European journal of pharmacology最新文献

{"title":"Osthole improves erectile function by increasing endogenous H2S production","authors":"Elif Alan-Albayrak ,&nbsp;Estéfano Pinilla ,&nbsp;Simon Comerma-Steffensen ,&nbsp;Yasemin Erac ,&nbsp;Gunay Yetik-Anacak ,&nbsp;Ulf Simonsen ,&nbsp;Gulnur Sevin","doi":"10.1016/j.ejphar.2025.177619","DOIUrl":"10.1016/j.ejphar.2025.177619","url":null,"abstract":"<div><h3>Background</h3><div>Phosphodiesterase type-5 inhibitors, first-line treatments for erectile dysfunction (ED), are insufficient in 30–40 % of patients, highlighting an unmet therapeutic need. Hydrogen sulfide (H₂S) compensates for NO deficiency and improves erectile function. We hypothesized that H₂S contributes to the smooth muscle relaxation in penile arteries and erectile tissue induced by osthole.</div></div><div><h3>Methods</h3><div>We investigated the effects of osthole on H₂S-producing enzyme expression and H₂S production in murine erectile tissues by Western blot and H₂S microsensor experiments. To evaluate the role of H₂S in osthole-induced relaxations, myography was conducted on mouse corpus cavernosum (MCC) and rat pudendal artery (RPA). While monitoring vascular responses, endogenous H₂S production was simultaneously measured by an H₂S microsensor inserted in the RPA lumen. Intracavernosal pressure was measured in anesthetized rats to evaluate the effect of osthole on erectile function.</div></div><div><h3>Results</h3><div>Osthole induced relaxation by increasing H₂S synthesis and enhancing the expression of H₂S-producing enzymes, as well as promoting H₂S formation in murine erectile tissues. Osthole relaxed RPA while simultaneously increasing H₂S levels in the arterial lumen. Osthole also amplified L-cysteine- and Na₂S-induced relaxations and increased luminal H₂S levels. Additionally, osthole increased endothelium-dependent and independent relaxations by inducing H₂S synthesis. Osthole improved erection by facilitating erectile responses in rats.</div></div><div><h3>Conclusion</h3><div>Our novel approach, based on simultaneous measurements of endogenous H₂S production in the arterial lumen and vascular contractility, suggests that H₂S contributes to osthole-induced relaxation of penile tissue, proposing that osthole may be a promising drug candidate for treating ED, particularly when caused by endothelial dysfunction.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177619"},"PeriodicalIF":4.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844061","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}

{"title":"SGLT2 inhibitor dapagliflozin mitigates skeletal muscle pathology by modulating key proteins involved in glucose and ion homeostasis in an animal model of heart failure","authors":"Elena Conte ,&nbsp;Paola Imbrici ,&nbsp;Giorgia Dinoi ,&nbsp;Brigida Boccanegra ,&nbsp;Martina Lanza ,&nbsp;Elena Mele ,&nbsp;Maria Antonietta Riemma ,&nbsp;Konrad Urbanek ,&nbsp;Donato Cappetta ,&nbsp;Annamaria De Luca ,&nbsp;Liberato Berrino ,&nbsp;Antonella De Angelis ,&nbsp;Antonella Liantonio","doi":"10.1016/j.ejphar.2025.177617","DOIUrl":"10.1016/j.ejphar.2025.177617","url":null,"abstract":"<div><div>Heart failure (HF) is a syndrome characterized by dyspnoea, fatigue and exercise intolerance. Among non-cardiac comorbidities which often accompany HF, skeletal muscle abnormalities impact patients’ daily activities and quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promise in improving clinical outcomes and enhancing physical performance in HF patients, although their mechanism of action remains unclear. In this context, altered muscle ions and glucose homeostasis may contribute to HF-related muscle changes and serve as indirect targets for SGLT2i effects. To explore this further, we used Dahl salt-sensitive rats fed with a high-salt diet for five weeks and then randomized to receive dapagliflozin (HS + DAP) or vehicle (HS) for the following six weeks. Control animals received a low-salt diet (LS). We investigated whether variations in indexes of glucose and ions homeostasis occur in extensor digitorum longus muscle of this rodent model of HF with preserved ejection fraction and are counteracted by dapagliflozin treatment. Gene and protein expression analysis revealed altered expression of proteins involved in glucose (SGLT2, GLUT4, GPD1) and Ca²⁺ and Na ⁺ homeostasis (NCX3, Ryr1, NHE1/6, Na⁺/K⁺-ATPase, Nav1.4) in HS <em>vs</em> LS animals. Furthermore, HS rats showed an increased CaMKII expression in its active phosphorylated form and a change in plasma pH toward acidification. Dapagliflozin treatment counteracted the altered expression of most of the components under investigation, also promoting an amelioration of atrophy indexes and a recovery of plasma pH. Thus, skeletal muscle appears highly responsive to SGLT2i treatment, supporting the potential of these drugs in mitigating HF-related muscle pathology.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177617"},"PeriodicalIF":4.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839121","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}

{"title":"Virtual rat web: A versatile simulation tool for pharmacology education in a variety of settings","authors":"Shiko Okabe ,&nbsp;Taichiro Goto ,&nbsp;Daisuke Hirayama ,&nbsp;Yuhei Nishimura","doi":"10.1016/j.ejphar.2025.177618","DOIUrl":"10.1016/j.ejphar.2025.177618","url":null,"abstract":"<div><div>Education and outreach activities are crucial elements in the popularization of various scientific fields, including pharmacology. Simulation-based learning can impart scientific knowledge and stimulate critical thinking in both children and adults. Here, we developed a standalone web-based simulation tool, Virtual Rat Web (VRW), to promote a greater understanding of pharmacology and assessed its usefulness in educational and outreach settings. VRW is a web-based application based on the source code of RatCVS, a program developed by Dr. John Dempster (University of Strathclyde) to model cardiovascular pharmacology. We evaluated VRW as part of a model pharmacology class taught to high-school students, and elementary/junior high-school students or older students attending university outreach classes. The two older student groups were given a 60-min class consisting of a brief introduction to drug effects on the cardiovascular system, training on the use of VRW, and a hands-on exercise using VRW to identify noradrenaline and acetylcholine from a panel of anonymized drugs based on their dose-response patterns. Most students correctly identified the effects of noradrenaline and acetylcholine and found VRW to be a more useful learning tool than a passive lecture. The elementary/junior high-school students received a 120-min class combining real-time visualization of the effects of adrenaline and propranolol on the heart rate of zebrafish larvae and hands-on use of VRW to confirm the <em>in vivo</em> observations. This cohort found the strength of VRW in understanding the dose-response. These findings suggest that VRW may be a versatile tool for pharmacology education in various settings.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177618"},"PeriodicalIF":4.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834289","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}

{"title":"Eeyarestatin I (ESI)-induced ERAD inhibition exhibits anti-cancer activity through multiple mechanisms in human colorectal cancer cells","authors":"Jing Peng,&nbsp;Cheng-I Wei,&nbsp;Seong-Ho Lee","doi":"10.1016/j.ejphar.2025.177623","DOIUrl":"10.1016/j.ejphar.2025.177623","url":null,"abstract":"<div><div>Endoplasmic reticulum (ER)-associated degradation (ERAD) is a cellular process for maintenance of protein homeostasis in the ER and aberration of ERAD regulation leads to abnormal function of ER. As an inhibitory compound to ERAD, Eeyarestatin I (ESI) exhibits anti-cancer activity. In this study, we elucidated the anti-cancer mechanisms of ESI-induced ERAD inhibition in human colorectal carcinoma cells. Cellular viability of three different types of human colorectal cancer cells decreased in a dose-dependent manner by treatment with ESI. Treatment of ESI to human colorectal cancer cells led to significant increase of ubiquitin accumulation, G2/M phase cell cycle arrest, apoptosis, ER stress and autophagy. In addition, ESI treatment reduced transcriptional activity of nuclear factor kappa B (NF-κB), and increased phosphorylation of c-Jun NH₂-terminal kinase (JNK) and intracellular production of reactive oxygen species (ROS). Decrease of cell viability and ROS release were JNK-dependent and apoptosis was ROS-dependent. On the other hand, treatment of the cells with ESI downregulated the expression of translocon-associated protein (TRAP) subunits including TRAPα, β, γ and δ, which was JNK- and ROS-dependent. In summary, ESI-induced ERAD inhibition triggers ER stress, G2/M cell cycle arrest, ROS-dependent apoptosis, and autophagy in human colorectal cancer cells. We are the first to identify TRAPs as novel target ER membrane proteins that are downregulated by ERAD inhibition in human colorectal cancer cells.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177623"},"PeriodicalIF":4.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834287","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}

{"title":"Taurine ameliorates liver fibrosis by repressing Fpr2-regulated macrophage M1 polarization","authors":"Kaiduan Xie ,&nbsp;Yiwang Zhang ,&nbsp;Xingtong Ou ,&nbsp;Yuelin Xiao ,&nbsp;Jiajie Luo ,&nbsp;Siwei Tan","doi":"10.1016/j.ejphar.2025.177614","DOIUrl":"10.1016/j.ejphar.2025.177614","url":null,"abstract":"<div><div>Liver fibrosis is a reversible pathophysiological condition characterized by excessive extracellular matrix deposition that can progress to cirrhosis and liver failure if left untreated. Taurine, a sulfur-containing amino acid, protects the liver from damage. However, the effects of taurine on liver fibrogenesis have not been completely elucidated. In this study, we used amino acid metabolomics, gene expression microanalysis, and single-cell RNA sequencing (scRNA-seq) to investigate the roles of taurine, formyl peptide receptor 2 (Fpr2), and proinflammatory macrophages in liver fibrosis in human fibrotic sections and two distinct mouse models of liver fibrosis. Taurine transporter <em>SLC6A6</em> wild-type and knockout littermate models and critical element inhibitors were also used. We found that taurine levels were significantly reduced in both human and murine fibrotic sections and that exogenous taurine supplementation alleviated fibrosis via SLC6A6. Furthermore, gene expression microarray analysis and scRNA-seq analyses demonstrated that exogenous taurine mitigated liver fibrosis, mainly by regulating Fpr2-related macrophage status. WRW4-mediated inhibition of Fpr2 ameliorated M1 macrophage polarization and alleviated liver fibrosis. Additionally, exogenous taurine suppressed Fpr2-modulated macrophage M1 polarization and the production of associated proinflammatory cytokines by repressing NF-κBp65 phosphorylation; moreover, <em>SLC6A6</em> deficiency or treatment of liver fibrosis mouse models with an NF-κB inhibitor, BAY, impaired this protective effect of taurine. Therefore, taurine exerts a protective effect against liver fibrosis by repressing Fpr2/NF-κBp65-regulated macrophage M1 polarization, highlighting its potential therapeutic agent.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177614"},"PeriodicalIF":4.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844059","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}

{"title":"Attendance at pharmacology workshops correlates with academic achievement regardless of delivery mode (on-campus or online)","authors":"Ross O'Shea,&nbsp;Elvan Djouma","doi":"10.1016/j.ejphar.2025.177616","DOIUrl":"10.1016/j.ejphar.2025.177616","url":null,"abstract":"<div><div>In recent years (2021–2023), we have offered pharmacology subjects in ‘StudyFlex’ mode, allowing students to attend workshops either on-campus (blended) or online. This study aimed to investigate changes in student preference for mode of attendance, and whether attendance or mode of attendance was related to academic performance.</div><div>We collected data from 559 students enrolled in an introductory pharmacology subject and examined preference for mode of study, workshop attendance and subject results. The only difference between the instances was the mode of delivery of weekly 2-h workshops; the same academics conducted all workshops for both cohorts, and all other learning materials were delivered online.</div><div>Student preference for on-campus (blended) workshops in this subject increased over this period, while preference for online workshops decreased accordingly. Workshop attendance increased for the blended cohort but decreased for the online cohort in 2023 (Kruskal-Wallis ANOVA followed by Dunn's post-hoc test). Test marks and overall subject marks were highly correlated with workshop attendance, independent of attendance mode (non-parametric Spearman's correlation, all P &lt; 0.05), but average marks were not different between the two cohorts in any semester (Kruskal-Wallis ANOVA followed by Dunn's post-hoc test).</div><div>Despite a shift in preference for on-campus versus online workshops, the mode of workshop attendance had no significant effect on academic performance. Greater workshop attendance, independent of attendance mode, was correlated with improved academic performance. This analysis highlights the utility of online workshops, which were equally effective as blended classes in pharmacology teaching in this subject.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177616"},"PeriodicalIF":4.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828932","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}

{"title":"Calycosin treats acute myocardial infarction via NLRP3 inflammasome: Bioinformatics, network pharmacology and experimental validation","authors":"Hua-jing Yuan ,&nbsp;Quan-cheng Han ,&nbsp;Hui Yu ,&nbsp;Yi-ding Yu ,&nbsp;Xiu-juan Liu ,&nbsp;Yi-tao Xue ,&nbsp;Yan Li","doi":"10.1016/j.ejphar.2025.177621","DOIUrl":"10.1016/j.ejphar.2025.177621","url":null,"abstract":"<div><h3>Background</h3><div>Calycosin (CA) is a flavonoid natural product that may effectively treats acute myocardial infarction (AMI), but its mechanism is unclear.</div></div><div><h3>Methods</h3><div>Targets related to AMI and CA were identified using the GEO database, SwissTargetPrediction, PharmMapper and literature searches. Protein-protein interactions analysis and Cytoscape were used to screen the core targets of CA for AMI treatment. Enrichment analysis identified biological pathways linked to AMI and potential mechanisms of CA. Immune infiltration analysis was used to explore the role of immune cells in AMI and the correlation between core targets and immune cells. And further validated in AMI rats with ligated left anterior descending.</div></div><div><h3>Results</h3><div>Bioinformatics identified relevant targets and biological mechanisms of AMI, and network pharmacology revealed 31 potential targets affected by CA, with NLRP3, IL-18, IL-1β, MMP9, and TLR4 as core targets. Enrichment analysis demonstrated the biological roles of these potential targets and NLRP3, IL1β and IL18 were selected for further analysis. Immune infiltration analysis showed that both NLRP3 and IL-1β were closely associated with monocytes, mast cells activated and neutrophils, and IL-18 was closely associated with monocytes. CA exerted cardioprotective effects in AMI rats by inhibiting NLRP3 inflammasome activation and reducing IL-18 and IL-1β levels, improving cardiac function and attenuating myocardial injury and fibrosis.</div></div><div><h3>Conclusion</h3><div>CA effectively protects cardiac function and mitigates myocardial injury in post-AMI rats, probably through NLRP3 inflammasome inhibition.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177621"},"PeriodicalIF":4.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834290","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}

{"title":"L-Arginine and immune modulation: A pharmacological perspective on inflammation and autoimmune disorders","authors":"Igbayilola Yusuff Dimeji ,&nbsp;Kasim Sakran Abass ,&nbsp;Ngabea Murtala Audu ,&nbsp;Adekola Saheed Ayodeji","doi":"10.1016/j.ejphar.2025.177615","DOIUrl":"10.1016/j.ejphar.2025.177615","url":null,"abstract":"<div><div>L- Arginine (2-Amino-5-guanidinovaleric acid, L-Arg) is a semi-essential amino acid that is mainly produced within the urea cycle. It acts as a key precursor in the synthesis of proteins, urea, creatine, prolamines (including putrescine, spermine, and spermidine), proline, and nitric oxide (NO). WhenL-Arg is metabolized, it produces NO, glutamate, and prolamines, which all play important regulatory roles in various physiological functions. In addition to its metabolic roles,L-Arg significantly influences immune responses, especially in the context of inflammation and autoimmune diseases. It affects the activity of immune cells by modulating T-cell function, the polarization of macrophages, and the release of cytokines. Importantly,L-Arg plays a dual role in immune regulation, functioning as both an immunostimulatory and immunosuppressive agent depending on the specific cellular and biochemical environments. This review examines the immunopharmacological mechanisms of L-Arg, emphasizing its involvement in inflammatory responses and its potential therapeutic uses in autoimmune conditions like rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. By influencing the pathways of nitric oxide synthase (NOS) and arginase (ARG), L-Arg helps maintain immune balance and contributes to the pathophysiology of diseases. Gaining a better understanding of the pharmacological effects of L-Arg on immune regulation could yield new perspectives on targeted treatments for immune-related diseases. Exploring its impact on immune signaling and metabolic pathways may result in novel therapeutic approaches for chronic inflammatory and autoimmune disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177615"},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850154","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}

{"title":"ARA290, an alternative of erythropoietin, inhibits activation of NLRP3 inflammasome in schwann cells after sciatic nerve injury","authors":"Guixian Liu ,&nbsp;Wei Li ,&nbsp;Suli Jiang ,&nbsp;Jie Liang ,&nbsp;Meiying Song ,&nbsp;Luoyang Wang ,&nbsp;Xiao Wang ,&nbsp;Xiaoli Liu ,&nbsp;Zijie Yang ,&nbsp;Li Zhang ,&nbsp;Yanyan Yang ,&nbsp;Bei Zhang","doi":"10.1016/j.ejphar.2025.177610","DOIUrl":"10.1016/j.ejphar.2025.177610","url":null,"abstract":"<div><div>The challenge of repairing peripheral nerve injury is a critical issue that needs to be addressed urgently. Previous research has shown that erythropoietin (EPO) and its prolonged peptides exhibit beneficial effects in neurological disorders. In our study, we demonstrated that both EPO and pyroglutamic acid helix B surface peptide (pHBSP, also known as ARA290) inhibit the early inflammatory response and promote functional recovery after sciatic nerve crush injury in rat models. Our experimental results demonstrate that significant inflammatory response occurred in Schwann cells after sciatic nerve injury, and that the activation of NLRP3 inflammasome in Schwann cells is inhibited after EPO and ARA290 treatment. Our study further demonstrated that EPO and ARA290 inhibit the activation of NLRP3 inflammasome in Schwann cells by inhibiting NF-κB phosphorylation and reducing reactive oxygen species (ROS) production. In summary, EPO and ARA290 promote repair and regeneration by inhibiting the activation of NLRP3 inflammasome after sciatic nerve injury.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177610"},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834288","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}

{"title":"Anti-Alzheimer effects of an HDAC6 inhibitor, WY118, alone and in combination of lithium chloride: Synergistic suppression of ferroptosis via the modulation of tau phosphorylation and MAPK signaling","authors":"Zhonghui Lu ,&nbsp;Zixing Jiang ,&nbsp;Xiaoling Huang,&nbsp;Yu Chen,&nbsp;Luanqi Feng,&nbsp;Jielin Mai,&nbsp;Linghui Lao,&nbsp;Lanqing Li,&nbsp;Wen-Hua Chen,&nbsp;Jinhui Hu","doi":"10.1016/j.ejphar.2025.177605","DOIUrl":"10.1016/j.ejphar.2025.177605","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a complex neurodegenerative disorder, and current therapies mainly offer symptomatic relief. Given that the pathophysiology of AD is multifaceted, a multimodal therapeutic strategy targeting multiple molecular pathways implicated in AD-related pathogenesis represents a pragmatic avenue for impeding the advancement of AD. In this study, we evaluated the anti-Alzheimer effects of an HDAC6 inhibitor <strong>WY118</strong>, both alone and in combination with lithium chloride (LiCl), a GSK-3<em>β</em> inhibitor, to synergistically suppress ferroptosis. The combination of compound <strong>WY118</strong> and LiCl demonstrated significant synergistic effects in both cellular models of AD induced by glutamate and streptozotocin. The findings suggest that compound <strong>WY118</strong>, in particular in combination with LiCl, exhibits potent anti-Alzheimer effects by synergistically suppressing ferroptosis. Studies on the mechanism of action indicated that the combination treatment significantly reduced tau phosphorylation and inhibited p38 MAPK signaling. This combination therapy holds promise for developing more effective treatments for AD.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177605"},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839119","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}