference products in healthy male volunteers. These findings support further clinical development of INTP23.1 as a denosumab biosimilar for approved indications.

Trial registration number: CTRI/2020/09/027619; Registered 07/09/2020.

目的:本i期研究评估了拟议的denosumab生物类似药INTP23.1在健康男性志愿者中的药代动力学(PK)、药效学(PD)、免疫原性和安全性,并与美国和欧盟许可的参考药denosumab (Xgeva®)进行了比较。方法:这项随机、双盲、三组、36周的平行组试验(CTRI/2020/09/027619),评估了单次35 mg皮下剂量的INTP23.1、Xgeva(美国)或Xgeva(欧盟),给药于上臂。采用几何最小二乘均值(LSM)和90%置信区间(CIs)对PK终点进行统计学比较。评估PD标志物,通过验证的方法评估免疫原性和安全性,并监测不良事件(ae)。结果:共纳入234名健康男性志愿者。三个治疗顺序组的基线人口统计数据相似。所有几何LSM比和90%的最大血清浓度CIs,从时间0到最后可测量浓度的浓度-时间曲线下面积(AUC),以及从时间0到无穷远的AUC都在预定的80.00%至125.00%的生物等效性范围内,证明了PK等效性。PD反应显示,不同治疗组的c端端肽(CTX)和1型前胶原n端前肽(P1NP)的抑制相似。免疫原性谱相似,抗药物抗体发生率低,未检测到中和抗体。ae一般为轻度或中度强度,未观察到意外的安全信号。结论:在健康男性志愿者中,INTP23.1表现出与美国和欧盟许可的denosumab参考产品相当的PK、PD、免疫原性和安全性。这些发现支持INTP23.1作为denosumab生物类似药用于已批准适应症的进一步临床开发。试验注册号:CTRI/2020/09/027619;07/09/2020注册。
{"title":"Comparison of pharmacokinetics, pharmacodynamics, safety, and immunogenicity of a candidate biosimilar INTP23.1 with EU and US‑approved denosumab reference products in healthy adult men.","authors":"Steve Fenwick, Vidhi Parekh, Naman Shah, Ronak Patel, Prashant Kale, Shrikrishna Kolte","doi":"10.1007/s00210-025-04964-5","DOIUrl":"https://doi.org/10.1007/s00210-025-04964-5","url":null,"abstract":"<p><strong>Purpose: </strong>This Phase 1 study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of INTP23.1, a proposed denosumab biosimilar, compared with US- and EU-licensed reference denosumab (Xgeva®) in healthy male volunteers.</p><p><strong>Methods: </strong>This randomized, double-blind, three-arm, 36 week, parallel-group trial (CTRI/2020/09/027619), assessed a single 35 mg subcutaneous dose of INTP23.1, Xgeva (US), or Xgeva (EU), administered in the upper arm. PK endpoints were statistically compared using geometric least-squares means (LSM) and 90% confidence intervals (CIs). PD markers were evaluated, immunogenicity and safety were assessed through validated assays, and adverse events (AEs) were monitored.</p><p><strong>Results: </strong>A total of 234 healthy male volunteers were enrolled. Baseline demographics were similar across the three treatment sequence groups. PK equivalence was demonstrated, with all geometric LSM ratios and 90% CIs for maximum serum concentration, area under the concentration-time curve (AUC) from time zero to the last measurable concentration, and AUC from time zero to infinity falling within the predefined bioequivalence range of 80.00% to 125.00%. PD responses showed comparable suppression of C-terminal telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) across treatment groups. Immunogenicity profiles were similar, with low anti-drug antibody incidence and no neutralizing antibodies detected. AEs were generally mild or moderate in intensity, and no unexpected safety signals were observed.</p><p><strong>Conclusions: </strong>INTP23.1 demonstrated comparable PK, PD, immunogenicity, and safety to US- and EU-licensed denosumab reference products in healthy male volunteers. These findings support further clinical development of INTP23.1 as a denosumab biosimilar for approved indications.</p><p><strong>Trial registration number: </strong>CTRI/2020/09/027619; Registered 07/09/2020.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146065235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Network pharmacology and experimental validation to explore the effects and mechanisms of flavonoids luteolin and chrysoeriol against non‑small cell lung cancer. 网络药理学和实验验证探讨黄酮类木犀草素和黄蜡醇抗非小细胞肺癌的作用和机制。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-28 DOI: 10.1007/s00210-026-05040-2
Haifang Du, Jianzhan Yang, Xinhao Xue, Siyu Wang

Luteolin and chrysoeriol, active flavonoids found in Fagopyrum dibotryis Rhizoma (FDR), possess similar molecular structures and demonstrate anti-tumor activity; however, their efficacy and mechanisms in non-small cell lung cancer (NSCLC) are still incomplete. This research aimed to reveal the therapeutic potential and mechanisms of these phytoconstituents in NSCLC through an integrated strategy of network pharmacology, molecular docking, and experimental validation. We used network pharmacology to discover possible targets and pathways for luteolin and chrysoeriol in NSCLC, which involved predicting targets, constructing protein-protein interaction (PPI) networks, and performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and dynamics simulations assessed the binding affinities of both phytoconstituents to core targets. Hub gene expression in NSCLC tissues was further examined using bioinformatics tools. The anti-NSCLC effects were evaluated by measuring A549 and PC9 cell viability, migration, apoptosis, and modulation of the PI3K/AKT pathway. We identified 64 potential therapeutic targets for NSCLC. Enrichment analysis revealed the PI3K-Akt signaling pathway as the most significantly associated. Molecular simulations indicated stable binding of both phytoconstituents to core targets, with luteolin exhibiting stronger binding affinity. In experimental validation, luteolin more potently inhibited NSCLC cell viability and migration, alleviated mitochondrial damage, and induced apoptosis relative to chrysoeriol. Luteolin also more effectively regulated PI3K/AKT signaling. Both luteolin and chrysoeriol represent promising natural agents for NSCLC treatment, with luteolin demonstrating superior bioactivity.

木犀草素和黄素是金荞麦根茎(Fagopyrum dibotryis Rhizoma, FDR)中的活性类黄酮,它们具有相似的分子结构和抗肿瘤活性;然而,它们在非小细胞肺癌(NSCLC)中的疗效和机制仍不完整。本研究旨在通过网络药理学、分子对接和实验验证等综合策略,揭示这些植物成分在非小细胞肺癌中的治疗潜力和机制。我们利用网络药理学发现木犀草素和黄叶醇在NSCLC中的可能靶点和通路,包括预测靶点、构建蛋白-蛋白相互作用(PPI)网络、进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析。分子对接和动力学模拟评估了这两种植物成分与核心靶点的结合亲和力。利用生物信息学工具进一步检测中枢基因在NSCLC组织中的表达。通过测量A549和PC9细胞活力、迁移、凋亡和PI3K/AKT通路的调节来评估其抗nsclc作用。我们确定了64个潜在的NSCLC治疗靶点。富集分析显示,PI3K-Akt信号通路相关性最显著。分子模拟表明,这两种植物成分与核心靶点的结合稳定,其中木犀草素表现出更强的结合亲和力。在实验验证中,木犀草素比黄蜡醇更有效地抑制非小细胞肺癌细胞的活力和迁移,减轻线粒体损伤,诱导细胞凋亡。木犀草素还能更有效地调节PI3K/AKT信号传导。木犀草素和黄松醇都是治疗非小细胞肺癌的有前途的天然药物,其中木犀草素显示出优越的生物活性。
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引用次数: 0
Repurposing ramipril to mitigate EMT-like transition in endometriosis by PI3K/AKT/S6K1 signalling pathway: a study in endometriosis induced rats. 利用雷米普利通过PI3K/AKT/S6K1信号通路减轻子宫内膜异位症中emt样转变:子宫内膜异位症大鼠的研究
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-28 DOI: 10.1007/s00210-026-05030-4
Piyali Mazumdar, Shampa Sarkar Biswas

Endometriosis, an atypical benign disorder, may disrupt epithelial-mesenchymal transition (EMT) due to a dysregulated balance between matrix metalloproteinases (MMPs) and their inhibitors. Ramipril, an angiotensin converting enzyme (ACE) inhibitor, is crucial in mediating angiogenesis, inflammation, oxidative stress, and apoptosis. In the current work, we investigated how ramipril modulates EMT in endometriosis rats. Five adult virgin female Wistar rats were donor rats, and thirty rats were randomly divided into three groups following peritoneal uterine tissue transplantation (group 2 and group 3). The sham control group was group 1. Morphological alterations were predominantly assessed through hematoxylin-eosin (H-E) staining, succeeded by the immunoreactivity analysis of MMP9, tissue inhibitor of metalloproteinases 1 (TIMP1), reversion-inducing cysteine-rich protein with Kazal motifs (RECK), epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), and vimentin in the uteri and ectopic lesions of the specified groups. Zymography was conducted to assess the activities of MMP9 and MMP2. Immunoblotting was subsequently conducted for MMP9, TIMP1, snail, E-cadherin, N-cadherin, and vimentin in both uteri and ectopic lesions. Immunoblotting was conducted for phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mechanistic target of rapamycin (mTOR), p70 ribosomal S6 kinase 1 (S6K1), and hypoxia-inducible factor 1-alpha (HIF-1ɑ) in the ectopic lesions. A significant reduction in the average quantity of ectopic endometrial glands was recorded in group 3. A significant decrease in the expressions of MMP9:TIMP1 (RECK) ratios (p = 0.00012; p = 0.001), snail, p-PI3K, p-AKT, p-mTOR, p-S6K1, and HIF-1ɑ (p < 0.05) proteins was observed in the ectopic lesions of group 3. A significant increase in the E-cadherin to N-cadherin (vimentin) ratios (p = 0.001) was observed in group 3 ectopic lesions. In conclusion, the administration of ramipril led to the reversal of EMT-like process by disrupting the MMP9/PI3K/AKT/S6K1 pathway in rats induced with endometriosis.

子宫内膜异位症是一种非典型的良性疾病,由于基质金属蛋白酶(MMPs)及其抑制剂之间的失衡,可能会破坏上皮-间质转化(EMT)。雷米普利是一种血管紧张素转换酶(ACE)抑制剂,在介导血管生成、炎症、氧化应激和细胞凋亡中起着至关重要的作用。在目前的工作中,我们研究了雷米普利如何调节子宫内膜异位症大鼠的EMT。5只成年雌性Wistar大鼠为供鼠,30只大鼠随机分为腹膜子宫组织移植后的3组(2组和3组)。假手术对照组为第1组。形态学改变主要通过苏木精-伊红(H-E)染色来评估,随后通过免疫反应性分析MMP9、组织金属蛋白酶抑制剂1 (TIMP1)、诱导逆转的富含半胱氨酸的Kazal基序蛋白(RECK)、上皮钙粘蛋白(E-cadherin)、神经钙粘蛋白(N-cadherin)和特定组子宫和异位病变中的vimentin。酶谱法测定了MMP9和MMP2的活性。随后对子宫和异位病变中的MMP9、TIMP1、snail、E-cadherin、N-cadherin和vimentin进行免疫印迹检测。免疫印迹法检测异位病变中磷酸肌肽3激酶(PI3K)、蛋白激酶B (Akt)、雷帕霉素机制靶点(mTOR)、p70核糖体S6激酶1 (S6K1)和缺氧诱导因子1- α (HIF-1)。第三组异位子宫内膜腺的平均数量显著减少。MMP9:TIMP1 (RECK)比值(p = 0.00012; p = 0.001)、snail、p- pi3k、p- akt、p- mtor、p- s6k1和HIF-1的表达均显著降低(p
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引用次数: 0
Computational-experimental identification of bioactive component combinations from Salvia miltiorrhiza for cardiovascular protection. 计算-实验鉴定丹参对心血管保护的生物活性成分组合。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-27 DOI: 10.1007/s00210-026-04980-z
Yanxia Liu, Jianing Zhang, Zewen Wang, Chaoqun Liu, Shijie Bi, Zhenzhen Xu, Bin Yu, Jiaye Tian, Yue Ren, Qun Li, Xiaoqian Huo, Yanling Zhang

Cardiovascular dysfunction represents a major global health challenge due to its high morbidity and mortality, underscoring the urgent need for more efficient drug discovery paradigms. This study developed and applied an integrative computational-experimental strategy to systematically explore and prioritize bioactive component combinations with crude extract-comparable activity (BECC) from traditional herbs, using Salvia miltiorrhiza (Danshen, DS) as a representative case relevant to cardiovascular protection. LC-MS/MS-based exposure-informed metabolite profiling, reverse target fishing, molecular docking, pharmacophore analysis were integrated to develop multidimensional component-target networks. Through this framework, 139 potential targets associated with 26 bioactive components and 41 metabolites were collected. Target activity spectrum (TAS) and pharmacodynamic activity spectrum (PAS) analyses were further employed to prioritize BECC, comprising rosmarinic acid, salvianolic acids A and B, cryptotanshinone, and tanshinone I. Within the tested in vitro systems and concentration ranges, this combination exhibited pharmacological activity profiles that were broadly comparable to those of the crude DS extract, as evaluated in three cardiovascular-relevant cellular models, supporting its potential as a representative multi-component candidate. In conclusion, this study provides a proof-of-concept case study demonstrating an integrative strategy to narrow complex herbal extracts into defined component combinations for subsequent translational evaluation, offering a methodological reference for studying the multi-component basis of traditional medicines in the context of cardiovascular-related research.

由于心血管功能障碍的高发病率和死亡率,它是一个重大的全球健康挑战,强调迫切需要更有效的药物发现模式。本研究以丹参(Salvia miltiorrhiza,简称丹参)为研究对象,采用计算-实验相结合的方法,系统地探索和优选具有可比较活性(crude - extraction -comparable activity, BECC)的传统草药生物活性成分组合。基于LC-MS/ ms的暴露信息代谢物分析、反向靶标捕捞、分子对接、药效团分析被整合到多维成分-靶标网络中。通过该框架,收集了与26种生物活性成分和41种代谢物相关的139个潜在靶点。靶标活性谱(TAS)和药效学活性谱(PAS)分析进一步确定BECC的优先级,BECC包括迷迭香酸、丹酚酸A和B、隐丹参酮和丹参酮i。在测试的体外系统和浓度范围内,该组合在三种心血管相关细胞模型中显示出与DS粗提取物大致相当的药理活性谱。支持其作为具有代表性的多组分候选人的潜力。总之,本研究提供了一个概念验证案例研究,展示了一种整合策略,将复杂的草药提取物缩小到确定的成分组合,用于后续的转化评估,为在心血管相关研究的背景下研究传统药物的多成分基础提供了方法学参考。
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引用次数: 0
Risk insights for clinical medication: a Mendelian randomization study of 23 drugs and lung cancer. 临床用药的风险洞察:23种药物和肺癌的孟德尔随机研究。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-27 DOI: 10.1007/s00210-025-04967-2
Huachuan Wang, Bo Zhou, Baowei Ma, Tao Zhang, Ranran Kong

The effect of clinical medications for common diseases on cancer risk has attracted extensive attention. However, whether they have a causal relationship with lung cancer remains unclear. Genome-wide association study datasets on 23 drugs and lung cancer were extracted from publicly available databases. Mendelian randomization methods were utilized to assess the causal effects of the drugs on the risk of lung cancer. Sensitivity analyses were also conducted to evaluate the stability and reliability. Our results found that salicylic acid and derivatives (OR = 0.779; 95% CI, 0.676-0.898; P = 5 × 10-4, P-adjusted = 0.0125) significantly reduced lung cancer risk, while opioids (OR = 1.16; 95% CI, 1.065-1.263; P = 6 × 10-4, P-adjusted = 0.0148) significantly increased lung cancer risk. These findings remained robust after removing outliers. Suggestive evidence for a protective effect was also found for antithrombotic agents, antihypertensives, β-blockers, thyroid preparations, and anilines (all 0.0022 < P < 0.05). Notably, after outlier correction, the suggestive association for antithrombotic agents became statistically significant, while that for β-blockers disappeared, and the other suggestive associations persisted. Sensitivity analyses further confirmed the robustness of these findings. This study identified several clinical drugs that were causally associated with lung cancer, involving cardiovascular and endocrine system medications, anti-inflammatory/antipyretic analgesics, and centrally acting analgesics. It provides a theoretical reference for clinical medication guidance and understanding medication risks.

常见疾病的临床用药对癌症风险的影响已引起广泛关注。然而,它们是否与肺癌有因果关系尚不清楚。从公开的数据库中提取了23种药物与肺癌的全基因组关联研究数据集。采用孟德尔随机化方法评估药物对肺癌风险的因果影响。并进行敏感性分析以评价其稳定性和可靠性。我们的研究结果发现,水杨酸及其衍生物(OR = 0.779; 95% CI, 0.676-0.898; P = 5 × 10-4, P校正= 0.0125)显著降低肺癌风险,而阿片类药物(OR = 1.16; 95% CI, 1.065-1.263; P = 6 × 10-4, P校正= 0.0148)显著增加肺癌风险。在去除异常值后,这些发现仍然是稳健的。抗血栓药、抗高血压药、β受体阻滞剂、甲状腺制剂和苯胺类药物也有保护作用(均为0.0022)
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引用次数: 0
Exploring the therapeutic potential of withaferin A by modulating key oncosignaling pathways. 通过调节关键的肿瘤信号通路,探索withaferin A的治疗潜力。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-27 DOI: 10.1007/s00210-026-05006-4
Prashant Chauhan, Md Nasar Mallick, Safia Obaidur Rab, Mohd Saeed, Fadwa Mohammed Alkhulaifi, Sorabh Lakhanpal, Ajay Singh, Pratibha Pandey, Meenakshi Verma, Fahad Khan

Withaferin A (WA) is an effective withanolide compound derived from Withania somnifera that exhibits a multifaceted pharmacological profile, making it a promising candidate for managing several types of carcinomas. WA has been shown to regulate multiple oncosignaling pathways, proteins, and molecular determinants critical for cancer cell survival, proliferation, and resistance. Its pro-apoptotic, anti-metastasis, antiangiogenic, and anti-proliferative properties demonstrate its efficacy as a multitargeted anticancer agent to manage persistent challenges associated with the complex etiology of cancer. Although several investigations have shown the anticancer efficacy of WA, comprehensive insights into the multitargeted modulation of oncosignaling pathways and synergistic therapeutic potential remain fragmented. Therefore, this review focused on bridging these gaps by providing an integrated overview of WA's mechanistic and translational relevance in cancer therapy. Specifically, this review explores the therapeutic potential of WA in targeting key oncogenic pathways, which are implicated in various types of malignancies. Additionally, this study illustrates the synergistic role of WA in combination with current cancer therapies including immunotherapy, radiation, and chemoradiotherapy. Alongside investigating WA's pharmacological potential as an anticancer agent, this study also examines its pharmacokinetics, bioavailability, and toxicity profile.

Withaferin A (WA)是从Withania somnifera中提取的有效的Withaferin化合物,具有多方面的药理特征,使其成为治疗多种类型癌症的有希望的候选者。WA已被证明可以调节多种肿瘤信号通路、蛋白质和对癌细胞存活、增殖和耐药性至关重要的分子决定因素。其促凋亡、抗转移、抗血管生成和抗增殖的特性证明了其作为一种多靶点抗癌药物的有效性,可以应对与复杂病因相关的癌症的持续挑战。尽管一些研究已经显示了WA的抗癌功效,但对肿瘤信号通路的多靶点调节和协同治疗潜力的全面了解仍然不完整。因此,本综述的重点是通过提供WA在癌症治疗中的机制和翻译相关性的综合概述来弥合这些差距。具体来说,这篇综述探讨了WA靶向关键致癌途径的治疗潜力,这些途径与各种类型的恶性肿瘤有关。此外,本研究说明了WA与当前癌症治疗(包括免疫治疗、放疗和放化疗)联合的协同作用。除了研究WA作为抗癌药物的药理潜力外,本研究还研究了其药代动力学、生物利用度和毒性。
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引用次数: 0
The in vivo disposition of mildronate and its regulatory effects on L-carnitine in rats. 米屈酸钠在大鼠体内的分布及其对左旋肉碱的调节作用。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-26 DOI: 10.1007/s00210-026-04993-8
Qiannan Zhang, Junwen Hu, Chuyao Yang, Jingtao Wang, Xia Wu, Lingchao Wang, Wenpeng Zhang, Xiaomei Zhuang

To develop an LC-MS/MS method for simultaneous quantification of mildronate and L-carnitine, and to investigate the pharmacokinetic profile of mildronate in rats, its effect on L-carnitine homeostasis, as well as the exposure characteristics, underlying mechanisms, and their associations with therapeutic efficacy and toxicity risks. We quantified mildronate using its deuterated analog ([2H₃]-mildronate) as an internal standard, while endogenous L-carnitine was relatively quantified using a surrogate matrix. A pharmacokinetic study was conducted in rats following oral administration of mildronate at doses of 40-160 mg/kg. Tissue distribution and excretion studies of mildronate were performed at the 80 mg/kg dose level. Mildronate exhibited nonlinear pharmacokinetics at 160 mg/kg, demonstrated by a greater-than-dose-proportional increase in systemic exposure. It exhibited high distribution and prolonged retention in cardiac and skeletal muscle. The cumulative urinary excretion of the parent drug amounted to only 3.01%. Furthermore, mildronate dose-dependently reduced plasma L-carnitine concentrations, depleted L-carnitine levels in cardiac and skeletal muscle tissues, and increased its urinary excretion. The developed LC-MS/MS method is reliable for simultaneous quantification of mildronate and L-carnitine. The integrated PK-PD findings, including nonlinear exposure, target tissue accumulation, and disruption of L-carnitine homeostasis, collectively elucidate mildronate's mechanism of action through energy substrate depletion, as well as its intrinsic efficacy-toxicity duality. These findings thus lay a robust scientific foundation for optimizing the drug's clinical dosing regimens and guiding safety monitoring practices.

建立米屈酸盐和左旋肉碱同时定量的LC-MS/MS方法,研究米屈酸盐在大鼠体内的药动学特征、对左旋肉碱稳态的影响、暴露特征、暴露机制及其与治疗效果和毒性风险的关系。我们用它的氘化类似物([2H₃]-米屈酸盐)作为内标来定量米屈酸盐,而内源性左卡尼汀则用替代矩阵来相对定量。口服米屈酸钠40 ~ 160 mg/kg后,在大鼠体内进行了药代动力学研究。在80 mg/kg剂量水平下进行米屈酸钠的组织分布和排泄研究。米屈膦酸钠在160 mg/kg时表现出非线性药代动力学,表现为全身暴露量大于剂量比例的增加。它在心脏和骨骼肌中分布广泛,滞留时间长。母体药物的累积尿排出量仅为3.01%。此外,米屈酸盐剂量依赖性地降低血浆左旋肉碱浓度,减少心脏和骨骼肌组织中的左旋肉碱水平,并增加其尿排泄。所建立的LC-MS/MS方法可同时测定米屈酸钠和左旋肉碱的含量。综合PK-PD研究结果,包括非线性暴露、靶组织积累和左卡尼汀稳态的破坏,共同阐明了米屈酸盐通过能量底物消耗的作用机制,以及其内在的药效-毒性二元性。因此,这些发现为优化药物的临床给药方案和指导安全监测实践奠定了坚实的科学基础。
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