Pub Date : 2026-01-29DOI: 10.1016/j.ejphar.2026.178617
Shanshan Ma , Qianqian Wang , Wenzhi Yang , Shenhong Zhang , Feifan Liu , Fangxia Guan , Hongtao Liu , Dongpeng Li
Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective therapies. 4,4′-Dimethoxychalcone (DMC) is a natural chalcone extracted from Angelica keiskei (Miq.) Koidz and Angelica sinensis (Oliv.) Diels, which could promote autophagy and prolong lifespan. However, the neuroprotective effects and mechanisms of DMC on AD mice have not been reported. In this study, we proved that DMC treatment significantly mitigated cognitive impairment and depressive behavior, ameliorated blood-brain barrier permeability and amyloid β pathology, and inhibited p-Tau expression in 5 × FAD mice. Also, DMC suppressed glial cell activation, enhanced neurogenesis, and decreased oxidative stress in vivo and in vitro by activating the Kelch-like ECH-associated protein1 (Keap1)/nuclear factor-erythrocyte 2-associated factor 2 (Nrf2) signaling pathway. However, Brusatol, an inhibitor of the Keap1/Nrf2 signalling, partly attenuated the neuroprotective effects of DMC on lipopolysaccharide-induced HT22 cells injury and 5 × FAD mice. In conclusion, DMC exhibited neuroprotective effects on 5 × FAD mice via the activation of Keap1/Nrf2 signalling pathway. Thus, DMC may be a promising therapeutic drug for AD.
{"title":"4,4′-dimethoxychalcone exerts neuroprotective effects in Alzheimer's disease mice by activating the Keap1/Nrf2 signaling pathway","authors":"Shanshan Ma , Qianqian Wang , Wenzhi Yang , Shenhong Zhang , Feifan Liu , Fangxia Guan , Hongtao Liu , Dongpeng Li","doi":"10.1016/j.ejphar.2026.178617","DOIUrl":"10.1016/j.ejphar.2026.178617","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective therapies. 4,4′-Dimethoxychalcone (DMC) is a natural chalcone extracted from <em>Angelica keiskei (Miq.) Koidz</em> and <em>Angelica sinensis (Oliv.) Diels</em>, which could promote autophagy and prolong lifespan. However, the neuroprotective effects and mechanisms of DMC on AD mice have not been reported. In this study, we proved that DMC treatment significantly mitigated cognitive impairment and depressive behavior, ameliorated blood-brain barrier permeability and amyloid β pathology, and inhibited p-Tau expression in 5 × FAD mice. Also, DMC suppressed glial cell activation, enhanced neurogenesis, and decreased oxidative stress <em>in vivo</em> and <em>in vitro</em> by activating the Kelch-like ECH-associated protein1 (Keap1)/nuclear factor-erythrocyte 2-associated factor 2 (Nrf2) signaling pathway. However, Brusatol, an inhibitor of the Keap1/Nrf2 signalling, partly attenuated the neuroprotective effects of DMC on lipopolysaccharide-induced HT22 cells injury and 5 × FAD mice. In conclusion, DMC exhibited neuroprotective effects on 5 × FAD mice via the activation of Keap1/Nrf2 signalling pathway. Thus, DMC may be a promising therapeutic drug for AD.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1016 ","pages":"Article 178617"},"PeriodicalIF":4.7,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096955","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}
Pub Date : 2026-01-28DOI: 10.1016/j.ejphar.2026.178614
Mariam Mohamedy Eladawy , Hany M. El-Bassossy , Shaimaa S. El-Sayed
Despite its efficacy in diabetes management, concerns about potential cardiovascular injury associated with alogliptin have limited its widespread use. This study investigated whether sustained, once-weekly low-dose alogliptin provides greater efficacy with fewer adverse effects than daily administration.
Type 2 diabetes was induced in rats using a high-fructose, high-fat, high-salt diet for three weeks, followed by streptozotocin (STZ) injection. Diabetic rats were then allocated into three groups: diabetic, S Alogliptin (weekly administered sustained alogliptin preparation), and F Alogliptin (daily administered standard fast-acting alogliptin). Postprandial blood glucose levels and body weight were monitored. Cardiovascular hemodynamics, cardiac enzymes, lipid profile, HOMA-IR, oxidative stress, and quantitative histopathological changes in the ventricles, aorta, liver, and skeletal muscle were evaluated at study end.
S alogliptin provided superior postprandial glycemic control over 40 days and improved metabolic parameters, including reduced bodyweight gain, triglycerides, HOMA-IR, and leptin, with increased adiponectin compared with F Alogliptin. More alleviation in cardiac dysfunction was observed in S alogliptin versus F alogliptin as manifested by reductions in cardiac enzymes, as well as improved hemodynamics (contractility index, pulse pressure, and dicrotic notch pressure). This was accompanied by more alleviation by S alogliptin in tissue inflammation and damage as evidenced by reductions in heart malondialdehyde (MDA) and histopathological examination of ventricles, aorta, liver, and skeletal muscles.
Conclusion
Overall, S Alogliptin achieved superior glycemic control and greater mitigation of metabolic and cardiovascular complications of diabetes than F Alogliptin.
{"title":"Sustained alogliptin elicits superior control of glycemia and related complications in diabetic rats: Effects on vital organs functions, biochemistry, and structure","authors":"Mariam Mohamedy Eladawy , Hany M. El-Bassossy , Shaimaa S. El-Sayed","doi":"10.1016/j.ejphar.2026.178614","DOIUrl":"10.1016/j.ejphar.2026.178614","url":null,"abstract":"<div><div>Despite its efficacy in diabetes management, concerns about potential cardiovascular injury associated with alogliptin have limited its widespread use. This study investigated whether sustained, once-weekly low-dose alogliptin provides greater efficacy with fewer adverse effects than daily administration.</div><div>Type 2 diabetes was induced in rats using a high-fructose, high-fat, high-salt diet for three weeks, followed by streptozotocin (STZ) injection. Diabetic rats were then allocated into three groups: diabetic, S Alogliptin (weekly administered sustained alogliptin preparation), and F Alogliptin (daily administered standard fast-acting alogliptin). Postprandial blood glucose levels and body weight were monitored. Cardiovascular hemodynamics, cardiac enzymes, lipid profile, HOMA-IR, oxidative stress, and quantitative histopathological changes in the ventricles, aorta, liver, and skeletal muscle were evaluated at study end.</div><div>S alogliptin provided superior postprandial glycemic control over 40 days and improved metabolic parameters, including reduced bodyweight gain, triglycerides, HOMA-IR, and leptin, with increased adiponectin compared with F Alogliptin. More alleviation in cardiac dysfunction was observed in S alogliptin versus F alogliptin as manifested by reductions in cardiac enzymes, as well as improved hemodynamics (contractility index, pulse pressure, and dicrotic notch pressure). This was accompanied by more alleviation by S alogliptin in tissue inflammation and damage as evidenced by reductions in heart malondialdehyde (MDA) and histopathological examination of ventricles, aorta, liver, and skeletal muscles.</div></div><div><h3>Conclusion</h3><div>Overall, S Alogliptin achieved superior glycemic control and greater mitigation of metabolic and cardiovascular complications of diabetes than F Alogliptin.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1016 ","pages":"Article 178614"},"PeriodicalIF":4.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092376","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}
Pub Date : 2026-01-28DOI: 10.1016/j.ejphar.2026.178606
Aude Burban , Raphael Faucard , Vincent Armand
NMDA receptor ligands have been the target of intensive research for the treatment of psychotic and various central nervous system disorders. Substantial evidence suggests that N-methyl-D-aspartate receptor hypofunction and its downregulation contribute to schizophrenia pathophysiology. The NMDA receptor histamine site (NMDA(HA)R) is a new potential target of NMDA receptor modulation, and ligands for this site have been developed.
In this study, we used various models to assess NMDA receptor activity and antipsychotic potential in rodents, highlighting the most potent ligand of NMDA (HA)R: FUBn203, a partial agonist with nanomolar affinity in vitro.
FUBn293 modulated MK 801 binding in vitro with an ED50 of 1 mg/kg. FUBn293 dose-dependently decreased MK-801-induced hyperlocomotion (ED50 = 3.8 mg/kg i. p). FUBn293 (10 mg/kg i. p.) significantly reduced the conditioned active avoidance test response and suppressed the MK-801-induced prepulse inhibition deficit.
According to these findings, NMDA (HA)R agonists may offer a novel class of antipsychotic medications for the treatment of some aspects of schizophrenia and other neurological or psychiatric disorders.
{"title":"Pharmacological activity of a new ligand binding at the histamine site of the NMDA receptor in rodents","authors":"Aude Burban , Raphael Faucard , Vincent Armand","doi":"10.1016/j.ejphar.2026.178606","DOIUrl":"10.1016/j.ejphar.2026.178606","url":null,"abstract":"<div><div>NMDA receptor ligands have been the target of intensive research for the treatment of psychotic and various central nervous system disorders. Substantial evidence suggests that N-methyl-D-aspartate receptor hypofunction and its downregulation contribute to schizophrenia pathophysiology. The NMDA receptor histamine site (NMDA<sub>(HA)</sub>R) is a new potential target of NMDA receptor modulation, and ligands for this site have been developed.</div><div>In this study, we used various models to assess NMDA receptor activity and antipsychotic potential in rodents, highlighting the most potent ligand of NMDA (HA)R: FUBn203, a partial agonist with nanomolar affinity <em>in vitro.</em></div><div>FUB<sub>n</sub>293 modulated MK 801 binding in <em>vitro</em> with an ED50 of 1 mg/kg. FUB<sub>n</sub>293 dose-dependently decreased MK-801-induced hyperlocomotion (ED50 = 3.8 mg/kg i. p). FUB<sub>n</sub>293 (10 mg/kg i. p.) significantly reduced the conditioned active avoidance test response and suppressed the MK-801-induced prepulse inhibition deficit.</div><div>According to these findings, NMDA (HA)R agonists may offer a novel class of antipsychotic medications for the treatment of some aspects of schizophrenia and other neurological or psychiatric disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1016 ","pages":"Article 178606"},"PeriodicalIF":4.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076954","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}
Pub Date : 2026-01-28DOI: 10.1016/j.ejphar.2026.178603
Yanan Liu , Jiajia Zhang , Zijun Liang , Jianing Zheng , Guoxuan Liu , Li Zhuang , Pan Chen , Qidong Tang , Guang Liang , Huazhong Ying , Xue Han , Qiaojuan Shi
Chronic hyperglycemia-induced inflammation promotes structural remodeling and dysfunction in the kidney and heart, ultimately leading to diabetic cardiorenal complications. The abnormal activation of the myeloid differentiation primary response gene 88 (MyD88)-dependent signaling pathway plays a critical role in this process. This study aimed to evaluate the therapeutic effects and underlying mechanisms of a novel small-molecule MyD88 inhibitor, A5S, in diabetic cardiorenal complications. We established a streptozotocin (STZ)-induced type 1 diabetes mouse model and administered A5S (10 or 20 mg/kg) for 8 weeks. Renal and cardiac function, as well as tissue pathology, were assessed. RNA sequencing and molecular biology experiments were performed to elucidate potential mechanisms. A5S treatment significantly improved kidney function, reduced glomerulosclerosis and fibrosis, and alleviated myocardial hypertrophy and collagen deposition. Mechanistically, A5S blocked the toll-like receptor 4 (TLR4)–MyD88 interaction and inhibited the transforming growth factor-β-activated kinase 1 (TAK1)/mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) inflammatory pathway, thereby reducing macrophage infiltration and downregulating the expression of pro-inflammatory cytokines (Tnfa, Il1b, and Il23) and chemotactic factors (Cxcl1 and Csf3). Furthermore, cell–cell crosstalk assays demonstrated that A5S prevented macrophage-induced renal mesangial cell fibrosis and cardiomyocyte hypertrophy. These findings validated the protective effects of A5S against inflammation-driven diabetic cardiorenal complications and highlighted its potential as a drug candidate for targeting MyD88 in anti-inflammatory therapy.
{"title":"The novel MyD88 inhibitor A5S ameliorates inflammation-driven diabetic cardiorenal complications","authors":"Yanan Liu , Jiajia Zhang , Zijun Liang , Jianing Zheng , Guoxuan Liu , Li Zhuang , Pan Chen , Qidong Tang , Guang Liang , Huazhong Ying , Xue Han , Qiaojuan Shi","doi":"10.1016/j.ejphar.2026.178603","DOIUrl":"10.1016/j.ejphar.2026.178603","url":null,"abstract":"<div><div>Chronic hyperglycemia-induced inflammation promotes structural remodeling and dysfunction in the kidney and heart, ultimately leading to diabetic cardiorenal complications. The abnormal activation of the myeloid differentiation primary response gene 88 (MyD88)-dependent signaling pathway plays a critical role in this process. This study aimed to evaluate the therapeutic effects and underlying mechanisms of a novel small-molecule MyD88 inhibitor, A5S, in diabetic cardiorenal complications. We established a streptozotocin (STZ)-induced type 1 diabetes mouse model and administered A5S (10 or 20 mg/kg) for 8 weeks. Renal and cardiac function, as well as tissue pathology, were assessed. RNA sequencing and molecular biology experiments were performed to elucidate potential mechanisms. A5S treatment significantly improved kidney function, reduced glomerulosclerosis and fibrosis, and alleviated myocardial hypertrophy and collagen deposition. Mechanistically, A5S blocked the toll-like receptor 4 (TLR4)–MyD88 interaction and inhibited the transforming growth factor-β-activated kinase 1 (TAK1)/mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) inflammatory pathway, thereby reducing macrophage infiltration and downregulating the expression of pro-inflammatory cytokines (<em>Tnfa</em>, <em>Il1b</em>, and <em>Il23</em>) and chemotactic factors (<em>Cxcl1</em> and <em>Csf3</em>). Furthermore, cell–cell crosstalk assays demonstrated that A5S prevented macrophage-induced renal mesangial cell fibrosis and cardiomyocyte hypertrophy. These findings validated the protective effects of A5S against inflammation-driven diabetic cardiorenal complications and highlighted its potential as a drug candidate for targeting MyD88 in anti-inflammatory therapy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1016 ","pages":"Article 178603"},"PeriodicalIF":4.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092525","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}
Pub Date : 2026-01-28DOI: 10.1016/j.ejphar.2026.178609
Zhuo-Chao Xiong , Xiong-Zhi Li , Si You , Ze-Gui Huang , Yu-Biao Wu , Zhao-Yu Liu , Shao-Ling Zhang , Bing Yang , Jing-Feng Wang , Jing-Wei Gao , Pin-Ming Liu
Prolonged use of proton pump inhibitors (PPIs) is associated with increased cardiovascular risks, including vascular calcification (VC). Patients with chronic kidney disease (CKD) are particularly vulnerable to the adverse vascular effects of PPIs. However, the underlying mechanism remains poorly understood. Clinical data from CKD patients treated with PPIs showed a higher incidence of elevated coronary artery calcium scores (adjusted odds ratio = 5.365, 95 % CI: 2.539–11.338, P < 0.001), indicating a link between PPI use and accelerated vascular damage. In CKD rats, omeprazole treatment dose-dependently induced aortic calcification, accompanied by a phenotypic switch of vascular smooth muscle cells (VSMCs) from a contractile to an osteoblastic state. This pathological process was associated with mitochondrial dysfunction and inhibited PINK1/Parkin-mediated mitophagy, as evidenced by reduced TOMM20, LC3B-II, PINK1, and Parkin protein levels, impaired mitochondrial-lysosomal colocalization (MitoTracker Green/LysoTracker Red staining), and swollen mitochondria with fewer mitophagosomes (transmission electron microscopy). Enhancement of mitophagy by rapamycin effectively mitigated omeprazole-induced VC. RNA sequencing identified cyclooxygenase-2 (COX-2) as a key mediator, with omeprazole significantly upregulating its expression. Silencing COX-2 reversed omeprazole-induced mitophagy inhibition and VSMC calcification. Esomeprazole and lansoprazole recapitulated these pro-calcific effects, indicating a class effect. Collectively, PPIs promote VC in CKD by upregulating COX-2, which directly inhibits PINK1/Parkin-related mitophagy. This study provides a novel COX-2-mitophagy axis in PPI-accelerated vascular injury, highlighting a potential therapeutic target for high-risk patients.
长期使用质子泵抑制剂（PPIs）与心血管风险增加相关，包括血管钙化（VC）。慢性肾脏疾病（CKD）患者特别容易受到PPIs对血管的不良影响。然而，其潜在的机制仍然知之甚少。PPIs治疗的CKD患者的临床数据显示冠状动脉钙评分升高的发生率更高(校正优势比=5.365,95% CI: 2.539-11.338， P
{"title":"Proton pump inhibitors accelerate vascular calcification via COX-2-mediated mitophagy inhibition in chronic kidney disease","authors":"Zhuo-Chao Xiong , Xiong-Zhi Li , Si You , Ze-Gui Huang , Yu-Biao Wu , Zhao-Yu Liu , Shao-Ling Zhang , Bing Yang , Jing-Feng Wang , Jing-Wei Gao , Pin-Ming Liu","doi":"10.1016/j.ejphar.2026.178609","DOIUrl":"10.1016/j.ejphar.2026.178609","url":null,"abstract":"<div><div>Prolonged use of proton pump inhibitors (PPIs) is associated with increased cardiovascular risks, including vascular calcification (VC). Patients with chronic kidney disease (CKD) are particularly vulnerable to the adverse vascular effects of PPIs. However, the underlying mechanism remains poorly understood. Clinical data from CKD patients treated with PPIs showed a higher incidence of elevated coronary artery calcium scores (adjusted odds ratio = 5.365, 95 % CI: 2.539–11.338, <em>P</em> < 0.001), indicating a link between PPI use and accelerated vascular damage. In CKD rats, omeprazole treatment dose-dependently induced aortic calcification, accompanied by a phenotypic switch of vascular smooth muscle cells (VSMCs) from a contractile to an osteoblastic state. This pathological process was associated with mitochondrial dysfunction and inhibited PINK1/Parkin-mediated mitophagy, as evidenced by reduced TOMM20, LC3B-II, PINK1, and Parkin protein levels, impaired mitochondrial-lysosomal colocalization (MitoTracker Green/LysoTracker Red staining), and swollen mitochondria with fewer mitophagosomes (transmission electron microscopy). Enhancement of mitophagy by rapamycin effectively mitigated omeprazole-induced VC. RNA sequencing identified cyclooxygenase-2 (COX-2) as a key mediator, with omeprazole significantly upregulating its expression. Silencing COX-2 reversed omeprazole-induced mitophagy inhibition and VSMC calcification. Esomeprazole and lansoprazole recapitulated these pro-calcific effects, indicating a class effect. Collectively, PPIs promote VC in CKD by upregulating COX-2, which directly inhibits PINK1/Parkin-related mitophagy. This study provides a novel COX-2-mitophagy axis in PPI-accelerated vascular injury, highlighting a potential therapeutic target for high-risk patients.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1016 ","pages":"Article 178609"},"PeriodicalIF":4.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092406","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}
Pub Date : 2026-01-27DOI: 10.1016/j.ejphar.2026.178604
Huan You , Lu Tai , Yulu Li , Tianmu Qi , Yan Yang , Chan Zhu , Xuefeng Qiu , Guang Yu , Yuan Zhou , Zongxiang Tang
Paeoniflorin (PAE), a bioactive monoterpene glycoside derived from the roots of Paeonia lactiflora (P. lactiflora), has been traditionally used in East Asian medicine for its anti-inflammatory and immunomodulatory properties. However, its potential therapeutic effects on plant allergen-induced dermatitis, particularly poison ivy-related allergic contact dermatitis (ACD), remain unexplored. This study aimed to investigate the immune mechanisms underlying urushiol-induced ACD, a prevalent environmental allergy caused by poison ivy, and to evaluate the efficacy of PAE in alleviating inflammatory and pruritic responses. A murine ACD model was established using urushiol and compared with oxazolone-induced dermatitis. PAE was administered intraperitoneally for 7 days. Skin lesion severity, epidermal thickness, and inflammatory markers were assessed. Behavioral tests evaluated pruritus intensity. Urushiol-induced ACD exhibited more severe dermatitis than oxazolone, with pronounced epidermal hyperplasia, elevated CCL2 levels, and increased macrophage recruitment. PAE treatment significantly alleviated scratching behavior and reduced epidermal thickness. PAE also ameliorates urushiol-induced ACD by inhibiting Erk/CCL2-mediated macrophage recruitment and TSLP production, highlighting its potential as a natural therapeutic agent for plant allergen-driven dermatitis. Overall, this study bridges traditional use of P. lactiflora with modern mechanistic validation, supporting ethnopharmacological applications in immune-related skin disorders.
{"title":"Paeoniflorin alleviates urushiol-induced pruritus in mice by inhibiting Erk/CCL2 pathway","authors":"Huan You , Lu Tai , Yulu Li , Tianmu Qi , Yan Yang , Chan Zhu , Xuefeng Qiu , Guang Yu , Yuan Zhou , Zongxiang Tang","doi":"10.1016/j.ejphar.2026.178604","DOIUrl":"10.1016/j.ejphar.2026.178604","url":null,"abstract":"<div><div>Paeoniflorin (PAE), a bioactive monoterpene glycoside derived from the roots of <em>Paeonia lactiflora</em> (<em>P. lactiflora</em>), has been traditionally used in East Asian medicine for its anti-inflammatory and immunomodulatory properties. However, its potential therapeutic effects on plant allergen-induced dermatitis, particularly poison ivy-related allergic contact dermatitis (ACD), remain unexplored. This study aimed to investigate the immune mechanisms underlying urushiol-induced ACD, a prevalent environmental allergy caused by poison ivy, and to evaluate the efficacy of PAE in alleviating inflammatory and pruritic responses. A murine ACD model was established using urushiol and compared with oxazolone-induced dermatitis. PAE was administered intraperitoneally for 7 days. Skin lesion severity, epidermal thickness, and inflammatory markers were assessed. Behavioral tests evaluated pruritus intensity. Urushiol-induced ACD exhibited more severe dermatitis than oxazolone, with pronounced epidermal hyperplasia, elevated CCL2 levels, and increased macrophage recruitment. PAE treatment significantly alleviated scratching behavior and reduced epidermal thickness. PAE also ameliorates urushiol-induced ACD by inhibiting Erk/CCL2-mediated macrophage recruitment and TSLP production, highlighting its potential as a natural therapeutic agent for plant allergen-driven dermatitis. Overall, this study bridges traditional use of <em>P. lactiflora</em> with modern mechanistic validation, supporting ethnopharmacological applications in immune-related skin disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1016 ","pages":"Article 178604"},"PeriodicalIF":4.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085185","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}
Pub Date : 2026-01-27DOI: 10.1016/j.ejphar.2026.178607
Chin-Chuan Chen , Tong-Hong Wang , Yann-Lii Leu , Chieh-Wen Chan , Yu-Xuan Chen , Yu-De Chu , Chi-Yuan Chen
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, remains a major therapeutic challenge in EGFR-mutant lung cancer. In this study, we evaluated the pharmacological activity of magnolol, a natural biphenolic compound, in EGFR-mutant lung cancer models, including osimertinib-resistant cells harboring tertiary mutations such as C797S. Magnolol inhibited proliferation and induced apoptosis in both sensitive and resistant cell lines. Molecular docking and cellular thermal shift assays suggested cellular engagement of magnolol with the ATP-binding pocket of mutant EGFR, accompanied by reduced EGFR phosphorylation. In addition, magnolol suppressed the AXL receptor tyrosine kinase (AXL)-cMyc signaling axis and impaired homologous recombination repair by downregulating Rad51, leading to accumulation of DNA damage. These effects were enhanced when combined with brigatinib, a clinically approved multi-kinase inhibitor with activity against mutant EGFR. In xenograft models, magnolol enhanced the antitumor activity of brigatinib through increased inhibition of EGFR, AXL, cMyc, Rad51, and Ki-67. Furthermore, Kaplan-Meier analysis demonstrated that patients with high co-expression of AXL, cMyc, and Rad51 had significantly worse survival, supporting the clinical relevance of this axis. Collectively, these findings suggest that magnolol exerts multitargeted effects involving inhibition of mutant EGFR, suppression of the AXL-cMyc signaling axis, and disruption of DNA repair, thereby sensitizing resistant tumors to EGFR-TKIs. Magnolol may represent a promising adjuvant strategy for overcoming acquired resistance in EGFR-mutant lung cancer.
{"title":"Magnolol suppresses TKI-resistant EGFR-mutant lung cancer by inhibiting EGFR and AXL-cMyc","authors":"Chin-Chuan Chen , Tong-Hong Wang , Yann-Lii Leu , Chieh-Wen Chan , Yu-Xuan Chen , Yu-De Chu , Chi-Yuan Chen","doi":"10.1016/j.ejphar.2026.178607","DOIUrl":"10.1016/j.ejphar.2026.178607","url":null,"abstract":"<div><div>Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, remains a major therapeutic challenge in EGFR-mutant lung cancer. In this study, we evaluated the pharmacological activity of magnolol, a natural biphenolic compound, in EGFR-mutant lung cancer models, including osimertinib-resistant cells harboring tertiary mutations such as C797S. Magnolol inhibited proliferation and induced apoptosis in both sensitive and resistant cell lines. Molecular docking and cellular thermal shift assays suggested cellular engagement of magnolol with the ATP-binding pocket of mutant EGFR, accompanied by reduced EGFR phosphorylation. In addition, magnolol suppressed the AXL receptor tyrosine kinase (AXL)-cMyc signaling axis and impaired homologous recombination repair by downregulating Rad51, leading to accumulation of DNA damage. These effects were enhanced when combined with brigatinib, a clinically approved multi-kinase inhibitor with activity against mutant EGFR. In xenograft models, magnolol enhanced the antitumor activity of brigatinib through increased inhibition of EGFR, AXL, cMyc, Rad51, and Ki-67. Furthermore, Kaplan-Meier analysis demonstrated that patients with high co-expression of AXL, cMyc, and Rad51 had significantly worse survival, supporting the clinical relevance of this axis. Collectively, these findings suggest that magnolol exerts multitargeted effects involving inhibition of mutant EGFR, suppression of the AXL-cMyc signaling axis, and disruption of DNA repair, thereby sensitizing resistant tumors to EGFR-TKIs. Magnolol may represent a promising adjuvant strategy for overcoming acquired resistance in EGFR-mutant lung cancer.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1016 ","pages":"Article 178607"},"PeriodicalIF":4.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076953","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}
Methotrexate (MTX) is widely used for treating rheumatoid arthritis (RA); however, its clinical application is limited because of its nonspecific distribution and significant long-term adverse effects. We developed a hyaluronic acid (HA)-modified exosome (Exo) encapsulating MTX to enhance therapeutic efficacy in a rat RA model.
Methods
Exosomes were isolated from Wharton's jelly–derived mesenchymal stem cells (WJ-MSCs) and loaded with MTX, then coated with HA. Exo/MTX/HA characterized using UV–visible spectrophotometry, and Fourier transform infrared (FTIR) spectroscopy. Encapsulation efficiency, in vitro drug release, and cytotoxicity were assessed. Serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-17 (IL-17), transforming growth factor-beta (TGF-β), aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), C-reactive protein (CRP), and rheumatoid factor (RF) were measured by ELISA and commercial kits. Gene expression of T-bet, GATA3, Foxp3, RORγt, matrix metalloproteinases (MMPs), lincRNA-p21, and MALAT1 was quantified by real-time PCR.
Results
The Exo/MTX/HA treatment group showed significantly decreased serum levels of TNF-α, IL-17, CRP, and RF but increased TGF-β levels (p < 0.001). Furthermore, Exo/MTX/HA significantly downregulated T-bet, RORγt, MALAT1, MMP-9, and MMP-13, and upregulated Foxp3, GATA3, and LncRNA-p21 expression (p < 0.001). Hematoxylin and Eosin (H&E) staining revealed that, compared with the other treatments, Exo/MTX/HA markedly reduced joint cell infiltration (p < 0.01). Safety assessments showed no hepatotoxicity in the Exo/MTX/HA, Exo/MTX, or Exo/HA groups compared to the MTX group.
Conclusion
This study presents a method to improve the therapeutic effect of methotrexate against rheumatoid arthritis using the Exo/MTX/HA.
{"title":"Therapeutic effects of methotrexate encapsulated in hyaluronic acid-coated exosomes derived from Wharton's jelly mesenchymal stem cells in a rat model of rheumatoid arthritis","authors":"Zahra Akbari Jonoush , Mahmoud Gharbavi , Mehri Ghafourian , Seyed Esmaeil Khoshnam , Ali Khodadadi , Farideh Khanom Farahbakhsh , Afshin Amari","doi":"10.1016/j.ejphar.2026.178610","DOIUrl":"10.1016/j.ejphar.2026.178610","url":null,"abstract":"<div><h3>Background</h3><div>Methotrexate (MTX) is widely used for treating rheumatoid arthritis (RA); however, its clinical application is limited because of its nonspecific distribution and significant long-term adverse effects. We developed a hyaluronic acid (HA)-modified exosome (Exo) encapsulating MTX to enhance therapeutic efficacy in a rat RA model.</div></div><div><h3>Methods</h3><div>Exosomes were isolated from Wharton's jelly–derived mesenchymal stem cells (WJ-MSCs) and loaded with MTX, then coated with HA. Exo/MTX/HA characterized using UV–visible spectrophotometry, and Fourier transform infrared (FTIR) spectroscopy. Encapsulation efficiency, in vitro drug release, and cytotoxicity were assessed. Serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-17 (IL-17), transforming growth factor-beta (TGF-β), aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), C-reactive protein (CRP), and rheumatoid factor (RF) were measured by ELISA and commercial kits. Gene expression of T-bet, GATA3, Foxp3, RORγt, matrix metalloproteinases (MMPs), lincRNA-p21, and MALAT1 was quantified by real-time PCR.</div></div><div><h3>Results</h3><div>The Exo/MTX/HA treatment group showed significantly decreased serum levels of TNF-α, IL-17, CRP, and RF but increased TGF-β levels (p < 0.001). Furthermore, Exo/MTX/HA significantly downregulated T-bet, RORγt, MALAT1, MMP-9, and MMP-13, and upregulated Foxp3, GATA3, and LncRNA-p21 expression (p < 0.001). Hematoxylin and Eosin (H&E) staining revealed that, compared with the other treatments, Exo/MTX/HA markedly reduced joint cell infiltration (p < 0.01). Safety assessments showed no hepatotoxicity in the Exo/MTX/HA, Exo/MTX, or Exo/HA groups compared to the MTX group.</div></div><div><h3>Conclusion</h3><div>This study presents a method to improve the therapeutic effect of methotrexate against rheumatoid arthritis using the Exo/MTX/HA.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178610"},"PeriodicalIF":4.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075064","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}
Pub Date : 2026-01-27DOI: 10.1016/j.ejphar.2026.178608
Wenbin Nan , Xiaoqing Jiang , Xu Cai , Yanke Chen , Zhenyu Peng
Background
Ferroptosis has emerged as a central driver of sepsis-induced cardiomyopathy. Epoxyeicosatrienoic acids (EETs) possess cardioprotective properties, but whether 14,15-EET confers protection in septic cardiomyopathy remains unclear. This study investigated the effect and mechanism of 14,15-EET on sepsis-induced cardiomyopathy.
Materials and methods
To establish models of sepsis, septic mice were induced by cecal ligation and puncture (CLP), whereas H9C2 cardiomyocytes were treated with lipopolysaccharide (LPS) to mimic sepsis in vitro. Echocardiography was used to assess cardiac function by measuring ejection fraction (EF) and fractional shortening (FS). ELISA assays measured serum levels of creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI). Lipid metabolomics was performed using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS)-based lipidomics. Network pharmacology and molecular docking were applied to identify potential targets linking 14,15-EET, ferroptosis, and sepsis-induced cardiomyopathy. Biochemical assays were performed to quantify myocardial ferrous iron (Fe2+), reduced glutathione (GSH), and malondialdehyde (MDA). Reactive oxygen species (ROS) were visualized using fluorescence-based probes in H9C2 cells and dihydroethidium in heart sections. Western blotting quantified GPX4, xCT, and PPARα expression.
Results
14,15-EET was markedly reduced in the myocardium of septic mice, as revealed by lipidomics. Network pharmacology and molecular docking identified PPARα as a central target mediating the anti-ferroptotic effects of 14,15-EET during sepsis. In LPS-stimulated cardiomyocytes, 14,15-EET inhibited ferroptosis by lowering intracellular Fe2+, MDA, and ROS levels, while restoring GSH and upregulating xCT and GPX4 expression. Stabilization of 14,15-EET through TPPU, a soluble epoxide hydrolase (sEH) inhibitor, attenuated myocardial ferroptosis and concurrently conferred cardioprotection in septic mice by improving EF and FS and lowering serum levels of creatine kinase-MB and cTnI. Notably, 14,15-EET upregulated PPARα expression in both septic myocardium and cardiomyocytes, whereas pharmacological inhibition with GW6471 abolished its anti-ferroptotic and cardioprotective actions.
Conclusions
14,15-EET attenuates sepsis-induced cardiomyopathy by suppressing ferroptosis through PPARα activation.
{"title":"14,15-EET mitigates sepsis-induced cardiomyopathy by inhibiting cardiomyocyte ferroptosis via PPARα activation","authors":"Wenbin Nan , Xiaoqing Jiang , Xu Cai , Yanke Chen , Zhenyu Peng","doi":"10.1016/j.ejphar.2026.178608","DOIUrl":"10.1016/j.ejphar.2026.178608","url":null,"abstract":"<div><h3>Background</h3><div>Ferroptosis has emerged as a central driver of sepsis-induced cardiomyopathy. Epoxyeicosatrienoic acids (EETs) possess cardioprotective properties, but whether 14,15-EET confers protection in septic cardiomyopathy remains unclear. This study investigated the effect and mechanism of 14,15-EET on sepsis-induced cardiomyopathy.</div></div><div><h3>Materials and methods</h3><div>To establish models of sepsis, septic mice were induced by cecal ligation and puncture (CLP), whereas H9C2 cardiomyocytes were treated with lipopolysaccharide (LPS) to mimic sepsis in vitro. Echocardiography was used to assess cardiac function by measuring ejection fraction (EF) and fractional shortening (FS). ELISA assays measured serum levels of creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI). Lipid metabolomics was performed using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS)-based lipidomics. Network pharmacology and molecular docking were applied to identify potential targets linking 14,15-EET, ferroptosis, and sepsis-induced cardiomyopathy. Biochemical assays were performed to quantify myocardial ferrous iron (Fe<sup>2+</sup>), reduced glutathione (GSH), and malondialdehyde (MDA). Reactive oxygen species (ROS) were visualized using fluorescence-based probes in H9C2 cells and dihydroethidium in heart sections. Western blotting quantified GPX4, xCT, and PPARα expression.</div></div><div><h3>Results</h3><div>14,15-EET was markedly reduced in the myocardium of septic mice, as revealed by lipidomics. Network pharmacology and molecular docking identified PPARα as a central target mediating the anti-ferroptotic effects of 14,15-EET during sepsis. In LPS-stimulated cardiomyocytes, 14,15-EET inhibited ferroptosis by lowering intracellular Fe<sup>2+</sup>, MDA, and ROS levels, while restoring GSH and upregulating xCT and GPX4 expression. Stabilization of 14,15-EET through TPPU, a soluble epoxide hydrolase (sEH) inhibitor, attenuated myocardial ferroptosis and concurrently conferred cardioprotection in septic mice by improving EF and FS and lowering serum levels of creatine kinase-MB and cTnI. Notably, 14,15-EET upregulated PPARα expression in both septic myocardium and cardiomyocytes, whereas pharmacological inhibition with GW6471 abolished its anti-ferroptotic and cardioprotective actions.</div></div><div><h3>Conclusions</h3><div>14,15-EET attenuates sepsis-induced cardiomyopathy by suppressing ferroptosis through PPARα activation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178608"},"PeriodicalIF":4.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075065","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}
Pub Date : 2026-01-24DOI: 10.1016/j.ejphar.2026.178599
Lucía Garrido-Matilla , Alberto Marcos , Carlos León , Leonor Nozal , Natalia Puig-Martínez , Antonio L. Crego , Emilio Ambrosio
The combined use of cocaine and alcohol is highly prevalent and produces more severe effects than either drug alone. This study investigates this polysubstance abuse pattern by modelling the incubation of cocaine craving, both alone and in combination with ethanol.
To investigate the mechanisms underlying this phenomenon, we performed an untargeted plasma metabolomic analysis using High-Performance Liquid Chromatography coupled with a High-Resolution Hybrid Quadrupole-Orbitrap mass spectrometer. Both positive and negative ionization modes, and two complementary chromatographic methods, were employed to maximize compound detection. We analysed metabolite differences after 30 versus 2 days of withdrawal in rats that self-administered cocaine alone or with ethanol and then, identified the pathways in which these metabolites are involved to reveal the biological processes that could be affected during craving incubation.
Although all rats were exposed to cocaine, those that also consumed ethanol showed distinct metabolic pathway alterations. Both sexes exhibited changes in similar pathways, yet the specific metabolites affected differed, revealing clear sex dimorphism. Cocaine primarily altered tryptophan metabolism and the urea cycle, whereas the combination with ethanol mainly affected α-linolenic acid metabolism, bile acid synthesis, and arginine, proline, glycine, serine, and threonine metabolism.
This study provides insight into peripheral metabolomic alterations during the incubation of cocaine and cocaine plus ethanol seeking, offering a framework for further investigation of the affected pathways in peripheral tissues and within the central nervous system in both sexes.
{"title":"Metabolomic profiling of cocaine plus ethanol poly-consumption in young adult rats: Insights into the incubation of drug seeking","authors":"Lucía Garrido-Matilla , Alberto Marcos , Carlos León , Leonor Nozal , Natalia Puig-Martínez , Antonio L. Crego , Emilio Ambrosio","doi":"10.1016/j.ejphar.2026.178599","DOIUrl":"10.1016/j.ejphar.2026.178599","url":null,"abstract":"<div><div>The combined use of cocaine and alcohol is highly prevalent and produces more severe effects than either drug alone. This study investigates this polysubstance abuse pattern by modelling the incubation of cocaine craving, both alone and in combination with ethanol.</div><div>To investigate the mechanisms underlying this phenomenon, we performed an untargeted plasma metabolomic analysis using High-Performance Liquid Chromatography coupled with a High-Resolution Hybrid Quadrupole-Orbitrap mass spectrometer. Both positive and negative ionization modes, and two complementary chromatographic methods, were employed to maximize compound detection. We analysed metabolite differences after 30 versus 2 days of withdrawal in rats that self-administered cocaine alone or with ethanol and then, identified the pathways in which these metabolites are involved to reveal the biological processes that could be affected during craving incubation.</div><div>Although all rats were exposed to cocaine, those that also consumed ethanol showed distinct metabolic pathway alterations. Both sexes exhibited changes in similar pathways, yet the specific metabolites affected differed, revealing clear sex dimorphism. Cocaine primarily altered tryptophan metabolism and the urea cycle, whereas the combination with ethanol mainly affected α-linolenic acid metabolism, bile acid synthesis, and arginine, proline, glycine, serine, and threonine metabolism.</div><div>This study provides insight into peripheral metabolomic alterations during the incubation of cocaine and cocaine plus ethanol seeking, offering a framework for further investigation of the affected pathways in peripheral tissues and within the central nervous system in both sexes.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178599"},"PeriodicalIF":4.7,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050968","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}
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