Pub Date : 2025-04-14DOI: 10.1016/j.ejphar.2025.177620
Fatemeh Hedayat , Elnaz Faghfuri
Many cancers are capable of hindering the immune response against tumor cells, promoting their growth and spread; this has inspired research aimed at reversing these processes to reactivate the immune system, resulting in significant therapeutic advantages. One of the strategies being explored involves histone deacetylase (HDAC) inhibitors (HDACis), which represent a new category of targeted therapies that alter the immune system's reaction to cancer via epigenetic changes. Recently, six HDACis have been authorized for clinical applications.
This review aims to provide a concise overview of how different classes of HDACis affect the immune system, based on both in vitro, in vivo, and clinical studies, and explore the latest advancements in combining new immunotherapies with these drugs.
HDACis have been found to influence how various cancer treatments work by, for instance, enhancing access to exposed DNA through the relaxation of chromatin, disrupting DNA repair mechanisms, and boosting the expression of immune checkpoint receptors. Combining HDACis with immunotherapy could enhance antitumor effects and reduce drug resistance.
{"title":"Harnessing histone deacetylase inhibitors for enhanced cancer immunotherapy","authors":"Fatemeh Hedayat , Elnaz Faghfuri","doi":"10.1016/j.ejphar.2025.177620","DOIUrl":"10.1016/j.ejphar.2025.177620","url":null,"abstract":"<div><div>Many cancers are capable of hindering the immune response against tumor cells, promoting their growth and spread; this has inspired research aimed at reversing these processes to reactivate the immune system, resulting in significant therapeutic advantages. One of the strategies being explored involves histone deacetylase (HDAC) inhibitors (HDACis), which represent a new category of targeted therapies that alter the immune system's reaction to cancer via epigenetic changes. Recently, six HDACis have been authorized for clinical applications.</div><div>This review aims to provide a concise overview of how different classes of HDACis affect the immune system, based on both in vitro, in vivo, and clinical studies, and explore the latest advancements in combining new immunotherapies with these drugs.</div><div>HDACis have been found to influence how various cancer treatments work by, for instance, enhancing access to exposed DNA through the relaxation of chromatin, disrupting DNA repair mechanisms, and boosting the expression of immune checkpoint receptors. Combining HDACis with immunotherapy could enhance antitumor effects and reduce drug resistance.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177620"},"PeriodicalIF":4.2,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834286","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}
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 in vivo 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.
{"title":"Virtual rat web: A versatile simulation tool for pharmacology education in a variety of settings","authors":"Shiko Okabe , Taichiro Goto , Daisuke Hirayama , 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}
Pub Date : 2025-04-11DOI: 10.1016/j.ejphar.2025.177623
Jing Peng, Cheng-I Wei, Seong-Ho Lee
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.
{"title":"Eeyarestatin I (ESI)-induced ERAD inhibition exhibits anti-cancer activity through multiple mechanisms in human colorectal cancer cells","authors":"Jing Peng, Cheng-I Wei, 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 NH<sub>2</sub>-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}
Pub Date : 2025-04-10DOI: 10.1016/j.ejphar.2025.177616
Ross O'Shea, Elvan Djouma
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.
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.
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 < 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).
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.
{"title":"Attendance at pharmacology workshops correlates with academic achievement regardless of delivery mode (on-campus or online)","authors":"Ross O'Shea, 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 < 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}
Pub Date : 2025-04-10DOI: 10.1016/j.ejphar.2025.177621
Hua-jing Yuan , Quan-cheng Han , Hui Yu , Yi-ding Yu , Xiu-juan Liu , Yi-tao Xue , Yan Li
Background
Calycosin (CA) is a flavonoid natural product that may effectively treats acute myocardial infarction (AMI), but its mechanism is unclear.
Methods
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.
Results
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.
Conclusion
CA effectively protects cardiac function and mitigates myocardial injury in post-AMI rats, probably through NLRP3 inflammasome inhibition.
背景萼萼霉素（CA）是一种黄酮类天然产物，可有效治疗急性心肌梗死（AMI），但其机制尚不清楚。方法利用GEO数据库、SwissTargetPrediction、PharmMapper和文献检索确定了与AMI和CA相关的靶点。利用蛋白质-蛋白质相互作用分析和Cytoscape筛选出治疗AMI的CA核心靶点。富集分析确定了与AMI相关的生物通路以及CA的潜在机制。免疫浸润分析用于探讨免疫细胞在 AMI 中的作用以及核心靶点与免疫细胞之间的相关性。结果生物信息学发现了AMI的相关靶点和生物学机制，网络药理学发现了31个受CA影响的潜在靶点，其中NLRP3、IL-18、IL-1β、MMP9和TLR4为核心靶点。富集分析表明了这些潜在靶点的生物学作用，并选择了NLRP3、IL1β和IL18作进一步分析。免疫浸润分析表明，NLRP3和IL-1β与单核细胞、肥大细胞活化和中性粒细胞密切相关，而IL-18与单核细胞密切相关。CA通过抑制NLRP3炎性体活化、降低IL-18和IL-1β水平，对AMI大鼠的心脏起到保护作用，从而改善心功能，减轻心肌损伤和纤维化。
{"title":"Calycosin treats acute myocardial infarction via NLRP3 inflammasome: Bioinformatics, network pharmacology and experimental validation","authors":"Hua-jing Yuan , Quan-cheng Han , Hui Yu , Yi-ding Yu , Xiu-juan Liu , Yi-tao Xue , 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}
Pub Date : 2025-04-09DOI: 10.1016/j.ejphar.2025.177610
Guixian Liu , Wei Li , Suli Jiang , Jie Liang , Meiying Song , Luoyang Wang , Xiao Wang , Xiaoli Liu , Zijie Yang , Li Zhang , Yanyan Yang , Bei Zhang
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.
{"title":"ARA290, an alternative of erythropoietin, inhibits activation of NLRP3 inflammasome in schwann cells after sciatic nerve injury","authors":"Guixian Liu , Wei Li , Suli Jiang , Jie Liang , Meiying Song , Luoyang Wang , Xiao Wang , Xiaoli Liu , Zijie Yang , Li Zhang , Yanyan Yang , 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}
Pub Date : 2025-04-09DOI: 10.1016/j.ejphar.2025.177606
Lishan Sun , Yang Zhang , Can Xu , Zhongqiu Xu , Xiayu Chen , Wei Wang , Cui Hao
Carnosol is a natural diterpenoid compound derived from rosemary, a traditional Chinese herbal medicine used to treat many diseases. Recent studies have shown that carnosol has many pharmacological activities, including antioxidant, anti-inflammatory, and anticancer effects. In this study, the inhibitory activity and mechanism of action of carnosol against the influenza A virus (IAV) were investigated both in vitro and in vivo. Plaque and immunofluorescence assays were performed to evaluate the anti-IAV effects of carnosol in vitro. The antiviral mechanism was investigated using hemagglutination inhibition (HI) assay, virucidal assay, electron microscopy, and western blotting. anti-IAV activity in vivo was determined using a mouse pneumonia model combined with HE staining. The results showed that carnosol significantly inhibited H1N1 virus propagation in vitro and may block IAV infection by inactivating viral particles and interfering with some early stages of virus adsorption. The cellular Jak2/STAT3 signaling pathway may be involved in the anti-IAV effects of carnosol. Importantly, oral administration of carnosol significantly improved survival and reduced the symptoms of pneumonia in IAV-infected mice, comparable to the effect of oseltamivir. Thus, the natural compound carnosol has the potential to be developed as a novel anti-IAV agent.
{"title":"Carnosol inhibits influenza A virus by disrupting the viral envelope and interfering with Jak2/STAT3 signaling pathway","authors":"Lishan Sun , Yang Zhang , Can Xu , Zhongqiu Xu , Xiayu Chen , Wei Wang , Cui Hao","doi":"10.1016/j.ejphar.2025.177606","DOIUrl":"10.1016/j.ejphar.2025.177606","url":null,"abstract":"<div><div>Carnosol is a natural diterpenoid compound derived from rosemary, a traditional Chinese herbal medicine used to treat many diseases. Recent studies have shown that carnosol has many pharmacological activities, including antioxidant, anti-inflammatory, and anticancer effects. In this study, the inhibitory activity and mechanism of action of carnosol against the influenza A virus (IAV) were investigated both <em>in vitro</em> and <em>in vivo</em>. Plaque and immunofluorescence assays were performed to evaluate the anti-IAV effects of carnosol <em>in vitro</em>. The antiviral mechanism was investigated using hemagglutination inhibition (HI) assay, virucidal assay, electron microscopy, and western blotting. anti-IAV activity <em>in vivo</em> was determined using a mouse pneumonia model combined with HE staining. The results showed that carnosol significantly inhibited H1N1 virus propagation <em>in vitro</em> and may block IAV infection by inactivating viral particles and interfering with some early stages of virus adsorption. The cellular Jak2/STAT3 signaling pathway may be involved in the anti-IAV effects of carnosol. Importantly, oral administration of carnosol significantly improved survival and reduced the symptoms of pneumonia in IAV-infected mice, comparable to the effect of oseltamivir. Thus, the natural compound carnosol has the potential to be developed as a novel anti-IAV agent.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177606"},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143823221","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 : 2025-04-09DOI: 10.1016/j.ejphar.2025.177609
Ahmed Amr Raouf , Aya H. El-Kadem , Samia S. Sokar , Mamdouh A. Oraby , Nagla A. El-Shitany
The dominant chemotherapeutic agent, cisplatin (CP), is widely used to manage various cancer types. Despite its effectiveness, CP use is associated with severe hepatotoxicity. Cilostazol (CSZ), a selective phosphodiesterase III inhibitor, has recently demonstrated remarkable anti-inflammatory and anti-apoptotic properties in different diseases. Additionally, it exhibits hepatoprotective effects against various forms of liver injury. Hence, this study aimed to assess the potential hepatoprotective and ameliorative effects of CSZ on CP-induced acute liver injury (ALI) and to elucidate the underlying molecular mechanisms. To achieve this, ALI was induced by a single injection of CP (20 mg/kg; i.p.) in male Wistar rats pretreated with CSZ (5 or 10 mg/kg) administered orally for one week. The findings revealed that CSZ effectively reversed CP-induced hepatic dysfunction, as evidenced by notable liver function tests and improvements in histological examination. Additionally, CSZ protected against CP-mediated liver oxidative stress by decreasing MDA levels while increasing GSH and GPx levels and enhancing SOD activity. Furthermore, CSZ exhibited a potent anti-inflammatory effect, reducing the expression of pro-inflammatory cytokines, including NF-κB, IL-1β, and TNF-α. Regarding hepatocyte apoptosis, CSZ suppressed Bax immunoexpression and caspase-3 and caspase-9 levels while enhancing Bcl-2 expression, thereby mitigating hepatic cell death. The hepatoprotective effects of CSZ could be attributed to the regulation of the miRNA-34a/AMPK/SIRT1/PGC-1α signaling pathway, leading to the activation of the Nrf2/HO-1-mediated antioxidative defense mechanism. In conclusion, CSZ could be a promising therapeutic agent for preventing CP-induced ALI, potentially improving the quality of life for cancer patients.
{"title":"Cilostazol attenuates cisplatin-induced acute liver injury by targeting the SIRT1/AMPK/PGC-1α signaling pathway, with an impact on miRNA-34a","authors":"Ahmed Amr Raouf , Aya H. El-Kadem , Samia S. Sokar , Mamdouh A. Oraby , Nagla A. El-Shitany","doi":"10.1016/j.ejphar.2025.177609","DOIUrl":"10.1016/j.ejphar.2025.177609","url":null,"abstract":"<div><div>The dominant chemotherapeutic agent, cisplatin (CP), is widely used to manage various cancer types. Despite its effectiveness, CP use is associated with severe hepatotoxicity. Cilostazol (CSZ), a selective phosphodiesterase III inhibitor, has recently demonstrated remarkable anti-inflammatory and anti-apoptotic properties in different diseases. Additionally, it exhibits hepatoprotective effects against various forms of liver injury. Hence, this study aimed to assess the potential hepatoprotective and ameliorative effects of CSZ on CP-induced acute liver injury (ALI) and to elucidate the underlying molecular mechanisms. To achieve this, ALI was induced by a single injection of CP (20 mg/kg; i.p.) in male Wistar rats pretreated with CSZ (5 or 10 mg/kg) administered orally for one week. The findings revealed that CSZ effectively reversed CP-induced hepatic dysfunction, as evidenced by notable liver function tests and improvements in histological examination. Additionally, CSZ protected against CP-mediated liver oxidative stress by decreasing MDA levels while increasing GSH and GPx levels and enhancing SOD activity. Furthermore, CSZ exhibited a potent anti-inflammatory effect, reducing the expression of pro-inflammatory cytokines, including NF-κB, IL-1β, and TNF-α. Regarding hepatocyte apoptosis, CSZ suppressed Bax immunoexpression and caspase-3 and caspase-9 levels while enhancing Bcl-2 expression, thereby mitigating hepatic cell death. The hepatoprotective effects of CSZ could be attributed to the regulation of the miRNA-34a/AMPK/SIRT1/PGC-1α signaling pathway, leading to the activation of the Nrf2/HO-1-mediated antioxidative defense mechanism. In conclusion, CSZ could be a promising therapeutic agent for preventing CP-induced ALI, potentially improving the quality of life for cancer patients.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177609"},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143823223","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 : 2025-04-09DOI: 10.1016/j.ejphar.2025.177608
Amina Tariq , Muhammad Shoaib , Lingbo Qu , Sana Shoukat , Xiaofei Nan , Jinshuai Song
Epidermal growth factor receptor (EGFR) is a potential target for anticancer therapies and plays a crucial role in cell growth, survival, and metastasis. EGFR gene mutations trigger aberrant signaling, leading to non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKIs) effectively target these mutations to treat NSCLC. While the first three generations of EGFR TKIs have been proven effective, the emergence of the EGFR-C797S resistance mutation poses a new challenge. To address this, various synthetic EGFR TKIs have been developed. In this review, we have summarized the EGFR TKIs reported in the past five years, focusing on their clinical outcomes and structure-activity relationship analysis. We have also explored binding modes and interactions between the binding pocket and ligands to provide insights into the mechanisms of these inhibitors, which contribute to advancements in targeted cancer therapy. Additionally, artificial Intelligence-driven methods, including recursive neural networks and reinforcement learning, have revolutionized EGFR inhibitor design by facilitating rapid screening, predicting EGFR mutations, and novel compound generation.
{"title":"Exploring 4th generation EGFR inhibitors: A review of clinical outcomes and structural binding insights","authors":"Amina Tariq , Muhammad Shoaib , Lingbo Qu , Sana Shoukat , Xiaofei Nan , Jinshuai Song","doi":"10.1016/j.ejphar.2025.177608","DOIUrl":"10.1016/j.ejphar.2025.177608","url":null,"abstract":"<div><div>Epidermal growth factor receptor (EGFR) is a potential target for anticancer therapies and plays a crucial role in cell growth, survival, and metastasis. EGFR gene mutations trigger aberrant signaling, leading to non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKIs) effectively target these mutations to treat NSCLC. While the first three generations of EGFR TKIs have been proven effective, the emergence of the EGFR-C797S resistance mutation poses a new challenge. To address this, various synthetic EGFR TKIs have been developed. In this review, we have summarized the EGFR TKIs reported in the past five years, focusing on their clinical outcomes and structure-activity relationship analysis. We have also explored binding modes and interactions between the binding pocket and ligands to provide insights into the mechanisms of these inhibitors, which contribute to advancements in targeted cancer therapy. Additionally, artificial Intelligence-driven methods, including recursive neural networks and reinforcement learning, have revolutionized EGFR inhibitor design by facilitating rapid screening, predicting EGFR mutations, and novel compound generation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177608"},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828953","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 : 2025-04-07DOI: 10.1016/j.ejphar.2025.177565
Sujin Choi , Hyun-Ju An , Hyunjeong Yeo , Soonchul Lee , So Young Kim
Objective
Fluoxetine was reported to restore critical period-like neural plasticity via alleviating perineuronal nets (PNNs). This study aimed to investigate the effect of fluoxetine on auditory processing and PNNs in auditory cortex and hippocampus.
Methods
Sprague-Dawley rats were exposed 2–20 kHz, 115 dB sound pressure level noise for 3 h per day from postnatal day 1–3 to postnatal day 21. After completion of noise exposure, 10 mg/kg/day of fluoxetine was administered for 19 days. There were four groups of rats according to the presence of noise exposure and fluoxetine treatment, vehicle, noise + vehicle, fluoxetine, and noise + fluoxetine rats. The gene expression changes of hippocampus were analyzed using RNA sequencing.
Results
In the auditory cortex, the expression of aggrecan (ACAN) was lower in noise-exposed rats than vehicle rats, while the noise + fluoxetine rats presented higher expression levels of ACAN which was comparable with that of the vehicle rats (p = 0.01 in Mann-Whitney U test; 146 ± 15 vs. 100 ± 11). In the hippocampus, the expression of brain-derived neurotrophic factor (BDNF) was lower in noise + vehicle rats while noise + fluoxetine rats presented higher expression of BDNF than noise + vehicle rats (p < 0.001 in Mann-Whitney U test; 389 ± 21 vs. 249 ± 16). The RNA sequencing of the hippocampus predicted the down regulation of genes involving extracellular matrix organization when compared noise + vehicle vs. noise + fluoxetine rats.
Conclusion
The fluoxetine administration in noise exposed rats improved the gap inhibition ability. The noise exposure decreased expression of BDNF and modulated the expression of genes related with extracellular matrix organization which was partially reversed after fluoxetine treatment.
{"title":"Effects of fluoxetine on the gene expression of hippocampus and gap inhibition in noise-induced hearing loss rats","authors":"Sujin Choi , Hyun-Ju An , Hyunjeong Yeo , Soonchul Lee , So Young Kim","doi":"10.1016/j.ejphar.2025.177565","DOIUrl":"10.1016/j.ejphar.2025.177565","url":null,"abstract":"<div><h3>Objective</h3><div>Fluoxetine was reported to restore critical period-like neural plasticity via alleviating perineuronal nets (PNNs). This study aimed to investigate the effect of fluoxetine on auditory processing and PNNs in auditory cortex and hippocampus.</div></div><div><h3>Methods</h3><div>Sprague-Dawley rats were exposed 2–20 kHz, 115 dB sound pressure level noise for 3 h per day from postnatal day 1–3 to postnatal day 21. After completion of noise exposure, 10 mg/kg/day of fluoxetine was administered for 19 days. There were four groups of rats according to the presence of noise exposure and fluoxetine treatment, vehicle, noise + vehicle, fluoxetine, and noise + fluoxetine rats. The gene expression changes of hippocampus were analyzed using RNA sequencing.</div></div><div><h3>Results</h3><div>In the auditory cortex, the expression of aggrecan (ACAN) was lower in noise-exposed rats than vehicle rats, while the noise + fluoxetine rats presented higher expression levels of ACAN which was comparable with that of the vehicle rats (<em>p</em> = 0.01 in Mann-Whitney <em>U</em> test; 146 ± 15 vs. 100 ± 11). In the hippocampus, the expression of brain-derived neurotrophic factor (BDNF) was lower in noise + vehicle rats while noise + fluoxetine rats presented higher expression of BDNF than noise + vehicle rats (<em>p</em> < 0.001 in Mann-Whitney <em>U</em> test; 389 ± 21 vs. 249 ± 16). The RNA sequencing of the hippocampus predicted the down regulation of genes involving extracellular matrix organization when compared noise + vehicle vs. noise + fluoxetine rats.</div></div><div><h3>Conclusion</h3><div>The fluoxetine administration in noise exposed rats improved the gap inhibition ability. The noise exposure decreased expression of BDNF and modulated the expression of genes related with extracellular matrix organization which was partially reversed after fluoxetine treatment.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177565"},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143815925","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号