Pub Date : 2025-02-27DOI: 10.1016/j.ejphar.2025.177436
Mamali Das , Chandramohan Kiruthiga , R. Beema Shafreen , Kathiresan Nachammai , Chandrabose Selvaraj , K. Langeswaran
The integration of microbiome research and nanotechnology represents a significant advancement in immuno-oncology, potentially improving the effectiveness of cancer immunotherapies. Recent studies highlight the influential role of the human microbiome in modulating immune responses, presenting new opportunities to enhance immune checkpoint inhibitors (ICIs) and other cancer therapies. Nanotechnology offers precise drug delivery and immune modulation capabilities, minimizing off-target effects while maximizing therapeutic outcomes. This review consolidates current knowledge on the interactions between the microbiome and the immune system, emphasizing the microbiome's impact on ICIs, and explores the incorporation of nanotechnology in cancer treatment strategies. Additionally, it provides a forward-looking perspective on the synergistic potential of microbiome modulation and nanotechnology to overcome existing challenges in immuno-oncology. This integrated approach may enhance the personalization and effectiveness of next-generation cancer treatments, paving the way for transformative patient care.
{"title":"Harnessing the human microbiome and its impact on immuno-oncology and nanotechnology for next-generation cancer therapies","authors":"Mamali Das , Chandramohan Kiruthiga , R. Beema Shafreen , Kathiresan Nachammai , Chandrabose Selvaraj , K. Langeswaran","doi":"10.1016/j.ejphar.2025.177436","DOIUrl":"10.1016/j.ejphar.2025.177436","url":null,"abstract":"<div><div>The integration of microbiome research and nanotechnology represents a significant advancement in immuno-oncology, potentially improving the effectiveness of cancer immunotherapies. Recent studies highlight the influential role of the human microbiome in modulating immune responses, presenting new opportunities to enhance immune checkpoint inhibitors (ICIs) and other cancer therapies. Nanotechnology offers precise drug delivery and immune modulation capabilities, minimizing off-target effects while maximizing therapeutic outcomes. This review consolidates current knowledge on the interactions between the microbiome and the immune system, emphasizing the microbiome's impact on ICIs, and explores the incorporation of nanotechnology in cancer treatment strategies. Additionally, it provides a forward-looking perspective on the synergistic potential of microbiome modulation and nanotechnology to overcome existing challenges in immuno-oncology. This integrated approach may enhance the personalization and effectiveness of next-generation cancer treatments, paving the way for transformative patient care.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177436"},"PeriodicalIF":4.2,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537054","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 : 2025-02-26DOI: 10.1016/j.ejphar.2025.177431
Roos de Jonge , Emma Wessel , Anneke H. van Houwelingen , Rahul Pandit
Safe and effective pharmacotherapy not only requires biomedical and pharmacological knowledge, but also insight into the patient's perspective. Although factors such as personal beliefs, acceptance of side effects or medicine costs influence pharmacotherapy, these non-clinical factors are not extensively discussed within the health professions education (HPE) curricula. Incorporating patient-perspective into pharmacology could therefore help minimize drug-related problems in patients. As videos provide a holistic depiction of the patient's life, using patient videos, instead of commonly used, paper-based case studies, could be suitable to reach this objective.
Here we aim to study effectiveness of patient videos as a tool for teaching HPE students on the value of patient's perspective in pharmacology and pharmacotherapy. An interactive lecture on pharmacokinetics was developed for first-year bachelor medical and pharmacy undergraduate students. The educational intervention included watching a patient video, followed by focused exercises and plenary discussions on various pharmacological and patient-perspective related topics. The lecture concluded with students filling up a questionnaire with both open-ended questions and Likert-scale based statements. Besides learning about pharmacological principles (e.g. clinical relevance of pharmacokinetics), students additionally learnt about other prescribing-related topics (e.g. therapy failure, shared decision making) and were able to identify skills required of healthcare professionals, beyond those connected directly to pharmacotherapy (e.g. empathy, listening). The study identifies patient videos as a highly suitable educational tool. Not only do videos teach about the various pharmacological principles, but they also add an extra dimension to pharmacology teaching and learning and can easily be integrated into existing teaching modalities.
{"title":"Using patient videos in pharmacology education within medicine and pharmacy curricula","authors":"Roos de Jonge , Emma Wessel , Anneke H. van Houwelingen , Rahul Pandit","doi":"10.1016/j.ejphar.2025.177431","DOIUrl":"10.1016/j.ejphar.2025.177431","url":null,"abstract":"<div><div>Safe and effective pharmacotherapy not only requires biomedical and pharmacological knowledge, but also insight into the patient's perspective. Although factors such as personal beliefs, acceptance of side effects or medicine costs influence pharmacotherapy, these non-clinical factors are not extensively discussed within the health professions education (HPE) curricula. Incorporating patient-perspective into pharmacology could therefore help minimize drug-related problems in patients. As videos provide a holistic depiction of the patient's life, using patient videos, instead of commonly used, paper-based case studies, could be suitable to reach this objective.</div><div>Here we aim to study effectiveness of patient videos as a tool for teaching HPE students on the value of patient's perspective in pharmacology and pharmacotherapy. An interactive lecture on pharmacokinetics was developed for first-year bachelor medical and pharmacy undergraduate students. The educational intervention included watching a patient video, followed by focused exercises and plenary discussions on various pharmacological and patient-perspective related topics. The lecture concluded with students filling up a questionnaire with both open-ended questions and Likert-scale based statements. Besides learning about pharmacological principles (e.g. clinical relevance of pharmacokinetics), students additionally learnt about other prescribing-related topics (e.g. therapy failure, shared decision making) and were able to identify skills required of healthcare professionals, beyond those connected directly to pharmacotherapy (e.g. empathy, listening). The study identifies patient videos as a highly suitable educational tool. Not only do videos teach about the various pharmacological principles, but they also add an extra dimension to pharmacology teaching and learning and can easily be integrated into existing teaching modalities.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177431"},"PeriodicalIF":4.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1016/j.ejphar.2025.177432
Md. Takdir Hossain, Md. Arafat Hossain
The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cancer, including cell growth, survival, metabolism, and metastasis. Its major role in tumor growth makes it a key target for cancer therapeutics, offering significant potential to slow tumor progression and enhance patient outcomes. Gain-of-function mutations, gene amplifications, and the loss of regulatory proteins like PTEN are frequently observed in malignancies, contributing to tumor development and resistance to conventional treatments such as chemotherapy and hormone therapy. As a result, PI3K inhibitors have received a lot of interest in cancer research. Several kinds of small-molecule PI3K inhibitors have been developed, including pan-PI3K inhibitors, isoform-specific inhibitors, and dual PI3K/mTOR inhibitors, each targeting a distinct component of the pathway. Some PI3K inhibitors such as idelalisib, copanlisib, duvelisib, alpelisib, and umbralisib have received FDA-approval, and are effective in the treatment of breast cancer and hematologic malignancies. Despite promising results in preclinical and clinical trials, the overall clinical success of PI3K inhibitors has been mixed. While some patients may get substantial advantages, a considerable number of them acquire resistance as a result of feedback activation of alternative pathways, adaptive tumor responses, and treatment-emergent mutations. The resistance mechanisms provide barriers to the sustained efficacy of PI3K-targeted treatments. This study reviews recent advancements in PI3K inhibitors, covering their clinical status, mechanism of action, resistance mechanisms, and strategies to overcome resistance.
{"title":"Targeting PI3K in cancer treatment: A comprehensive review with insights from clinical outcomes","authors":"Md. Takdir Hossain, Md. Arafat Hossain","doi":"10.1016/j.ejphar.2025.177432","DOIUrl":"10.1016/j.ejphar.2025.177432","url":null,"abstract":"<div><div>The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cancer, including cell growth, survival, metabolism, and metastasis. Its major role in tumor growth makes it a key target for cancer therapeutics, offering significant potential to slow tumor progression and enhance patient outcomes. Gain-of-function mutations, gene amplifications, and the loss of regulatory proteins like PTEN are frequently observed in malignancies, contributing to tumor development and resistance to conventional treatments such as chemotherapy and hormone therapy. As a result, PI3K inhibitors have received a lot of interest in cancer research. Several kinds of small-molecule PI3K inhibitors have been developed, including pan-PI3K inhibitors, isoform-specific inhibitors, and dual PI3K/mTOR inhibitors, each targeting a distinct component of the pathway. Some PI3K inhibitors such as idelalisib, copanlisib, duvelisib, alpelisib, and umbralisib have received FDA-approval, and are effective in the treatment of breast cancer and hematologic malignancies. Despite promising results in preclinical and clinical trials, the overall clinical success of PI3K inhibitors has been mixed. While some patients may get substantial advantages, a considerable number of them acquire resistance as a result of feedback activation of alternative pathways, adaptive tumor responses, and treatment-emergent mutations. The resistance mechanisms provide barriers to the sustained efficacy of PI3K-targeted treatments. This study reviews recent advancements in PI3K inhibitors, covering their clinical status, mechanism of action, resistance mechanisms, and strategies to overcome resistance.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177432"},"PeriodicalIF":4.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531381","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 : 2025-02-25DOI: 10.1016/j.ejphar.2025.177430
Yi-chao Sheng , Jia-ni Huang , Wei-long Wu , Xiao-rui Wan , Jing Wang , Zheng-hong Qin , Yan Wang
Parkinson's disease (PD) is a common neurodegenerative disorder worldwide, characterized by the loss of dopaminergic (DA) neurons in the substantia nigra and is associated with iron dyshomeostasis. Ferroptosis, a form of programmed cell death, involves iron-dependent lipid peroxidation and serves as a significant regulatory mechanism in PD. This study identified Tp53-induced glycolysis and apoptosis regulator (TIGAR) as a potential regulator of ferroptosis resistance in PD development. In this study, we demonstrated that in HT22 cells, 1-methyl-4-phenylpyridinium (MPP+) increased lipid peroxidation levels and reduced cell viability. These effects were reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). MPP+ also induced elevated intracellular iron ion deposition, reactive oxygen species (ROS), and the lipid peroxidation product malondialdehyde (MDA). Meanwhile, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) significantly decreased glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) levels, glutathione peroxidase (GPX) activity, and TIGAR expression, all of which were reversible with TIGAR overexpression. In an MPTP-induced in vivo PD model, TIGAR overexpression markedly increased DA neurons and reduced iron deposition. To summarize, TIGAR enhances intracellular NADPH production via the promotion of the pentose phosphate pathway (PPP), reduces intracellular glutathione disulfide (GSSG) to GSH, boosts GPX activity, and inhibits ferroptosis, thus providing neuronal protection.
{"title":"TIGAR plays neuroprotective roles in MPP+/MPTP-induced Parkinson's disease by alleviating ferroptosis","authors":"Yi-chao Sheng , Jia-ni Huang , Wei-long Wu , Xiao-rui Wan , Jing Wang , Zheng-hong Qin , Yan Wang","doi":"10.1016/j.ejphar.2025.177430","DOIUrl":"10.1016/j.ejphar.2025.177430","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a common neurodegenerative disorder worldwide, characterized by the loss of dopaminergic (DA) neurons in the substantia nigra and is associated with iron dyshomeostasis. Ferroptosis, a form of programmed cell death, involves iron-dependent lipid peroxidation and serves as a significant regulatory mechanism in PD. This study identified Tp53-induced glycolysis and apoptosis regulator (TIGAR) as a potential regulator of ferroptosis resistance in PD development. In this study, we demonstrated that in HT22 cells, 1-methyl-4-phenylpyridinium (MPP<sup>+</sup>) increased lipid peroxidation levels and reduced cell viability. These effects were reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). MPP<sup>+</sup> also induced elevated intracellular iron ion deposition, reactive oxygen species (ROS), and the lipid peroxidation product malondialdehyde (MDA). Meanwhile, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) significantly decreased glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) levels, glutathione peroxidase (GPX) activity, and TIGAR expression, all of which were reversible with TIGAR overexpression. In an MPTP-induced <em>in vivo</em> PD model, TIGAR overexpression markedly increased DA neurons and reduced iron deposition. To summarize, TIGAR enhances intracellular NADPH production via the promotion of the pentose phosphate pathway (PPP), reduces intracellular glutathione disulfide (GSSG) to GSH, boosts GPX activity, and inhibits ferroptosis, thus providing neuronal protection.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"995 ","pages":"Article 177430"},"PeriodicalIF":4.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neurological disorders arising from structural and functional disruptions in the nervous system present major global health challenges. This review examines the intricacies of various cellular signaling pathways, including Nrf2/Keap1/HO-1, SIRT-1, JAK/STAT3/mTOR, and BACE-1/gamma-secretase/MAPT, which play pivotal roles in neuronal health and pathology. The Nrf2-Keap1 pathway, a key antioxidant response mechanism, mitigates oxidative stress, while SIRT-1 contributes to mitochondrial integrity and inflammation control. Dysregulation of these pathways has been identified in neurodegenerative and neuropsychiatric disorders, including Alzheimer's and Parkinson's diseases, characterized by inflammation, protein aggregation, and mitochondrial dysfunction. Additionally, the JAK/STAT3 signaling pathway emphasizes the connection between cytokine responses and neuroinflammation, further compounding disease progression. This review explores the crosstalk among these signaling networks, elucidating how their disruption leads to neuronal decline. It also addresses the dual roles of these pathways, presenting challenges in targeting them for therapeutic purposes. Despite the potential benefits of activating neuroprotective pathways, excessive stimulation may cause deleterious effects, including tumorigenesis. Future research should focus on designing multi-targeted therapies that enhance the effectiveness and safety of treatments, considering individual variabilities and the obstacles posed by the blood-brain barrier to drug delivery. Understanding these complex signaling interactions is crucial for developing innovative and effective neuroprotective strategies that could significantly improve the management of neurological disorders.
{"title":"Navigating the complexities of neuronal signaling and targets in neurological disorders: From pathology to therapeutics","authors":"Divya Choudhary , MD Nasiruddin Khan , Zuber Khan , Sidharth Mehan , Ghanshyam Das Gupta , Acharan S. Narula , Rajaram Samant","doi":"10.1016/j.ejphar.2025.177417","DOIUrl":"10.1016/j.ejphar.2025.177417","url":null,"abstract":"<div><div>Neurological disorders arising from structural and functional disruptions in the nervous system present major global health challenges. This review examines the intricacies of various cellular signaling pathways, including Nrf2/Keap1/HO-1, SIRT-1, JAK/STAT3/mTOR, and BACE-1/gamma-secretase/MAPT, which play pivotal roles in neuronal health and pathology. The Nrf2-Keap1 pathway, a key antioxidant response mechanism, mitigates oxidative stress, while SIRT-1 contributes to mitochondrial integrity and inflammation control. Dysregulation of these pathways has been identified in neurodegenerative and neuropsychiatric disorders, including Alzheimer's and Parkinson's diseases, characterized by inflammation, protein aggregation, and mitochondrial dysfunction. Additionally, the JAK/STAT3 signaling pathway emphasizes the connection between cytokine responses and neuroinflammation, further compounding disease progression. This review explores the crosstalk among these signaling networks, elucidating how their disruption leads to neuronal decline. It also addresses the dual roles of these pathways, presenting challenges in targeting them for therapeutic purposes. Despite the potential benefits of activating neuroprotective pathways, excessive stimulation may cause deleterious effects, including tumorigenesis. Future research should focus on designing multi-targeted therapies that enhance the effectiveness and safety of treatments, considering individual variabilities and the obstacles posed by the blood-brain barrier to drug delivery. Understanding these complex signaling interactions is crucial for developing innovative and effective neuroprotective strategies that could significantly improve the management of neurological disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"995 ","pages":"Article 177417"},"PeriodicalIF":4.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515093","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 : 2025-02-25DOI: 10.1016/j.ejphar.2025.177344
Ming-Hui Li , Yang Yang , Qi-Qi Dong , Hui Tao , Chao Lu , Jing-Jing Yang
Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) and the activation of hepatic stellate cells (HSCs), which are influenced by epitranscriptomic and epigenetic factors. Recent advancements in epigenetic and epitranscriptomic research have revealed new opportunities for therapeutic interventions, particularly through the regulation of ferroptosis, a type of programmed cell death that is specifically linked to iron-dependent lipid peroxidation. In the context of liver fibrosis, a progressive scarring process that can progress to cirrhosis and ultimately end-stage liver disease, targeting these regulatory mechanisms to modulate ferroptosis presents a promising therapeutic strategy. This review aims to consolidate current knowledge on the epigenetic and epitranscriptomic control of ferroptosis and investigate its potential implications for the treatment of liver fibrosis.
{"title":"Novel epitranscriptomic and epigenetic therapeutic strategies and targets for ferroptosis in liver fibrosis","authors":"Ming-Hui Li , Yang Yang , Qi-Qi Dong , Hui Tao , Chao Lu , Jing-Jing Yang","doi":"10.1016/j.ejphar.2025.177344","DOIUrl":"10.1016/j.ejphar.2025.177344","url":null,"abstract":"<div><div>Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) and the activation of hepatic stellate cells (HSCs), which are influenced by epitranscriptomic and epigenetic factors. Recent advancements in epigenetic and epitranscriptomic research have revealed new opportunities for therapeutic interventions, particularly through the regulation of ferroptosis, a type of programmed cell death that is specifically linked to iron-dependent lipid peroxidation. In the context of liver fibrosis, a progressive scarring process that can progress to cirrhosis and ultimately end-stage liver disease, targeting these regulatory mechanisms to modulate ferroptosis presents a promising therapeutic strategy. This review aims to consolidate current knowledge on the epigenetic and epitranscriptomic control of ferroptosis and investigate its potential implications for the treatment of liver fibrosis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177344"},"PeriodicalIF":4.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522922","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}
The present work was conducted to evaluate the pharmacological effect of Arctiin(ARC) on high fat diet(HFD)-induced Non-alcoholic steatohepatitis(NASH) and investigate its potential mechanism. The network pharmacology and bioinformatic analyses predicted that FGFR2 might be the potential target of ARC. Palmitic acid(PA)-induced AML12 cell was employed as the in vitro model. ARC reduced the levels of ALT, AST, TC, TG, and attenuated histopathological alteration. ARC inhibited inflammatory cytokines, inflammatory molecules, downregulated the expressions of FGFR2/CSF1R, inhibited glycolysis and promoted oxidative phosphorylation both in vivo and in vitro. ARC enhanced mitochondrial membrane potential and reduced oxidative stress. The application of FGFR2-OE plasmid, CSF1R-OE plasmid, CSF1R inhibitor PLX indicated that ARC attenuated glycolysis and inflammation in PA-induced AML12 cells via FGFR2/CSF1R signaling. HIF1A was proved to be involved in this process using HIF1A agonist DEF and HIF1A inhibitor PX478. Molecular docking and molecular dynamic suggested that ARC might combine with FGFR2. In conclusion, the present study demonstrated that ARC ameliorated NASH by inhibiting glycolysis and inflammation via FGFR2/CSF1R signaling.
{"title":"Arctiin attenuated NASH by inhibiting glycolysis and inflammation via FGFR2/CSF1R signaling","authors":"Yeliu Fu, Xiaolin Li, Yuanyuan Zeng, Aizhen Zhang, Shengchen Qiu","doi":"10.1016/j.ejphar.2025.177424","DOIUrl":"10.1016/j.ejphar.2025.177424","url":null,"abstract":"<div><div>The present work was conducted to evaluate the pharmacological effect of Arctiin(ARC) on high fat diet(HFD)-induced Non-alcoholic steatohepatitis(NASH) and investigate its potential mechanism. The network pharmacology and bioinformatic analyses predicted that FGFR2 might be the potential target of ARC. Palmitic acid(PA)-induced AML12 cell was employed as the in vitro model. ARC reduced the levels of ALT, AST, TC, TG, and attenuated histopathological alteration. ARC inhibited inflammatory cytokines, inflammatory molecules, downregulated the expressions of FGFR2/CSF1R, inhibited glycolysis and promoted oxidative phosphorylation both in vivo and in vitro. ARC enhanced mitochondrial membrane potential and reduced oxidative stress. The application of FGFR2-OE plasmid, CSF1R-OE plasmid, CSF1R inhibitor PLX indicated that ARC attenuated glycolysis and inflammation in PA-induced AML12 cells via FGFR2/CSF1R signaling. HIF1A was proved to be involved in this process using HIF1A agonist DEF and HIF1A inhibitor PX478. Molecular docking and molecular dynamic suggested that ARC might combine with FGFR2. In conclusion, the present study demonstrated that ARC ameliorated NASH by inhibiting glycolysis and inflammation via FGFR2/CSF1R signaling.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177424"},"PeriodicalIF":4.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515090","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 : 2025-02-23DOI: 10.1016/j.ejphar.2025.177411
Andrea Pignatelli-Espejo, Róisín Kelly-Laubscher, Órla P. Barry
Background
Designing appropriate assessments is essential in driving student learning. As pharmacology lecturers we aspire to create teaching and learning activities which allow students to gain both depth of understanding and ability to transfer their knowledge. Thus, carefully designed assessments are a key requirement to align with educator's intentions and students' needs.
Objective
To investigate whether Legitimation Code Theory and one of its three dimensions, Semantics, is an effective tool to reveal the types of knowledge demands embedded in a dental pharmacology assessment.
Study
Three independent researchers developed a ‘translation device’ to code assessment demands in terms of semantic gravity (the context-dependence of meaning) and semantic density (the degree of complexity of meaning). Coding was plotted on the Cartesian plane, the four quadrants representing how semantic gravity and semantic density fluctuated throughout individual questions.
Results
Using our translation device the semantic gravity and semantic density coding analysis identified a range of both abstraction and complexity embedded in dental pharmacology summative questions. Coding resulted in Kappa interrater values of 1.0 for semantic gravity and ranging from 0.85 to 1.0 for semantic density. Compulsory clinical case studies had knowledge demands mainly embedded in strong semantic gravity (SG+) and weak semantic density (SD–) while the optional questions had knowledge demands with a wider semantic range and were distributed throughout three quadrants of the semantic plane.
Conclusion
This study introduces a semi-objective approach to analyse and uncover the knowledge demands embedded in pharmacology assessments, ensuring alignment with students’ learning outcomes and fostering awareness of the knowledge required for exam success.
{"title":"Exploring the knowledge demands of a pharmacology assessment using Legitimation Code Theory","authors":"Andrea Pignatelli-Espejo, Róisín Kelly-Laubscher, Órla P. Barry","doi":"10.1016/j.ejphar.2025.177411","DOIUrl":"10.1016/j.ejphar.2025.177411","url":null,"abstract":"<div><h3>Background</h3><div>Designing appropriate assessments is essential in driving student learning. As pharmacology lecturers we aspire to create teaching and learning activities which allow students to gain both depth of understanding and ability to transfer their knowledge. Thus, carefully designed assessments are a key requirement to align with educator's intentions and students' needs.</div></div><div><h3>Objective</h3><div>To investigate whether Legitimation Code Theory and one of its three dimensions, Semantics, is an effective tool to reveal the types of knowledge demands embedded in a dental pharmacology assessment.</div></div><div><h3>Study</h3><div>Three independent researchers developed a ‘translation device’ to code assessment demands in terms of semantic gravity (the context-dependence of meaning) and semantic density (the degree of complexity of meaning). Coding was plotted on the Cartesian plane, the four quadrants representing how semantic gravity and semantic density fluctuated throughout individual questions.</div></div><div><h3>Results</h3><div>Using our translation device the semantic gravity and semantic density coding analysis identified a range of both abstraction and complexity embedded in dental pharmacology summative questions. Coding resulted in Kappa interrater values of 1.0 for semantic gravity and ranging from 0.85 to 1.0 for semantic density. Compulsory clinical case studies had knowledge demands mainly embedded in strong semantic gravity (SG+) and weak semantic density (SD<strong>–)</strong> while the optional questions had knowledge demands with a wider semantic range and were distributed throughout three quadrants of the semantic plane.</div></div><div><h3>Conclusion</h3><div>This study introduces a semi-objective approach to analyse and uncover the knowledge demands embedded in pharmacology assessments, ensuring alignment with students’ learning outcomes and fostering awareness of the knowledge required for exam success.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177411"},"PeriodicalIF":4.2,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-22DOI: 10.1016/j.ejphar.2025.177416
Meitian Zhang , Yuetong Sha , Jiaxin Wang , Hanping Qi , Pilong Shi , Yongsheng Liu , Man Jiang , Lina Ba , Yuhang Liu , Yonggang Cao , Qianhui Zhang , Hongli Sun
UNC-51-like kinase 1 (ULK1), a primary serine/threonine kinase, is implicated in diverse pathophysiological processes. Previous findings have linked ULK1-dependent autophagy to cardiac hypertrophy. Our study further explored the functional role and molecular mechanisms of ULK1 in non-autophagic signaling pathways. Notably, ULK1 expression was significantly elevated in both transverse aortic constriction (TAC)-induced hypertrophic mouse hearts and Angiotensin II (Ang II)-treated cardiomyocytes, suggesting an increased sensitivity to hypertrophic stimuli potentially mediated by ULK1-induced ferroptosis in hypertrophic cardiomyocytes. Treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reduced ULK1-induced cardiomyocyte hypertrophy and ferroptosis. Proteomic analysis identified the upregulation of transcription factor high mobility group A2 (HMGA2) as a key mechanism in this ferroptotic process. Elevated HMGA2 levels exacerbated ferroptosis, evidenced by increased cell death, lipid peroxidation, ROS production, and reduced GPX4 expression. Furthermore, HMGA2 was shown to promote cardiomyocyte ferroptosis via binding to methyltransferase-like 14 (METTL14), which in turn enhanced ferroptosis in cardiomyocytes through solute carrier family 7 member 11 (SLC7A11) m6A modification. In vivo, a delivery system using neutrophil membrane (NM)-coated mesoporous silica nanoparticles (MSN) was developed to inhibit cardiac hypertrophy, underscoring the therapeutic potential of targeting ULK1. Overall, this study demonstrates that ULK1 promotes cardiac hypertrophy through HMGA2/METTL14/SLC7A11 axis-mediated cardiomyocyte ferroptosis, suggesting a novel therapeutic approach for cardiac hypertrophy.
{"title":"Inhibition of ULK1 attenuates ferroptosis-mediated cardiac hypertrophy via HMGA2/METTL14/SLC7A11 axis in mice","authors":"Meitian Zhang , Yuetong Sha , Jiaxin Wang , Hanping Qi , Pilong Shi , Yongsheng Liu , Man Jiang , Lina Ba , Yuhang Liu , Yonggang Cao , Qianhui Zhang , Hongli Sun","doi":"10.1016/j.ejphar.2025.177416","DOIUrl":"10.1016/j.ejphar.2025.177416","url":null,"abstract":"<div><div>UNC-51-like kinase 1 (ULK1), a primary serine/threonine kinase, is implicated in diverse pathophysiological processes. Previous findings have linked ULK1-dependent autophagy to cardiac hypertrophy. Our study further explored the functional role and molecular mechanisms of ULK1 in non-autophagic signaling pathways. Notably, ULK1 expression was significantly elevated in both transverse aortic constriction (TAC)-induced hypertrophic mouse hearts and Angiotensin II (Ang II)-treated cardiomyocytes, suggesting an increased sensitivity to hypertrophic stimuli potentially mediated by ULK1-induced ferroptosis in hypertrophic cardiomyocytes. Treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reduced ULK1-induced cardiomyocyte hypertrophy and ferroptosis. Proteomic analysis identified the upregulation of transcription factor high mobility group A2 (HMGA2) as a key mechanism in this ferroptotic process. Elevated HMGA2 levels exacerbated ferroptosis, evidenced by increased cell death, lipid peroxidation, ROS production, and reduced GPX4 expression. Furthermore, HMGA2 was shown to promote cardiomyocyte ferroptosis <em>via</em> binding to methyltransferase-like 14 (METTL14), which in turn enhanced ferroptosis in cardiomyocytes through solute carrier family 7 member 11 (SLC7A11) m<sup>6</sup>A modification. <em>In vivo</em>, a delivery system using neutrophil membrane (NM)-coated mesoporous silica nanoparticles (MSN) was developed to inhibit cardiac hypertrophy, underscoring the therapeutic potential of targeting ULK1. Overall, this study demonstrates that ULK1 promotes cardiac hypertrophy through HMGA2/METTL14/SLC7A11 axis-mediated cardiomyocyte ferroptosis, suggesting a novel therapeutic approach for cardiac hypertrophy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"995 ","pages":"Article 177416"},"PeriodicalIF":4.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491399","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 : 2025-02-22DOI: 10.1016/j.ejphar.2025.177426
Yitong Wang , Ying Zhang , Xiangbo An , Yinong Jiang , Feng Wang
Background
The interaction between monocytes and vascular endothelium often leads to inflammatory reactions and vascular remodeling. The lymphocyte function-associated antigen 1 (LFA1) plays a crucial role in promoting leukocyte adhesion and migration during inflammatory diseases. However, the role of LFA1 in angiotensin II (Ang II)-induced hypertension and vascular remodeling is not clear. Orientin (Ori) has antioxidant, anti-inflammatory, anticancer, and resistance to myocardial remodeling. However, the role of Orientin remains unclear in angiotensin II (Ang II)-induced hypertension and vascular remodeling.
Methods
In this study, Ang II was used to induce hypertension in mice. We employed various techniques including blood pressure monitoring, pathological staining, Immunofluorescent and Immunohistochemical staining, real time-PCR, vasodilation analysis and other methods to study whether LFA1 antibody and Orientin can regulate vascular remoding.
Results
Our results showed that LFA1 significantly improved Ang II-induced hypertension, inflammation, fibrosis, and oxidative stress. Furthermore, in vitro experiments have substantiated that the use of neutralizing antibodies targeting LFA1 can effectively hinder the migration of macrophages to endothelial cells, which is triggered by Ang II. Additionally, the antibodies also reduce the extent of DNA damage and oxidative stress. Orientin can interact with LFA-1. Then, it was proved by pathological staining that Orientin can inhibit Ang II-induced vascular remodeling.
Conclusion
Here, we identified Orientin as a small molecule inhibitor of LFA-1 with anti-vascular remodeling function. These findings not only suggest that Orientin is a promising compound for the clinical treatment of vascular injury and hypertension, but also provide strategies for the treatment of cardiovascular diseases.
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