European journal of pharmacology最新文献_第7页

Therapeutic potential of butyrate supplementation in sepsis: a review of preclinical evidence and translational perspectives 补充丁酸盐治疗败血症的潜力：临床前证据和翻译观点的回顾。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-22 DOI: 10.1016/j.ejphar.2026.178594

Nicola Benvenuto , Filippo Mearelli , Gianni Biolo , Filippo Giorgio Di Girolamo , Erik Roman-Pognuz , Abbas Yadegar , Annalisa Serio , Saveria Lory Crocè , Mauro Giuffrè , Paolo De Cristofaro , Nina Grasselli Kmet , Maria Vittoria Micioni Di Bonaventura , Verena Zerbato , Stefano Di Bella

Sepsis remains a major global health problem and is responsible for millions of deaths annually despite significant progress in antimicrobial therapy and organ support. Increasing evidence highlights the role of the gut–immune axis in shaping host responses during sepsis, with particular interest in microbiota-derived metabolites such as short-chain fatty acids (SCFAs). Among these, butyrate has emerged as a promising candidate due to its anti-inflammatory, immunomodulatory, and intestinal barrier–preserving properties. This narrative review summarizes current evidence regarding the biological activities of butyrate and its potential therapeutic relevance in sepsis and septic shock.

A comprehensive literature search of PubMed and additional sources up to April 2025 identified experimental and clinical studies evaluating butyrate supplementation in sepsis. Preclinical studies show that butyrate improves function across organ systems (neurologic, hepatic, intestinal, cardiac, pulmonary, and renal) mainly by reducing inflammation, oxidative stress, and epithelial barrier disruption. In models like cecal ligation and puncture (CLP) or endotoxemia, survival improved by 20–40 % with butyrate administration. Human data are limited: an observational study found higher circulating β-hydroxybutyrate levels in sepsis survivors, while a randomized trial reported fewer gastrointestinal complications and ventilator-associated pneumonia in patients with synbiotic-induced butyrate increases.

Overall, current evidence suggests that butyrate may modulate key pathophysiological pathways in sepsis and holds potential as an adjunctive therapy. Nonetheless, dedicated early-phase clinical trials are required to clarify safety, optimal dosing, pharmacodynamics, and clinical effectiveness.

尽管在抗菌治疗和器官支持方面取得了重大进展，但败血症仍然是一个重大的全球健康问题，每年造成数百万人死亡。越来越多的证据强调了肠道免疫轴在脓毒症期间塑造宿主反应中的作用，特别是对微生物衍生代谢物如短链脂肪酸（SCFAs）的兴趣。其中，丁酸盐因其抗炎、免疫调节和肠道屏障保护特性而成为有希望的候选药物。本文综述了目前关于丁酸盐的生物活性及其在脓毒症和感染性休克中的潜在治疗意义的证据。截至2025年4月，PubMed和其他来源的综合文献检索确定了评估丁酸盐补充治疗败血症的实验和临床研究。临床前研究表明，丁酸盐主要通过减少炎症、氧化应激和上皮屏障破坏来改善各器官系统（神经系统、肝脏、肠道、心脏、肺和肾脏）的功能。在盲肠结扎穿刺（CLP）或内毒素血症模型中，丁酸盐组的生存率提高了20-40%。人体数据有限：一项观察性研究发现，败血症幸存者的循环β-羟基丁酸水平较高，而一项随机试验报告，合成诱导丁酸升高的患者的胃肠道并发症和呼吸机相关肺炎较少。总的来说，目前的证据表明，丁酸盐可能调节败血症的关键病理生理途径，并具有作为辅助治疗的潜力。尽管如此，需要专门的早期临床试验来阐明安全性、最佳剂量、药效学和临床有效性。

{"title":"Therapeutic potential of butyrate supplementation in sepsis: a review of preclinical evidence and translational perspectives","authors":"Nicola Benvenuto , Filippo Mearelli , Gianni Biolo , Filippo Giorgio Di Girolamo , Erik Roman-Pognuz , Abbas Yadegar , Annalisa Serio , Saveria Lory Crocè , Mauro Giuffrè , Paolo De Cristofaro , Nina Grasselli Kmet , Maria Vittoria Micioni Di Bonaventura , Verena Zerbato , Stefano Di Bella","doi":"10.1016/j.ejphar.2026.178594","DOIUrl":"10.1016/j.ejphar.2026.178594","url":null,"abstract":"<div><div>Sepsis remains a major global health problem and is responsible for millions of deaths annually despite significant progress in antimicrobial therapy and organ support. Increasing evidence highlights the role of the gut–immune axis in shaping host responses during sepsis, with particular interest in microbiota-derived metabolites such as short-chain fatty acids (SCFAs). Among these, butyrate has emerged as a promising candidate due to its anti-inflammatory, immunomodulatory, and intestinal barrier–preserving properties. This narrative review summarizes current evidence regarding the biological activities of butyrate and its potential therapeutic relevance in sepsis and septic shock.</div><div>A comprehensive literature search of PubMed and additional sources up to April 2025 identified experimental and clinical studies evaluating butyrate supplementation in sepsis. Preclinical studies show that butyrate improves function across organ systems (neurologic, hepatic, intestinal, cardiac, pulmonary, and renal) mainly by reducing inflammation, oxidative stress, and epithelial barrier disruption. In models like cecal ligation and puncture (CLP) or endotoxemia, survival improved by 20–40 % with butyrate administration. Human data are limited: an observational study found higher circulating β-hydroxybutyrate levels in sepsis survivors, while a randomized trial reported fewer gastrointestinal complications and ventilator-associated pneumonia in patients with synbiotic-induced butyrate increases.</div><div>Overall, current evidence suggests that butyrate may modulate key pathophysiological pathways in sepsis and holds potential as an adjunctive therapy. Nonetheless, dedicated early-phase clinical trials are required to clarify safety, optimal dosing, pharmacodynamics, and clinical effectiveness.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178594"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Corilagin reduces ischemic stroke damage by neural stem cell-mediated neurorepair 胶原蛋白通过神经干细胞介导的神经修复减少缺血性中风损伤。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-22 DOI: 10.1016/j.ejphar.2026.178555

Qiang Wang , Mengzhen Wei , Rang Wu , Yu Ma , Jie Hu , Yanxin Ding , Shizhe Wang , Hezhong Jiang , Yawen Wang , Jian Gu , Rui Tan

Ischemic stroke (IS) is a common and refractory cerebrovascular disease that imposes a heavy burden on patients' families and society due to its high incidence, complex pathological mechanisms, and high mortality rate. Corilagin, the primary active component of the traditional Tibetan medicines Terminalia chebula and Phyllanthus emblica, is widely used in Tibetan medicine for treating cerebrovascular diseases. This study aims to comprehensively elucidate the mechanism of Corilagin in treating cerebral ischemia in IS through RNA transcriptome sequencing, validate its neurorestorative effects in cerebral ischemic rats, and explore the therapeutic potential of Corilagin for IS.

Methodology

In vitro, a glucose-oxygen deprivation (OGD) model of neural stem cells (NSCs) was established. Cell viability was assessed using the CCK8 assay, followed by RNA extraction for transcriptome analysis.In vivo, the therapeutic efficacy of Corilagin was validated using a rat model of cerebral ischemia.

Results

In the rat MCAO model, Corilagin was found to improve neurological deficits, promote the survival of damaged neurons in the cortex and hippocampal CA1 region, and exert neuroprotective effects. Transcriptome sequencing revealed that Corilagin acts on NSCs by regulating mitochondrial function, energy metabolism, and oxidative stress levels.Western blotting further validated its modulation of the HIF-α/ALDOA pathway. In the in vitro OGD model, Corilagin effectively mitigated NSC injury.

Conclusion

Corilagin exhibits therapeutic potential for ischemic stroke through neural stem cell-mediated neurorepair.

缺血性脑卒中（Ischemic stroke， IS）是一种常见的难治性脑血管疾病，其发病率高、病理机制复杂、死亡率高，给患者家庭和社会带来了沉重的负担。香桐素是藏药天竺、余甘子的主要有效成分，在藏药中广泛用于治疗脑血管疾病。本研究旨在通过RNA转录组测序全面阐明Corilagin治疗IS脑缺血的机制，验证其对缺血大鼠的神经修复作用，探索Corilagin治疗IS的潜力。方法：体外建立神经干细胞（NSCs）葡萄糖-氧剥夺（OGD）模型。使用CCK8法评估细胞活力，然后提取RNA进行转录组分析。在体内，用大鼠脑缺血模型验证了Corilagin的治疗效果。结果：在大鼠MCAO模型中，发现科里拉金可改善神经功能缺损，促进皮层和海马CA1区受损神经元的存活，并发挥神经保护作用。转录组测序显示，Corilagin通过调节线粒体功能、能量代谢和氧化应激水平作用于NSCs。Western blotting进一步验证了其对HIF-α/ALDOA通路的调节作用。在体外OGD模型中，Corilagin可有效减轻NSC损伤。结论：胶原蛋白通过神经干细胞介导的神经修复，具有治疗缺血性脑卒中的潜力。

{"title":"Corilagin reduces ischemic stroke damage by neural stem cell-mediated neurorepair","authors":"Qiang Wang , Mengzhen Wei , Rang Wu , Yu Ma , Jie Hu , Yanxin Ding , Shizhe Wang , Hezhong Jiang , Yawen Wang , Jian Gu , Rui Tan","doi":"10.1016/j.ejphar.2026.178555","DOIUrl":"10.1016/j.ejphar.2026.178555","url":null,"abstract":"<div><div>Ischemic stroke (IS) is a common and refractory cerebrovascular disease that imposes a heavy burden on patients' families and society due to its high incidence, complex pathological mechanisms, and high mortality rate. Corilagin, the primary active component of the traditional Tibetan medicines <em>Terminalia chebula</em> and <em>Phyllanthus emblica</em>, is widely used in Tibetan medicine for treating cerebrovascular diseases. This study aims to comprehensively elucidate the mechanism of Corilagin in treating cerebral ischemia in IS through RNA transcriptome sequencing, validate its neurorestorative effects in cerebral ischemic rats, and explore the therapeutic potential of Corilagin for IS.</div></div><div><h3>Methodology</h3><div>In vitro, a glucose-oxygen deprivation (OGD) model of neural stem cells (NSCs) was established. Cell viability was assessed using the CCK8 assay, followed by RNA extraction for transcriptome analysis.In vivo, the therapeutic efficacy of Corilagin was validated using a rat model of cerebral ischemia.</div></div><div><h3>Results</h3><div>In the rat MCAO model, Corilagin was found to improve neurological deficits, promote the survival of damaged neurons in the cortex and hippocampal CA1 region, and exert neuroprotective effects. Transcriptome sequencing revealed that Corilagin acts on NSCs by regulating mitochondrial function, energy metabolism, and oxidative stress levels.Western blotting further validated its modulation of the HIF-α/ALDOA pathway. In the in vitro OGD model, Corilagin effectively mitigated NSC injury.</div></div><div><h3>Conclusion</h3><div>Corilagin exhibits therapeutic potential for ischemic stroke through neural stem cell-mediated neurorepair.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178555"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

The TWEAK/FN14 axis influences the phenotype of cardiac fibroblasts during pathological cardiac remodeling through the regulation of EGR1 在病理性心脏重塑过程中，TWEAK/FN14轴通过调控EGR1影响心肌成纤维细胞的表型。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-22 DOI: 10.1016/j.ejphar.2026.178568

Wenqiang Han , Qingsu Lan , Runtian Zhang , Zimeng Shen , Jingquan Zhong , Li Hao

Background

Pathological cardiac remodeling is a critical process in the progression of cardiovascular diseases. To investigate the role and underlying mechanisms of the TWEAK/FN14 axis in cardiac fibrosis, we conducted both in vivo and in vitro experiments.

Methods and results

Transcriptomic analysis and Western blotting revealed that FN14 expression was upregulated in animal models of pathological cardiac remodeling. Knockdown of FN14 using adeno-associated virus in spontaneously hypertensive rats significantly attenuated cardiac remodeling. In cardiac fibroblasts, FN14 knockdown and overexpression, validated by Western blotting, wound healing assay, and EdU assay, confirmed that the TWEAK/FN14 axis regulates fibroblast phenotypes. Activation of the TWEAK/FN14 axis increased the expression of pro-fibrotic genes and extracellular matrix deposition. Furthermore, inhibitor and rescue experiments demonstrated that EGR1 functions as a critical downstream mediator in the TWEAK/FN14 axis–induced regulation of fibrosis.

Conclusions

These findings suggest that targeting the TWEAK/FN14 axis in cardiac fibroblasts may provide a novel therapeutic strategy for preventing and treating cardiac fibrosis and adverse remodeling.

背景：病理性心脏重构是心血管疾病发展的关键过程。为了研究TWEAK/FN14轴在心脏纤维化中的作用和潜在机制，我们进行了体内和体外实验。方法和结果：转录组学分析和Western blotting显示FN14在病理性心脏重构动物模型中表达上调。在自发性高血压大鼠中使用腺相关病毒敲除FN14可显著减弱心脏重构。在心脏成纤维细胞中，经Western blotting、伤口愈合试验和EdU试验验证，FN14敲低和过表达证实了TWEAK/FN14轴调节成纤维细胞表型。TWEAK/FN14轴的激活增加了促纤维化基因的表达和细胞外基质沉积。此外，抑制剂和救援实验表明，EGR1在TWEAK/FN14轴诱导的纤维化调节中是一个关键的下游介质。结论：这些发现表明，靶向心脏成纤维细胞中的TWEAK/FN14轴可能为预防和治疗心脏纤维化和不良重构提供一种新的治疗策略。

{"title":"The TWEAK/FN14 axis influences the phenotype of cardiac fibroblasts during pathological cardiac remodeling through the regulation of EGR1","authors":"Wenqiang Han , Qingsu Lan , Runtian Zhang , Zimeng Shen , Jingquan Zhong , Li Hao","doi":"10.1016/j.ejphar.2026.178568","DOIUrl":"10.1016/j.ejphar.2026.178568","url":null,"abstract":"<div><h3>Background</h3><div>Pathological cardiac remodeling is a critical process in the progression of cardiovascular diseases. To investigate the role and underlying mechanisms of the TWEAK/FN14 axis in cardiac fibrosis, we conducted both in vivo and in vitro experiments.</div></div><div><h3>Methods and results</h3><div>Transcriptomic analysis and Western blotting revealed that FN14 expression was upregulated in animal models of pathological cardiac remodeling. Knockdown of FN14 using adeno-associated virus in spontaneously hypertensive rats significantly attenuated cardiac remodeling. In cardiac fibroblasts, FN14 knockdown and overexpression, validated by Western blotting, wound healing assay, and EdU assay, confirmed that the TWEAK/FN14 axis regulates fibroblast phenotypes. Activation of the TWEAK/FN14 axis increased the expression of pro-fibrotic genes and extracellular matrix deposition. Furthermore, inhibitor and rescue experiments demonstrated that EGR1 functions as a critical downstream mediator in the TWEAK/FN14 axis–induced regulation of fibrosis.</div></div><div><h3>Conclusions</h3><div>These findings suggest that targeting the TWEAK/FN14 axis in cardiac fibroblasts may provide a novel therapeutic strategy for preventing and treating cardiac fibrosis and adverse remodeling.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178568"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Modulation of mineralocorticoid and peroxisome proliferator activated receptors in attenuating hyperlipidemia induced endothelial dysfunction and vascular dementia 调节矿化皮质激素和过氧化物酶体增殖物激活受体在减轻高脂血症诱导的内皮功能障碍和血管性痴呆中的作用。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-22 DOI: 10.1016/j.ejphar.2026.178588

Baldev Raj , Pankaj Bhatia , Amit Kumar , Nirmal Singh , Amteshwar Singh Jaggi

Vascular dementia (VaD) is closely associated with metabolic disturbances and endothelial dysfunction. The present study evaluated the effects of eplerenone, a mineralocorticoid receptor antagonist, pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, and fenofibrate, a PPARα agonist, administered alone and in combination, in a high-fat diet (HFD)-induced rat model of endothelial dysfunction and VaD. Rats were fed an HFD for 90 days to induce metabolic and vascular alterations. Cognitive performance was assessed using the Morris Water Maze test. Endothelial function was evaluated by measuring endothelium-dependent vasorelaxation in isolated aortic rings and serum nitrite levels. Biochemical markers of oxidative stress, inflammation, and cholinergic function, along with histopathological changes in brain tissue, were also analysed.

HFD feeding resulted in marked endothelial dysfunction, evidenced by impaired vasorelaxation and reduced serum nitrite levels, along with significant cognitive deficits. These changes were accompanied by increased oxidative stress, indicated by elevated thiobarbituric acid reactive substances and reduced glutathione levels, as well as increased acetylcholinesterase and myeloperoxidase activities and neutrophil infiltration in the brain. Treatment with eplerenone, pioglitazone, and fenofibrate, individually and in combination, attenuated endothelial dysfunction, improved cognitive performance, and normalized biochemical and histopathological alterations, with combination therapy showing greater overall efficacy.

The novelty of this study lies in its systematic comparison and rational combination of mineralocorticoid receptors (MR) antagonism with PPARα and PPARγ activation in a high-fat diet–induced model of vascular dementia, demonstrating enhanced neurovascular protection with low-dose combination therapy.

血管性痴呆（VaD）与代谢紊乱和内皮功能障碍密切相关。本研究评估了矿皮质激素受体拮抗剂eplerenone、过氧化物酶体增殖物激活受体(PPAR) γ激动剂吡格列酮和PPARα激动剂非诺贝特在高脂肪饮食（HFD）诱导的内皮功能障碍和VaD大鼠模型中单独或联合使用的效果。大鼠连续90天饲喂HFD，以诱导代谢和血管改变。认知能力评估采用莫里斯水迷宫测试。通过测量离体主动脉环内皮依赖性血管松弛和血清亚硝酸盐水平来评估内皮功能。我们还分析了氧化应激、炎症和胆碱能功能的生化指标，以及脑组织的组织病理学变化。HFD喂养导致明显的内皮功能障碍，表现为血管松弛受损和血清亚硝酸盐水平降低，以及显著的认知障碍。这些变化伴随着氧化应激的增加，表现为硫代巴比妥酸活性物质升高和谷胱甘肽水平降低，以及乙酰胆碱酯酶和髓过氧化物酶活性增加和脑中性粒细胞浸润。依普利酮、吡格列酮和非诺贝特单独或联合治疗可减轻内皮功能障碍，改善认知能力，并使生化和组织病理学改变正常化，联合治疗显示出更大的总体疗效。本研究的新颖之处在于，在高脂饮食诱导的血管性痴呆模型中，系统比较并合理结合矿化皮质激素受体（MR）拮抗剂与PPARα和PPARγ激活，证明低剂量联合治疗可增强神经血管保护。

{"title":"Modulation of mineralocorticoid and peroxisome proliferator activated receptors in attenuating hyperlipidemia induced endothelial dysfunction and vascular dementia","authors":"Baldev Raj , Pankaj Bhatia , Amit Kumar , Nirmal Singh , Amteshwar Singh Jaggi","doi":"10.1016/j.ejphar.2026.178588","DOIUrl":"10.1016/j.ejphar.2026.178588","url":null,"abstract":"<div><div>Vascular dementia (VaD) is closely associated with metabolic disturbances and endothelial dysfunction. The present study evaluated the effects of eplerenone, a mineralocorticoid receptor antagonist, pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, and fenofibrate, a PPARα agonist, administered alone and in combination, in a high-fat diet (HFD)-induced rat model of endothelial dysfunction and VaD. Rats were fed an HFD for 90 days to induce metabolic and vascular alterations. Cognitive performance was assessed using the Morris Water Maze test. Endothelial function was evaluated by measuring endothelium-dependent vasorelaxation in isolated aortic rings and serum nitrite levels. Biochemical markers of oxidative stress, inflammation, and cholinergic function, along with histopathological changes in brain tissue, were also analysed.</div><div>HFD feeding resulted in marked endothelial dysfunction, evidenced by impaired vasorelaxation and reduced serum nitrite levels, along with significant cognitive deficits. These changes were accompanied by increased oxidative stress, indicated by elevated thiobarbituric acid reactive substances and reduced glutathione levels, as well as increased acetylcholinesterase and myeloperoxidase activities and neutrophil infiltration in the brain. Treatment with eplerenone, pioglitazone, and fenofibrate, individually and in combination, attenuated endothelial dysfunction, improved cognitive performance, and normalized biochemical and histopathological alterations, with combination therapy showing greater overall efficacy.</div><div>The novelty of this study lies in its systematic comparison and rational combination of mineralocorticoid receptors (MR) antagonism with PPARα and PPARγ activation in a high-fat diet–induced model of vascular dementia, demonstrating enhanced neurovascular protection with low-dose combination therapy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1016 ","pages":"Article 178588"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Triple drug co-delivery within nanosystems for synergistic anti-infective, anti-inflammatory, antinociceptive and neuroregenerative therapeutic effects: a focus on pharmacological and nanotechnological aspects 纳米系统内三联药共递送的协同抗感染、抗炎、抗伤害和神经再生治疗效果：药理学和纳米技术方面的重点。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.ejphar.2026.178585

Maria Sofia Anastácio , Francisco Veiga , Ana Cláudia Paiva-Santos , Patrícia C. Pires

Nanotechnology has emerged as an innovative tool capable of overcoming the limitations of traditional drug delivery systems, by enabling enhanced drug solubility and stability, controlled drug release, and improved drug targeting. Additionally, nanosystems can allow the co-encapsulation of multiple drugs simultaneously, harnessing their synergistic pharmacological effects, leading to increased therapeutic efficacy and safety. The purpose of this review is to critically analyze studies that have developed triple drug-loaded nanosystems, exploring various different nanoplatforms, such as polymeric nanoparticles, lipid nanoparticles, microcapsules, nanoemulsions, nanoemulgels, thermosensitive hydrogels, and nanocomposite hydrogels. Triple drug co-encapsulation has been achieved for non-steroidal anti-inflammatory drugs such as indomethacin, analgesic and antipyretic drugs such as paracetamol, immunosuppressant drugs such as methotrexate, antiretroviral drugs such as efavirenz, lopinavir, ritonavir, and tenofovir, antibacterial drugs such as amoxicillin and clarithromycin, antiulcer drugs such as omeprazole and famotidine, ion channel antagonists such as lomerizine hydrochloride, oxidized adenosine triphosphate, and zonampanel monohydrate, photosensitive molecules such as indocyanine green, genetic material such as MMP-9 siRNA, enzymes such as catalase, and/or plant-derived bioactive compounds such as curcumin, resveratrol, sinomenine, and thymoquinone. These molecules’ triple co-encapsulation into nanometric formulations has led to controlled and sustained drug release, extended circulation time, enhanced bioavailability, and reduced systemic toxicity, with an overall improvement in drug targeting and therapeutic outcomes in rheumatoid arthritis, psoriasis and other inflammation-based conditions, HIV and Helicobacter pylori infection, and trauma-induced central nervous system secondary degeneration, ultimately opening a door for improved patient compliance due to simplified dosing regimens.

纳米技术已经成为一种创新的工具，能够克服传统药物传递系统的局限性，通过增强药物的溶解度和稳定性，控制药物释放，改善药物靶向性。此外，纳米系统可以允许多种药物同时共包封，利用它们的协同药理作用，从而提高治疗效果和安全性。本综述的目的是批判性地分析已经开发的三重药物负载纳米系统的研究，探索各种不同的纳米平台，如聚合纳米颗粒、脂质纳米颗粒、微胶囊、纳米乳液、纳米凝胶、热敏水凝胶和纳米复合水凝胶。非甾体抗炎药如吲哚美辛，镇痛解热药如扑热息痛，免疫抑制剂如甲氨喋呤，抗逆转录病毒药物如依非韦伦、洛匹那韦、利托那韦、替诺福韦，抗菌药物如阿莫西林、克拉霉素，抗溃疡药物如奥美拉唑、法莫替丁，离子通道拮抗剂如盐酸洛美嗪、氧化三磷酸腺苷，光敏分子如吲哚菁绿，遗传物质如MMP-9 siRNA，酶如过氧化氢酶，和/或植物源性生物活性化合物如姜黄素、白藜芦醇、青藤碱和百里醌。这些分子的三重共包被纳米制剂，导致了药物的可控和持续释放，延长了循环时间，提高了生物利用度，降低了全身毒性，在类风湿关节炎、牛皮癣和其他炎症性疾病、HIV和幽门螺杆菌感染以及创伤性中枢神经系统继发性变性方面的药物靶向性和治疗效果得到了全面改善。由于简化了给药方案，最终为提高患者依从性打开了大门。

{"title":"Triple drug co-delivery within nanosystems for synergistic anti-infective, anti-inflammatory, antinociceptive and neuroregenerative therapeutic effects: a focus on pharmacological and nanotechnological aspects","authors":"Maria Sofia Anastácio , Francisco Veiga , Ana Cláudia Paiva-Santos , Patrícia C. Pires","doi":"10.1016/j.ejphar.2026.178585","DOIUrl":"10.1016/j.ejphar.2026.178585","url":null,"abstract":"<div><div>Nanotechnology has emerged as an innovative tool capable of overcoming the limitations of traditional drug delivery systems, by enabling enhanced drug solubility and stability, controlled drug release, and improved drug targeting. Additionally, nanosystems can allow the co-encapsulation of multiple drugs simultaneously, harnessing their synergistic pharmacological effects, leading to increased therapeutic efficacy and safety. The purpose of this review is to critically analyze studies that have developed triple drug-loaded nanosystems, exploring various different nanoplatforms, such as polymeric nanoparticles, lipid nanoparticles, microcapsules, nanoemulsions, nanoemulgels, thermosensitive hydrogels, and nanocomposite hydrogels. Triple drug co-encapsulation has been achieved for non-steroidal anti-inflammatory drugs such as indomethacin, analgesic and antipyretic drugs such as paracetamol, immunosuppressant drugs such as methotrexate, antiretroviral drugs such as efavirenz, lopinavir, ritonavir, and tenofovir, antibacterial drugs such as amoxicillin and clarithromycin, antiulcer drugs such as omeprazole and famotidine, ion channel antagonists such as lomerizine hydrochloride, oxidized adenosine triphosphate, and zonampanel monohydrate, photosensitive molecules such as indocyanine green, genetic material such as MMP-9 siRNA, enzymes such as catalase, and/or plant-derived bioactive compounds such as curcumin, resveratrol, sinomenine, and thymoquinone. These molecules’ triple co-encapsulation into nanometric formulations has led to controlled and sustained drug release, extended circulation time, enhanced bioavailability, and reduced systemic toxicity, with an overall improvement in drug targeting and therapeutic outcomes in rheumatoid arthritis, psoriasis and other inflammation-based conditions, HIV and <em>Helicobacter pylori</em> infection, and trauma-induced central nervous system secondary degeneration, ultimately opening a door for improved patient compliance due to simplified dosing regimens.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178585"},"PeriodicalIF":4.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

CRISPR/Cas9-based genome-wide screen reveals a synergistic effect of Irinotecan and USP1 inhibitor in colorectal cancer 基于CRISPR/ cas9的全基因组筛选揭示了伊立替康和USP1抑制剂在结直肠癌中的协同作用。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.ejphar.2026.178558

Lei Wang , Min Miao , Lijing Bao , Junfeng Chu , Juan Zhou , Wenbo Song , Peipei Cai , Chen Cheng , Hongye Xu , Tao Wang , Rongrong Zhao , Hang Wang , Feng Liu , Ming Xu , Guangyu Tian

Irinotecan resistance remains a significant challenge in metastatic colorectal cancer (mCRC) therapy. To address this, we identified USP1 as a synthetic lethal partner of Irinotecan through genome-wide CRISPR/Cas9 screening in HCT-116 cells. Combining the USP1 inhibitor I-138 with Irinotecan in HCT-116, HT-29, and SW620 cell lines significantly reduced IC₅₀, suppressed proliferation, and diminished colony formation compared to monotherapy, demonstrating a synergistic effect (combination index CI < 1). The synergistic therapeutic efficacy was further validated in the xenograft mouse model. Mechanistic studies revealed that I-138 significantly upregulated pCREB (Ser133), concurrently dynamically regulating the activity of USP1, FANCD2/FANCI, and PCNA upon DNA damage response and repair. RNA sequencing further highlighted the enrichment of cAMP, PI3K-AKT, and Wnt pathways, which are all linked to CREB activity in the combination group. These findings establish USP1 inhibition as a promising strategy to overcome Irinotecan resistance through the combination strategy, providing a novel therapeutic avenue for CRC.

在转移性结直肠癌（mCRC）治疗中，伊立替康耐药性仍然是一个重大挑战。为了解决这个问题，我们通过在HCT-116细胞中进行全基因组CRISPR/Cas9筛选，确定了USP1是伊立替康的合成致死伴侣。与单药治疗相比，USP1抑制剂I-138与伊立替康联合治疗HCT-116、HT-29和SW620细胞系可显著降低IC50，抑制增殖，减少菌落形成，显示出协同效应（联合指数CI）

{"title":"CRISPR/Cas9-based genome-wide screen reveals a synergistic effect of Irinotecan and USP1 inhibitor in colorectal cancer","authors":"Lei Wang , Min Miao , Lijing Bao , Junfeng Chu , Juan Zhou , Wenbo Song , Peipei Cai , Chen Cheng , Hongye Xu , Tao Wang , Rongrong Zhao , Hang Wang , Feng Liu , Ming Xu , Guangyu Tian","doi":"10.1016/j.ejphar.2026.178558","DOIUrl":"10.1016/j.ejphar.2026.178558","url":null,"abstract":"<div><div>Irinotecan resistance remains a significant challenge in metastatic colorectal cancer (mCRC) therapy. To address this, we identified USP1 as a synthetic lethal partner of Irinotecan through genome-wide CRISPR/Cas9 screening in HCT-116 cells. Combining the USP1 inhibitor I-138 with Irinotecan in HCT-116, HT-29, and SW620 cell lines significantly reduced IC<sub>50</sub>, suppressed proliferation, and diminished colony formation compared to monotherapy, demonstrating a synergistic effect (combination index CI < 1). The synergistic therapeutic efficacy was further validated in the xenograft mouse model. Mechanistic studies revealed that I-138 significantly upregulated pCREB (Ser133), concurrently dynamically regulating the activity of USP1, FANCD2/FANCI, and PCNA upon DNA damage response and repair. RNA sequencing further highlighted the enrichment of cAMP, PI3K-AKT, and Wnt pathways, which are all linked to CREB activity in the combination group. These findings establish USP1 inhibition as a promising strategy to overcome Irinotecan resistance through the combination strategy, providing a novel therapeutic avenue for CRC.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178558"},"PeriodicalIF":4.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Transglutaminase 2 activation is involved in thoracic aortic dissection through disruption of endothelial adherens junctions 转谷氨酰胺酶2激活通过破坏内皮粘附连接参与胸主动脉夹层

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.ejphar.2026.178548

Xinyao Li , Weixin Zhang , Jie Gao , Lin Zhang , Yuqing Liao , Qin Liu , Qinghua Zhang , Chaoyun Wang , Lin Zhong , Xinkang Wang , Yumei Li

Thoracic aortic dissection (TAD) is a life-threatening condition. While medial degeneration is a hallmark of TAD, emerging evidence underscores endothelial dysfunction as a critical initiating event. However, the specific molecular mediators orchestrating endothelial damage in TAD remain poorly defined. Transglutaminase 2 (TGM2), a multifunctional enzyme upregulated in TAD tissues, has been implicated in vascular pathology but its cell-specific roles, particularly in endothelium, are unknown. Here, we hypothesize that endothelial TGM2 is a key instigator of TAD pathogenesis. Using transmission electron microscopy in a β-aminopropionitrile (BAPN)-induced rat TAD model, we further identified profound ultrastructural damage in the aortic intima, including disrupted endothelial junctions and cell loss, etc. We found that TGM2 expression was significantly elevated specifically within the damaged aortic intima of patients and rats with TAD. In vitro, TGM2 knockdown in human aortic endothelial cells (HAECs) preserved intercellular junction integrity, whereas its overexpression exacerbated endothelial dysfunction. Mechanistically, TGM2 activation triggered the nuclear factor kappa-B (NF-κB) signaling pathway, leading to downregulation of VE-cadherin and upregulation of matrix metalloproteinase 2 (MMP2), thereby disrupting adherens junctions and promoting extracellular matrix degradation. In vivo, the TGM2 inhibitor cystamine dihydrochloride (Cys-D) attenuated aortic intima thickening, restored junctional integrity, reduced plasma TGM2 levels, and decreased TAD-related morbidity and mortality in rats. Our findings unveil a previously unrecognized endothelium-intrinsic role for TGM2 in driving TAD, positioning it as a promising therapeutic target directed at the endothelial origin of this devastating disease.

胸主动脉夹层（TAD）是危及生命的疾病。虽然内侧退变是TAD的标志，但新出现的证据强调内皮功能障碍是一个关键的起始事件。然而，在TAD中协调内皮损伤的特定分子介质仍然不明确。转谷氨酰胺酶2 （TGM2）是一种在TAD组织中上调的多功能酶，与血管病理有关，但其细胞特异性作用，特别是在内皮细胞中的作用尚不清楚。在这里，我们假设内皮细胞TGM2是TAD发病的一个关键促动因子。在β-氨基丙腈（BAPN）诱导的大鼠TAD模型中，我们进一步发现了主动脉内膜的严重超微结构损伤，包括内皮连接破坏和细胞丢失等。我们发现，在TAD患者和大鼠受损的主动脉内膜中，TGM2的表达显著升高。在体外，TGM2在人主动脉内皮细胞（HAECs）中下调可保持细胞间连接的完整性，而其过表达则会加剧内皮功能障碍。机制上，TGM2激活触发核因子κ b （NF-κB）信号通路，导致VE-cadherin下调，基质金属蛋白酶2 （MMP2）上调，从而破坏粘附体连接，促进细胞外基质降解。在体内，TGM2抑制剂盐酸半胺（cyys - d）可减轻大鼠主动脉内膜增厚，恢复连接完整性，降低血浆TGM2水平，降低tad相关的发病率和死亡率。我们的研究结果揭示了TGM2在驱动TAD中以前未被认识到的内皮内在作用，将其定位为针对这种毁灭性疾病的内皮起源的有希望的治疗靶点。

{"title":"Transglutaminase 2 activation is involved in thoracic aortic dissection through disruption of endothelial adherens junctions","authors":"Xinyao Li , Weixin Zhang , Jie Gao , Lin Zhang , Yuqing Liao , Qin Liu , Qinghua Zhang , Chaoyun Wang , Lin Zhong , Xinkang Wang , Yumei Li","doi":"10.1016/j.ejphar.2026.178548","DOIUrl":"10.1016/j.ejphar.2026.178548","url":null,"abstract":"<div><div>Thoracic aortic dissection (TAD) is a life-threatening condition. While medial degeneration is a hallmark of TAD, emerging evidence underscores endothelial dysfunction as a critical initiating event. However, the specific molecular mediators orchestrating endothelial damage in TAD remain poorly defined. Transglutaminase 2 (TGM2), a multifunctional enzyme upregulated in TAD tissues, has been implicated in vascular pathology but its cell-specific roles, particularly in endothelium, are unknown. Here, we hypothesize that endothelial TGM2 is a key instigator of TAD pathogenesis. Using transmission electron microscopy in a β-aminopropionitrile (BAPN)-induced rat TAD model, we further identified profound ultrastructural damage in the aortic intima, including disrupted endothelial junctions and cell loss, etc. We found that TGM2 expression was significantly elevated specifically within the damaged aortic intima of patients and rats with TAD. In vitro, TGM2 knockdown in human aortic endothelial cells (HAECs) preserved intercellular junction integrity, whereas its overexpression exacerbated endothelial dysfunction. Mechanistically, TGM2 activation triggered the nuclear factor kappa-B (NF-κB) signaling pathway, leading to downregulation of VE-cadherin and upregulation of matrix metalloproteinase 2 (MMP2), thereby disrupting adherens junctions and promoting extracellular matrix degradation. In vivo, the TGM2 inhibitor cystamine dihydrochloride (Cys-D) attenuated aortic intima thickening, restored junctional integrity, reduced plasma TGM2 levels, and decreased TAD-related morbidity and mortality in rats. Our findings unveil a previously unrecognized endothelium-intrinsic role for TGM2 in driving TAD, positioning it as a promising therapeutic target directed at the endothelial origin of this devastating disease.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178548"},"PeriodicalIF":4.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Modulatory effect of dopamine receptors on long-term potentiation in dorsal and ventral hippocampus in anesthetized kindled rats 多巴胺受体对麻醉点燃大鼠海马背侧和腹侧长期增强的调节作用。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.ejphar.2026.178590

Maryam Sharifi , Shahrbanoo Oryan , Alireza Komaki , Abdolrahman Sarihi , Javad Mirnajafi-Zadeh

The dopaminergic system acts as a crucial regulator of synaptic plasticity. Nonetheless, the exact role of dopamine receptors in modulating this process following seizure remains unclear. We investigated the role of dopamine receptors on synaptic plasticity in the dorsal and ventral hippocampal CA1 regions of PTZ-kindled rats. Following kindling induction with repeated PTZ (37.5 mg/kg), evoked field potentials were obtained from the CA1 region in response to Schaffer collateral stimulation in urethane-anesthetized (1.5 g/kg) rats. Quinpirole hydrochloride (D2-like receptor agonist, 2.5, 5, 10, and 20μg/2.5 μL) or SKF38393 hydrochloride (D1-like receptor agonist, 5 and 10 μg/μL) were microinjected into the lateral ventricle 30 or 25 min before long-term potentiation (LTP) induction, respectively. Haloperidol (D2-like receptor antagonist, 2 μg/μL) was administered 15 min prior to quinpirole hydrochloride. D2-like receptors activation had a dual effect on synaptic potentiation in control and kindled animals across both hippocampal regions. Quinpirole hydrochloride affected on synaptic plasticity in a U-shaped manner in control rats, while restored impaired LTP in kindled animals. Haloperidol inhibited theses effects in both groups, while SKF38393 had no impact on synaptic plasticity. These findings underscore the function of dopaminergic receptors in synaptic plasticity and their potential therapeutic implications for alleviating seizure-induced dysfunction.

多巴胺能系统是突触可塑性的关键调节器。尽管如此，多巴胺受体在癫痫发作后调节这一过程中的确切作用仍不清楚。我们研究了多巴胺受体在ptz点燃大鼠海马CA1区背侧和腹侧突触可塑性中的作用。经反复PTZ （37.5 mg/kg）点燃后，对麻醉大鼠（1.5 g/kg）的CA1区进行Schaffer侧枝刺激的诱发场电位测定。将盐酸喹匹罗（d2样受体激动剂，2.5、5、10和20μg/2.5μL）或盐酸SKF38393 （d1样受体激动剂，5和10μg/μL）分别在长时程增强（LTP）诱导前30和25 min微注射到侧脑室。氟哌啶醇（d2样受体拮抗剂，2μg/μL）在盐酸喹匹罗治疗前15 min给药。d2样受体的激活对对照组和点燃动物的两个海马区域的突触增强有双重影响。盐酸喹匹罗对对照组大鼠突触可塑性的影响呈u型，对点燃大鼠LTP损伤有恢复作用。氟哌啶醇抑制了两组的这些作用，而SKF38393对突触可塑性没有影响。这些发现强调了多巴胺能受体在突触可塑性中的作用及其在缓解癫痫诱发功能障碍方面的潜在治疗意义。

{"title":"Modulatory effect of dopamine receptors on long-term potentiation in dorsal and ventral hippocampus in anesthetized kindled rats","authors":"Maryam Sharifi , Shahrbanoo Oryan , Alireza Komaki , Abdolrahman Sarihi , Javad Mirnajafi-Zadeh","doi":"10.1016/j.ejphar.2026.178590","DOIUrl":"10.1016/j.ejphar.2026.178590","url":null,"abstract":"<div><div>The dopaminergic system acts as a crucial regulator of synaptic plasticity. Nonetheless, the exact role of dopamine receptors in modulating this process following seizure remains unclear. We investigated the role of dopamine receptors on synaptic plasticity in the dorsal and ventral hippocampal CA1 regions of PTZ-kindled rats. Following kindling induction with repeated PTZ (37.5 mg/kg), evoked field potentials were obtained from the CA1 region in response to Schaffer collateral stimulation in urethane-anesthetized (1.5 g/kg) rats. Quinpirole hydrochloride (D2-like receptor agonist, 2.5, 5, 10, and 20μg/2.5 μL) or SKF38393 hydrochloride (D1-like receptor agonist, 5 and 10 μg/μL) were microinjected into the lateral ventricle 30 or 25 min before long-term potentiation (LTP) induction, respectively. Haloperidol (D2-like receptor antagonist, 2 μg/μL) was administered 15 min prior to quinpirole hydrochloride. D2-like receptors activation had a dual effect on synaptic potentiation in control and kindled animals across both hippocampal regions. Quinpirole hydrochloride affected on synaptic plasticity in a U-shaped manner in control rats, while restored impaired LTP in kindled animals. Haloperidol inhibited theses effects in both groups, while SKF38393 had no impact on synaptic plasticity. These findings underscore the function of dopaminergic receptors in synaptic plasticity and their potential therapeutic implications for alleviating seizure-induced dysfunction.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1016 ","pages":"Article 178590"},"PeriodicalIF":4.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

YAP inhibition by gloriosine unlocks autophagic cell death as an anticancer strategy in lung malignancies glosine抑制YAP开启自噬细胞死亡作为肺恶性肿瘤的抗癌策略。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.ejphar.2026.178582

Biswajit Dey , Bharat Goel , Essha Chatterjee , Hoshiyar Singh , Hari Chander Reddy , Anjali Cholkar , Santanu Basak , Anamika Sharma , Rahul Kumar , Swathi Lakshmi S. , Shreyans Kumar Jain , Pankaj Kumar Singh , Nandkumar Doijad , Santosh Kumar Guru

Historically, lung cancer has been considered the leading cause of cancer-related death worldwide. Though some of the chemotherapeutic agents show promising outcomes in the ongoing battle against cancer, the overall survival rate for advanced-stage disease remains poor due to drug resistance, toxicity, and limited efficacy. Therefore, new chemotherapeutic agents are required to enhance efficacy, reduce side effects, and combat drug resistance. In the present study, we isolated a compound, gloriosine, and investigated its anticancer potential against different cancer cells, with a special focus on A549 lung adenocarcinoma cells. Treatment with gloriosine resulted in a significant reduction in cell viability in a dose- and time-dependent manner and reduced tumor size in the tumor xenograft model. Interestingly, gloriosine exhibited minimal cytotoxicity on normal cells, indicating its selective activity on cancer cells. Mechanistically, gloriosine induced G2/M cell cycle arrest in A549 cells within an hour of treatment and was found to affect the Hippo signaling pathway, leading to the retention and phosphorylation of the Yes-associated protein (YAP) in the cytoplasm, thereby inhibiting the activation of downstream target genes. This, in turn, led to the suppression of the AKT/mTOR pathway and the activation of autophagy-dependent cell death. These findings suggest that gloriosine could be a promising candidate for the development of new lung cancer therapies.

从历史上看，肺癌一直被认为是全球癌症相关死亡的主要原因。尽管一些化疗药物在与癌症的持续斗争中显示出有希望的结果，但由于耐药性、毒性和有限的疗效，晚期疾病的总体生存率仍然很低。因此，需要新的化疗药物来提高疗效，减少副作用，并对抗耐药性。在本研究中，我们分离了一种化合物，光荣苷，并研究了它对不同癌细胞的抗癌潜力，特别关注A549肺腺癌细胞。在异种肿瘤移植模型中，用光荣苷治疗导致细胞活力以剂量和时间依赖的方式显著降低，肿瘤大小减小。有趣的是，光荣苷对正常细胞表现出最小的细胞毒性，表明它对癌细胞有选择性活性。在机制上，在A549细胞中，荣光苷在1小时内诱导G2/M细胞周期阻滞，并发现影响Hippo信号通路，导致细胞质中yes相关蛋白（YAP）的保留和磷酸化，从而抑制下游靶基因的激活。这进而导致AKT/mTOR通路的抑制和自噬依赖性细胞死亡的激活。这些发现表明，荣耀氨酸可能是开发新的肺癌治疗方法的有希望的候选者。

{"title":"YAP inhibition by gloriosine unlocks autophagic cell death as an anticancer strategy in lung malignancies","authors":"Biswajit Dey , Bharat Goel , Essha Chatterjee , Hoshiyar Singh , Hari Chander Reddy , Anjali Cholkar , Santanu Basak , Anamika Sharma , Rahul Kumar , Swathi Lakshmi S. , Shreyans Kumar Jain , Pankaj Kumar Singh , Nandkumar Doijad , Santosh Kumar Guru","doi":"10.1016/j.ejphar.2026.178582","DOIUrl":"10.1016/j.ejphar.2026.178582","url":null,"abstract":"<div><div>Historically, lung cancer has been considered the leading cause of cancer-related death worldwide. Though some of the chemotherapeutic agents show promising outcomes in the ongoing battle against cancer, the overall survival rate for advanced-stage disease remains poor due to drug resistance, toxicity, and limited efficacy. Therefore, new chemotherapeutic agents are required to enhance efficacy, reduce side effects, and combat drug resistance. In the present study, we isolated a compound, gloriosine, and investigated its anticancer potential against different cancer cells, with a special focus on A549 lung adenocarcinoma cells. Treatment with gloriosine resulted in a significant reduction in cell viability in a dose- and time-dependent manner and reduced tumor size in the tumor xenograft model. Interestingly, gloriosine exhibited minimal cytotoxicity on normal cells, indicating its selective activity on cancer cells. Mechanistically, gloriosine induced G2/M cell cycle arrest in A549 cells within an hour of treatment and was found to affect the Hippo signaling pathway, leading to the retention and phosphorylation of the Yes-associated protein (YAP) in the cytoplasm, thereby inhibiting the activation of downstream target genes. This, in turn, led to the suppression of the AKT/mTOR pathway and the activation of autophagy-dependent cell death. These findings suggest that gloriosine could be a promising candidate for the development of new lung cancer therapies.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178582"},"PeriodicalIF":4.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

4-Phenylbutyrate attenuates doxorubicin-induced cardiorenal comorbidity by suppressing ER stress-mediated epithelial-mesenchymal transition and endothelial-mesenchymal transition 4-苯基丁酸通过抑制内质电应激介导的上皮-间质转化和内皮-间质转化，减轻阿霉素诱导的心肾合并症

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2026-01-20 DOI: 10.1016/j.ejphar.2026.178580

Wenyu Hui , Weiwei Cui , Jie Li , Mengyuan Cheng , Yangyang Liu , Yunru Peng , Yongfang Ding

Objective

Cardiorenal syndrome (CRS), a spectrum of disorders involving intertwined cardiac and renal dysfunction, poses a significant challenge to mechanistic research due to a lack of accurate in vivo models. This study investigated the role of endoplasmic reticulum (ER) stress in mediating endothelial-to-mesenchymal transition (EndMT) and epithelial-to-mesenchymal transition (EMT) in a mouse model of cardiorenal comorbidity. Moreover, we investigated the therapeutic potential of 4-phenylbutyrate (4-PBA), an ER stress inhibitor, in attenuating cardiorenal comorbidity.

Methods

We employed a doxorubicin (Dox)-induced mouse model of cardiorenal comorbidity to investigate the role of ER stress in mediating EndMT and EMT. Six weeks post-Dox treatment, echocardiography, urinalysis, and blood tests were performed, complemented by immunofluorescence and Western blot analyses of cardiac and renal tissues. 4-PBA was intraperitoneally administered to evaluate the effect of ER stress inhibition on cardiorenal comorbidity.

Results

Dox administration significantly impaired cardiac and renal function, accompanied by pronounced fibrosis and upregulation of EndMT, EMT and ER stress markers. 4-PBA treatment attenuated cardiac injury, restored function, and ameliorated renal lesions. Consistent with in vivo results, Dox activated ER stress in HUVEC and HK-2 cells, promoting mesenchymal transformation. Critically, 4-PBA suppressed EndMT and EMT in vitro, supporting ER stress involvement in these processes.

Conclusions

Our findings demonstrate that Dox induces concurrent cardiorenal dysfunction, primarily through ER stress-mediated EndMT and EMT transitions. Importantly, pharmacological inhibition of ER stress with 4-PBA attenuated these pathological changes, suggesting its potential as a therapeutic strategy for cardiorenal syndrome.

心肾综合征（CRS）是一系列涉及心脏和肾脏功能紊乱的疾病，由于缺乏准确的体内模型，对其机制研究构成了重大挑战。本研究探讨了内质网应激在心肾合并症小鼠模型中介导内皮-间质转化（EndMT）和上皮-间质转化（EMT）中的作用。此外，我们还研究了内质网应激抑制剂4-苯基丁酸酯（4-PBA）在减轻心肾合并症方面的治疗潜力。方法采用多柔比星（Dox）诱导的心肾合并症小鼠模型，探讨内质网应激在EndMT和EMT中的作用。dox治疗6周后，进行超声心动图、尿液分析和血液检查，并辅以心脏和肾脏组织的免疫荧光和Western blot分析。腹腔注射4-PBA以评估内质网应激抑制对心肾合并症的影响。结果dox给药显著损害了心脏和肾脏功能，伴有明显的纤维化和EndMT、EMT和ER应激标志物的上调。4-PBA治疗可减轻心脏损伤，恢复功能，改善肾脏病变。与体内实验结果一致，Dox激活HUVEC和HK-2细胞的内质网应激，促进间质转化。关键的是，4-PBA在体外抑制了EndMT和EMT，支持内质网应激参与这些过程。结论研究结果表明，Dox主要通过内质网应激介导的EndMT和EMT转换诱导并发心肾功能障碍。重要的是，4-PBA对内质网应激的药理学抑制减轻了这些病理变化，表明其作为心肾综合征治疗策略的潜力。

{"title":"4-Phenylbutyrate attenuates doxorubicin-induced cardiorenal comorbidity by suppressing ER stress-mediated epithelial-mesenchymal transition and endothelial-mesenchymal transition","authors":"Wenyu Hui , Weiwei Cui , Jie Li , Mengyuan Cheng , Yangyang Liu , Yunru Peng , Yongfang Ding","doi":"10.1016/j.ejphar.2026.178580","DOIUrl":"10.1016/j.ejphar.2026.178580","url":null,"abstract":"<div><h3>Objective</h3><div>Cardiorenal syndrome (CRS), a spectrum of disorders involving intertwined cardiac and renal dysfunction, poses a significant challenge to mechanistic research due to a lack of accurate <em>in vivo</em> models. This study investigated the role of endoplasmic reticulum (ER) stress in mediating endothelial-to-mesenchymal transition (EndMT) and epithelial-to-mesenchymal transition (EMT) in a mouse model of cardiorenal comorbidity. Moreover, we investigated the therapeutic potential of 4-phenylbutyrate (4-PBA), an ER stress inhibitor, in attenuating cardiorenal comorbidity.</div></div><div><h3>Methods</h3><div>We employed a doxorubicin (Dox)-induced mouse model of cardiorenal comorbidity to investigate the role of ER stress in mediating EndMT and EMT. Six weeks post-Dox treatment, echocardiography, urinalysis, and blood tests were performed, complemented by immunofluorescence and Western blot analyses of cardiac and renal tissues. 4-PBA was intraperitoneally administered to evaluate the effect of ER stress inhibition on cardiorenal comorbidity.</div></div><div><h3>Results</h3><div>Dox administration significantly impaired cardiac and renal function, accompanied by pronounced fibrosis and upregulation of EndMT, EMT and ER stress markers. 4-PBA treatment attenuated cardiac injury, restored function, and ameliorated renal lesions. Consistent with <em>in vivo</em> results, Dox activated ER stress in HUVEC and HK-2 cells, promoting mesenchymal transformation. Critically, 4-PBA suppressed EndMT and EMT <em>in vitro</em>, supporting ER stress involvement in these processes.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that Dox induces concurrent cardiorenal dysfunction, primarily through ER stress-mediated EndMT and EMT transitions. Importantly, pharmacological inhibition of ER stress with 4-PBA attenuated these pathological changes, suggesting its potential as a therapeutic strategy for cardiorenal syndrome.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178580"},"PeriodicalIF":4.7,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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