Pub Date : 2025-12-24DOI: 10.1016/j.ejphar.2025.178512
Chuqiao Shen , Shuo Chen , Fanjing Wang , Li Sun , Liang Yuan , Qiang Zuo , Yixuan Lin
Astragaloside IV (AS-IV), as the primary active component and nutritional supplement of Astragali Radix, has a definite cardioprotective effect. However, it is unknown whether AS-IV could prevent myocardial ischemia by triggering M3 subtype of muscarinic acetylcholine receptor (M3 receptor) and control cardiomyocytes apoptosis via p53/Akt.
The objective of this research is to create an in vivo model of myocardial ischemia (MI) and use morphological, bioinformatics, and molecular biology techniques to clarify how AS-IV controls MI and apoptosis via the M3 receptor and p53/Akt pathways. The findings implied that AS-IV could mitigate the MI damage and exacerbated apoptosis of cardiomyocytes brought onby M3 receptor inhibitors 4-DAMP in vivo. Furthermore, AS-IV may have a protective effect on MI by directly interacting with M3 receptor. In terms of mechanism, AS-IV's anti-apoptotic effect could be associated with the regulation of the p53/Akt signalling pathway.
Altogether, our findings suggest that AS-IV may reduce MI and exert myocardial protective effects via influencing on the M3 receptor and p53/Akt signalling pathways. This study offers a theoretical foundation for investigating possible protective targets of AS-IV and clarifying novel roles and mechanisms of AS-IV.
黄芪甲苷（Astragaloside IV, as -IV）作为黄芪的主要活性成分和营养补充剂，具有一定的心脏保护作用。然而，AS-IV是否通过触发毒蕈碱乙酰胆碱受体M3亚型（M3受体）来预防心肌缺血，并通过p53/Akt调控心肌细胞凋亡，目前尚不清楚。本研究的目的是建立心肌缺血（MI）的体内模型，并使用形态学，生物信息学和分子生物学技术来阐明AS-IV如何通过M3受体和p53/Akt途径控制MI和凋亡。提示AS-IV在体内可减轻M3受体抑制剂4-DAMP引起的心肌细胞心肌梗死损伤，并加重心肌细胞凋亡。此外，AS-IV可能通过直接与M3受体相互作用对心肌梗死具有保护作用。从机制上看，AS-IV的抗凋亡作用可能与调控p53/Akt信号通路有关。总之，我们的研究结果表明，AS-IV可能通过影响M3受体和p53/Akt信号通路来降低心肌梗死并发挥心肌保护作用。本研究为探究AS-IV可能的保护靶点，阐明AS-IV的新作用和机制提供了理论基础。
{"title":"Astragaloside IV alleviates M3 subtype of the muscarinic acetylcholine receptor blockade-induced myocardial apoptosis through p53/Akt signaling pathway in myocardial ischemia model","authors":"Chuqiao Shen , Shuo Chen , Fanjing Wang , Li Sun , Liang Yuan , Qiang Zuo , Yixuan Lin","doi":"10.1016/j.ejphar.2025.178512","DOIUrl":"10.1016/j.ejphar.2025.178512","url":null,"abstract":"<div><div>Astragaloside IV (AS-IV), as the primary active component and nutritional supplement of Astragali Radix, has a definite cardioprotective effect. However, it is unknown whether AS-IV could prevent myocardial ischemia by triggering M3 subtype of muscarinic acetylcholine receptor (M3 receptor) and control cardiomyocytes apoptosis via p53/Akt.</div><div>The objective of this research is to create an in vivo model of myocardial ischemia (MI) and use morphological, bioinformatics, and molecular biology techniques to clarify how AS-IV controls MI and apoptosis via the M3 receptor and p53/Akt pathways. The findings implied that AS-IV could mitigate the MI damage and exacerbated apoptosis of cardiomyocytes brought onby M3 receptor inhibitors 4-DAMP in vivo. Furthermore, AS-IV may have a protective effect on MI by directly interacting with M3 receptor. In terms of mechanism, AS-IV's anti-apoptotic effect could be associated with the regulation of the p53/Akt signalling pathway.</div><div>Altogether, our findings suggest that AS-IV may reduce MI and exert myocardial protective effects via influencing on the M3 receptor and p53/Akt signalling pathways. This study offers a theoretical foundation for investigating possible protective targets of AS-IV and clarifying novel roles and mechanisms of AS-IV.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1013 ","pages":"Article 178512"},"PeriodicalIF":4.7,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145824089","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}
Immune and inflammatory responses play a major role in cerebral ischemia-reperfusion injury (CIRI). The spleen participates in the regulation of immune and inflammatory responses. However, the exact mechanism through which the spleen participates in CIRI remains unclear. The goal of this study is to explore the brain-spleen communication mechanism in CIRI.
Methods
Transient middle cerebral artery occlusion model (tMCAO) was performed in rats. Dynamic observation of brain injury severity was performed using neurological function scoring and TTC staining. Changes in spleen morphology, immune cells in spleen and brain infiltrating immune cells were observed by weighing method and flow cytometry. Subsequently, the splenectomy experiments further confirmed the role of immune cells as intermediaries in brain-spleen communication.
Results
The results demonstrated that the spleen exhibited a biphasic “V”-shaped curve, characterized by marked atrophy during the acute phase followed by a return to baseline levels. This change was significantly correlated with the degree of brain injury. Flow cytometry and correlation analysis showed that splenic atrophy was accompanied by the release of splenic T cells and NKT cells into brain tissue, exacerbating neuroinflammatory responses. After splenectomy, the proportion of immune cells in the brain tissue decreased, and the degree of brain injury was significantly reduced.
Conclusions
Our research results indicate that the spleen initially contracts and then expands after CIRI, and mediates ischemic brain injury through immune cells. Thus, focusing on indirect spleen regulation in future studies will provide a new perspective for the treatment of inflammation after CIRI.
{"title":"Spleen-derived immune cells potentiate cerebral ischemia-reperfusion injury through brain-spleen communication","authors":"Huanhuan Wang , Mengli Chang , Liying Tang , Jing Xu , Shihuan Tang , Fanzheng Meng , Hongwei Wu , Hongjun Yang","doi":"10.1016/j.ejphar.2025.178509","DOIUrl":"10.1016/j.ejphar.2025.178509","url":null,"abstract":"<div><h3>Background</h3><div>Immune and inflammatory responses play a major role in cerebral ischemia-reperfusion injury (CIRI). The spleen participates in the regulation of immune and inflammatory responses. However, the exact mechanism through which the spleen participates in CIRI remains unclear. The goal of this study is to explore the brain-spleen communication mechanism in CIRI.</div></div><div><h3>Methods</h3><div>Transient middle cerebral artery occlusion model (tMCAO) was performed in rats. Dynamic observation of brain injury severity was performed using neurological function scoring and TTC staining. Changes in spleen morphology, immune cells in spleen and brain infiltrating immune cells were observed by weighing method and flow cytometry. Subsequently, the splenectomy experiments further confirmed the role of immune cells as intermediaries in brain-spleen communication.</div></div><div><h3>Results</h3><div>The results demonstrated that the spleen exhibited a biphasic “V”-shaped curve, characterized by marked atrophy during the acute phase followed by a return to baseline levels. This change was significantly correlated with the degree of brain injury. Flow cytometry and correlation analysis showed that splenic atrophy was accompanied by the release of splenic T cells and NKT cells into brain tissue, exacerbating neuroinflammatory responses. After splenectomy, the proportion of immune cells in the brain tissue decreased, and the degree of brain injury was significantly reduced.</div></div><div><h3>Conclusions</h3><div>Our research results indicate that the spleen initially contracts and then expands after CIRI, and mediates ischemic brain injury through immune cells. Thus, focusing on indirect spleen regulation in future studies will provide a new perspective for the treatment of inflammation after CIRI.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1013 ","pages":"Article 178509"},"PeriodicalIF":4.7,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839150","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 : 2025-12-23DOI: 10.1016/j.ejphar.2025.178506
Gilnei B. da Silva , Daiane Manica , Bruna C. Ozelame , Maísa Marcolin , Vitória Stormowski , Margarete D. Bagatini , Aniela P. Kempka
Cancer cases have increased worldwide, and cutaneous melanoma (CM) is one of the types that contributes to the epidemiology. Given the aggressiveness and recurrence, adjuvant therapies may ameliorate the CM treatment. In this context, evidence suggests that rosmarinic acid (RA) is a promising candidate for use as adjuvant. In this study, we advance our research, aiming not only to verify whether RA can induce melanoma cells death and modulate the expression of purinergic signaling components, but also to analyze the molecular interactions between this phenolic acid and purinergic elements. We treated the melanoma cells A375 with different concentrations of RA for 24h and assessed the cell viability, mitochondrial transmembrane potential, expression of CD39, CD73, and P2Y12, as well as the ectonucleotidase activity. Furthermore, we also analyzed the interactions between the RA and the purinergic components that it modulated. We found that RA significantly decreased cell viability and mitochondrial transmembrane potential. In addition, the treatment with RA modulated the expression of CD39, CD73, and P2Y12. Similarly, RA treatment also modulated the ectonucleotidases activity, with reducing in ATP, ADP and AMP hydrolysis. Regarding molecular docking, RA interacts with targets (CD39, CD73 and P2Y12) and has shown to be a promising inhibitor of CD73. Our results add new insights about the biological properties of RA and its modulatory potential on the purinergic signaling. We encourage new studies to better understand the dynamic chemical interactions between RA and purinergic signaling components, especially on its inhibitory potential against CD73, to improve the treatment of CM.
{"title":"An in vitro and in silico study focused on the potential modulation of purinergic signaling by rosmarinic acid against cutaneous melanoma","authors":"Gilnei B. da Silva , Daiane Manica , Bruna C. Ozelame , Maísa Marcolin , Vitória Stormowski , Margarete D. Bagatini , Aniela P. Kempka","doi":"10.1016/j.ejphar.2025.178506","DOIUrl":"10.1016/j.ejphar.2025.178506","url":null,"abstract":"<div><div>Cancer cases have increased worldwide, and cutaneous melanoma (CM) is one of the types that contributes to the epidemiology. Given the aggressiveness and recurrence, adjuvant therapies may ameliorate the CM treatment. In this context, evidence suggests that rosmarinic acid (RA) is a promising candidate for use as adjuvant. In this study, we advance our research, aiming not only to verify whether RA can induce melanoma cells death and modulate the expression of purinergic signaling components, but also to analyze the molecular interactions between this phenolic acid and purinergic elements. We treated the melanoma cells A375 with different concentrations of RA for 24h and assessed the cell viability, mitochondrial transmembrane potential, expression of CD39, CD73, and P2Y12, as well as the ectonucleotidase activity. Furthermore, we also analyzed the interactions between the RA and the purinergic components that it modulated. We found that RA significantly decreased cell viability and mitochondrial transmembrane potential. In addition, the treatment with RA modulated the expression of CD39, CD73, and P2Y12. Similarly, RA treatment also modulated the ectonucleotidases activity, with reducing in ATP, ADP and AMP hydrolysis. Regarding molecular docking, RA interacts with targets (CD39, CD73 and P2Y12) and has shown to be a promising inhibitor of CD73. Our results add new insights about the biological properties of RA and its modulatory potential on the purinergic signaling. We encourage new studies to better understand the dynamic chemical interactions between RA and purinergic signaling components, especially on its inhibitory potential against CD73, to improve the treatment of CM.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1012 ","pages":"Article 178506"},"PeriodicalIF":4.7,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827090","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 : 2025-12-23DOI: 10.1016/j.ejphar.2025.178508
Yanmin Zhang , Jianqiang Hu , Yan Zhang , Xiaolin Yang , Weihua Tong , Xinxin Ci
Background
The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is a significant cause of kidney failure. Although the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been demonstrated to inhibit ferroptosis and alleviate cisplatin-induced AKI, the specific roles of Nrf2 and the alkaloid leonurine in modulating the AKI-CKD transition remain incompletely elucidated.
Methods
Murine and human proximal tubular epithelial cell models of the AKI-CKD transition were established using repeated low-dose cisplatin (RLDC) to investigate the roles of Nrf2 and leonurine in ferroptosis regulation and disease progression.
Key results
In mice, RLDC administration induced persistent tubular injury, ferroptosis, and progressive renal fibrosis. In HK-2 cells, RLDC triggered oxidative stress and ferroptosis. Although Nrf2 expression was transiently upregulated during the acute phase (4 weeks post-RLDC), it was downregulated by the chronic phase (8 weeks post-RLDC), correlating with impaired antioxidant capacity and exacerbated ferroptosis. Nrf2 knockout mice exhibited more severe oxidative damage, ferroptosis, and renal dysfunction following RLDC challenge. Pharmacological activation of Nrf2 by leonurine attenuated oxidative injury and ferroptosis and promoted tubular repair. Leonurine also suppressed the epithelial–mesenchymal transition and aberrant extracellular matrix deposition, ultimately mitigating renal fibrosis. The protective effects of leonurine were abolished in Nrf2 knockout mice.
Conclusion
These findings demonstrate that Nrf2 activation mitigates cisplatin-induced AKI-CKD transition by counteracting oxidative stress and ferroptosis, thereby attenuating renal fibrosis. Leonurine, as a potent Nrf2 activator, represents a promising therapeutic agent for preventing AKI-CKD transition.
{"title":"Leonurine attenuates cisplatin-induced AKI-CKD transition via Nrf2-Mediated ferroptosis suppression","authors":"Yanmin Zhang , Jianqiang Hu , Yan Zhang , Xiaolin Yang , Weihua Tong , Xinxin Ci","doi":"10.1016/j.ejphar.2025.178508","DOIUrl":"10.1016/j.ejphar.2025.178508","url":null,"abstract":"<div><h3>Background</h3><div>The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is a significant cause of kidney failure. Although the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been demonstrated to inhibit ferroptosis and alleviate cisplatin-induced AKI, the specific roles of Nrf2 and the alkaloid leonurine in modulating the AKI-CKD transition remain incompletely elucidated.</div></div><div><h3>Methods</h3><div>Murine and human proximal tubular epithelial cell models of the AKI-CKD transition were established using repeated low-dose cisplatin (RLDC) to investigate the roles of Nrf2 and leonurine in ferroptosis regulation and disease progression.</div></div><div><h3>Key results</h3><div>In mice, RLDC administration induced persistent tubular injury, ferroptosis, and progressive renal fibrosis. In HK-2 cells, RLDC triggered oxidative stress and ferroptosis. Although Nrf2 expression was transiently upregulated during the acute phase (4 weeks post-RLDC), it was downregulated by the chronic phase (8 weeks post-RLDC), correlating with impaired antioxidant capacity and exacerbated ferroptosis. Nrf2 knockout mice exhibited more severe oxidative damage, ferroptosis, and renal dysfunction following RLDC challenge. Pharmacological activation of Nrf2 by leonurine attenuated oxidative injury and ferroptosis and promoted tubular repair. Leonurine also suppressed the epithelial–mesenchymal transition and aberrant extracellular matrix deposition, ultimately mitigating renal fibrosis. The protective effects of leonurine were abolished in Nrf2 knockout mice.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate that Nrf2 activation mitigates cisplatin-induced AKI-CKD transition by counteracting oxidative stress and ferroptosis, thereby attenuating renal fibrosis. Leonurine, as a potent Nrf2 activator, represents a promising therapeutic agent for preventing AKI-CKD transition.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1013 ","pages":"Article 178508"},"PeriodicalIF":4.7,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833462","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 : 2025-12-22DOI: 10.1016/j.ejphar.2025.178505
Li Wang , Xiandong Kuang , Huan Li, Ye Zhang, Dongling Tang, Zhili Niu, Pingan Zhang
Sepsis-associated liver injury (SALI) is a common and severe complication of sepsis, and effective clinical treatment strategies are still lacking. Macrophages, a highly heterogeneous population of immune cells, play a key role in triggering and regulating the cytokine storm. Enhanced glycolysis is the key driver behind the increased proportion of M1 macrophages and the elevated release of pro-inflammatory factors. Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine with anti-inflammatory and tissue repair functions. However, the specific role and mechanism of GDF15 in SALI remain unclear. In this study, a mouse SALI model and a macrophage M1 polarization model were established using lipopolysaccharide (LPS). Recombinant GDF15 protein was used to investigate its role and related mechanisms. The results showed that GDF15 markedly alleviated liver injury and effectively suppressed the release of pro-inflammatory cytokines. In both in vivo and in vitro experiments, GDF15 promoted the polarization of macrophages from the M1 to the M2 phenotype. Mechanistically, GDF15 inhibits the pyruvate kinase M2 (PKM2)/hypoxia inducible factor 1α (HIF-1α) axis-mediated glycolysis and macrophage M1 polarization by activating AMP-activated protein kinase (AMPK). These findings indicate that GDF15 is a potential target for the clinical prevention and treatment of SALI.
{"title":"GDF15 attenuates sepsis-associated liver injury by regulating macrophage polarization via the AMPK/PKM2/HIF-1a pathway","authors":"Li Wang , Xiandong Kuang , Huan Li, Ye Zhang, Dongling Tang, Zhili Niu, Pingan Zhang","doi":"10.1016/j.ejphar.2025.178505","DOIUrl":"10.1016/j.ejphar.2025.178505","url":null,"abstract":"<div><div>Sepsis-associated liver injury (SALI) is a common and severe complication of sepsis, and effective clinical treatment strategies are still lacking. Macrophages, a highly heterogeneous population of immune cells, play a key role in triggering and regulating the cytokine storm. Enhanced glycolysis is the key driver behind the increased proportion of M1 macrophages and the elevated release of pro-inflammatory factors. Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine with anti-inflammatory and tissue repair functions. However, the specific role and mechanism of GDF15 in SALI remain unclear. In this study, a mouse SALI model and a macrophage M1 polarization model were established using lipopolysaccharide (LPS). Recombinant GDF15 protein was used to investigate its role and related mechanisms. The results showed that GDF15 markedly alleviated liver injury and effectively suppressed the release of pro-inflammatory cytokines. In both in vivo and in vitro experiments, GDF15 promoted the polarization of macrophages from the M1 to the M2 phenotype. Mechanistically, GDF15 inhibits the pyruvate kinase M2 (PKM2)/hypoxia inducible factor 1α (HIF-1α) axis-mediated glycolysis and macrophage M1 polarization by activating AMP-activated protein kinase (AMPK). These findings indicate that GDF15 is a potential target for the clinical prevention and treatment of SALI.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1013 ","pages":"Article 178505"},"PeriodicalIF":4.7,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827097","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":"Corrigendum to “Cortical excitatory and inhibitory neuron deficits may underlie the cognitive and social impairments in a mouse model of schizophrenia with exonic Reln deletion” [Europ. J. Pharmacol. 1010 (2026) 178407]","authors":"Youyun Zhu , Kanako Kitagawa , Daisuke Mori , Tetsuo Matsuzaki , Taku Nagai , Toshitaka Nabeshima , Sayaka Takemoto-Kimura , Hiroaki Ikesue , Norio Ozaki , Hiroyuki Mizoguchi , Kiyofumi Yamada","doi":"10.1016/j.ejphar.2025.178469","DOIUrl":"10.1016/j.ejphar.2025.178469","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1012 ","pages":"Article 178469"},"PeriodicalIF":4.7,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818658","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 : 2025-12-20DOI: 10.1016/j.ejphar.2025.178495
Jae-Eun Jung, Su-Bin Park, Hwa Young Yu, Su-Bin Yoon, Junghyun Kim
{"title":"Corrigendum to “Amelioration of D-galactose-induced hyposalivation in aging rats by the GLP-1 receptor agonist Exendin-4” [Eur. J. Pharmacol. 1011 (2026) 178445]","authors":"Jae-Eun Jung, Su-Bin Park, Hwa Young Yu, Su-Bin Yoon, Junghyun Kim","doi":"10.1016/j.ejphar.2025.178495","DOIUrl":"10.1016/j.ejphar.2025.178495","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1012 ","pages":"Article 178495"},"PeriodicalIF":4.7,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803119","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 : 2025-12-19DOI: 10.1016/j.ejphar.2025.178499
Guangyuan Liu , Yawei Han , Yuhao Wei, Pengyu Qian, Yirong Zhou , Mengzhu Zheng
Chalcone derivatives, characterized by their α, β-unsaturated ketone structure, represent an important class of compounds with notable anti-cancer and anti-inflammatory properties. Strategic modifications at specific positions of these derivatives have enabled their broad application in treating various types of cancer. The indole group, as a prevalent pharmacophore, also exhibits diverse biological activities including anticancer, anti-inflammatory, and antioxidant effects. Given their complementary properties, the incorporation of indole motif into chalcone scaffolds has emerged as a promising strategy to enhance anticancer efficacy. Recent studies have demonstrated that indole-chalcone derivatives exert potent anticancer effects through various molecular targets, including tubulin, thioredoxin reductase (TrxR), carbonic anhydrase IX (CA IX), and DNA, etc. This review aims to summarize recent advances in the development of indole-chalcone derivatives, examining their diverse structural frameworks and structure-activity relationships. Additionally, we analyzed the molecular targets of these derivatives and explored the application of Proteolysis Targeting Chimera (PROTAC) technology for target identification, with the goal of advancing targeted protein degradation strategies in cancer treatment.
{"title":"Recent advances in antitumor indole-chalcone derivatives: a mini review","authors":"Guangyuan Liu , Yawei Han , Yuhao Wei, Pengyu Qian, Yirong Zhou , Mengzhu Zheng","doi":"10.1016/j.ejphar.2025.178499","DOIUrl":"10.1016/j.ejphar.2025.178499","url":null,"abstract":"<div><div>Chalcone derivatives, characterized by their α, β-unsaturated ketone structure, represent an important class of compounds with notable anti-cancer and anti-inflammatory properties. Strategic modifications at specific positions of these derivatives have enabled their broad application in treating various types of cancer. The indole group, as a prevalent pharmacophore, also exhibits diverse biological activities including anticancer, anti-inflammatory, and antioxidant effects. Given their complementary properties, the incorporation of indole motif into chalcone scaffolds has emerged as a promising strategy to enhance anticancer efficacy. Recent studies have demonstrated that indole-chalcone derivatives exert potent anticancer effects through various molecular targets, including tubulin, thioredoxin reductase (TrxR), carbonic anhydrase IX (CA IX), and DNA, etc. This review aims to summarize recent advances in the development of indole-chalcone derivatives, examining their diverse structural frameworks and structure-activity relationships. Additionally, we analyzed the molecular targets of these derivatives and explored the application of Proteolysis Targeting Chimera (PROTAC) technology for target identification, with the goal of advancing targeted protein degradation strategies in cancer treatment.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1012 ","pages":"Article 178499"},"PeriodicalIF":4.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803261","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 : 2025-12-19DOI: 10.1016/j.ejphar.2025.178502
Yixiang Qiu , Hui Chen , Yufei Xie , Yaping Wang , Xiaoyang Huang , Longying Li , Pingping Hu , Weimin Yu , Xiaoyong Tong
Our prior research has demonstrated that dysfunction of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is a common causal factor in the development of pulmonary vascular remodeling, as it accelerates cell proliferation and migration in pulmonary artery smooth muscle cells (PASMCs). Inflammation is known to play a critical role in pulmonary vascular remodeling. However, the contribution of SERCA2 dysfunction to inflammation within the pulmonary vasculature has not been previously reported. In this study, we observed significant inflammatory cell infiltration in the lungs of mice with SERCA2 dysfunction, particularly around the blood vessels. In PASMCs, SERCA2 dysfunction triggers inflammation and oxidative stress by downregulating peroxisome proliferator-activated receptor γ (PPARγ) and its downstream targets peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) and nuclear factor erythroid 2-related factor 2 (Nrf2). Targeting to improve PPARγ with pioglitazone, PGC1α with nicotinamide riboside, or to suppress reactive oxygen species (ROS) with 4-Hydroxy-TEMPO could efficiently ameliorate SERCA2 dysfunction-induced pulmonary vascular remodeling. Our study elucidates the direct regulation of SERCA2 dysfunction in initiating inflammation, which promotes cell proliferation, migration, and recruitment of inflammatory cells in PASMCs, ultimately contributing to the development of pulmonary vascular remodeling. Furthermore, SERCA2, PPARγ, PGC1α, and ROS may serve as potential therapeutic targets in the prevention and treatment of pulmonary hypertension.
{"title":"SERCA2 dysfunction stimulates inflammation and causes pulmonary vascular remodeling by downregulating PPARγ/PGC1α/Nrf2","authors":"Yixiang Qiu , Hui Chen , Yufei Xie , Yaping Wang , Xiaoyang Huang , Longying Li , Pingping Hu , Weimin Yu , Xiaoyong Tong","doi":"10.1016/j.ejphar.2025.178502","DOIUrl":"10.1016/j.ejphar.2025.178502","url":null,"abstract":"<div><div>Our prior research has demonstrated that dysfunction of sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup> ATPase 2 (SERCA2) is a common causal factor in the development of pulmonary vascular remodeling, as it accelerates cell proliferation and migration in pulmonary artery smooth muscle cells (PASMCs). Inflammation is known to play a critical role in pulmonary vascular remodeling. However, the contribution of SERCA2 dysfunction to inflammation within the pulmonary vasculature has not been previously reported. In this study, we observed significant inflammatory cell infiltration in the lungs of mice with SERCA2 dysfunction, particularly around the blood vessels. In PASMCs, SERCA2 dysfunction triggers inflammation and oxidative stress by downregulating peroxisome proliferator-activated receptor <em>γ</em> (PPAR<em>γ</em>) and its downstream targets peroxisome proliferator-activated receptor <em>γ</em> coactivator-1<em>α</em> (PGC1<em>α</em>) and nuclear factor erythroid 2-related factor 2 (Nrf2). Targeting to improve PPAR<em>γ</em> with pioglitazone, PGC1<em>α</em> with nicotinamide riboside, or to suppress reactive oxygen species (ROS) with 4-Hydroxy-TEMPO could efficiently ameliorate SERCA2 dysfunction-induced pulmonary vascular remodeling. Our study elucidates the direct regulation of SERCA2 dysfunction in initiating inflammation, which promotes cell proliferation, migration, and recruitment of inflammatory cells in PASMCs, ultimately contributing to the development of pulmonary vascular remodeling. Furthermore, SERCA2, PPAR<em>γ</em>, PGC1<em>α</em>, and ROS may serve as potential therapeutic targets in the prevention and treatment of pulmonary hypertension.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1012 ","pages":"Article 178502"},"PeriodicalIF":4.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789064","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 : 2025-12-19DOI: 10.1016/j.ejphar.2025.178497
Jingyi Yang , Lukuan Li , Xuening Chen , Peipei Cai , Mengran Chen , Jieyu Cheng , Lijuan Ma , Xinghua Zhao , Pengfei Yang
Ischemic stroke is one of the leading causes of disability and death worldwide. Despite the effectiveness of thrombolysis and mechanical thrombectomy in restoring blood flow and improving ischemic brain injury, patients often face worsening neurological function due to ischemia/reperfusion (I/R) injury after treatment. I/R injury exacerbates brain damage through various mechanisms, including oxidative stress, neuroinflammation, blood-brain barrier (BBB) disruption, and cell death, which in turn affects patient prognosis and long-term recovery. Isoflurane (ISO), a commonly used inhalational anesthetic, has demonstrated significant neuroprotective effects in preclinical studies in recent years. The mechanisms of action include inhibition of oxidative stress, reduction of neuroinflammation, stabilization of BBB, regulation of cell death pathways, attenuation of excitotoxicity, and promotion of neurological recovery. Additionally, studies have shown that isoflurane provides long-term neuroprotection in rats with brain ischemia. These promising findings suggest that isoflurane could play a role in improving both short-term and long-term outcomes for ischemic stroke patients. However, despite the promising neuroprotective effects of isoflurane in preclinical studies, its clinical application in ischemic stroke patients still requires further validation to determine the optimal anesthesia protocol for improving long-term patient outcomes. This review aims to summarize the potential neuroprotective effects of isoflurane in ischemic stroke, elucidate its mechanisms of action, and provide a theoretical basis for its clinical application. Such insights could lead to improved therapeutic strategies and better patient prognoses in ischemic stroke management.
{"title":"Research progress of isoflurane in alleviating cerebral ischemia/reperfusion injury","authors":"Jingyi Yang , Lukuan Li , Xuening Chen , Peipei Cai , Mengran Chen , Jieyu Cheng , Lijuan Ma , Xinghua Zhao , Pengfei Yang","doi":"10.1016/j.ejphar.2025.178497","DOIUrl":"10.1016/j.ejphar.2025.178497","url":null,"abstract":"<div><div>Ischemic stroke is one of the leading causes of disability and death worldwide. Despite the effectiveness of thrombolysis and mechanical thrombectomy in restoring blood flow and improving ischemic brain injury, patients often face worsening neurological function due to ischemia/reperfusion (I/R) injury after treatment. I/R injury exacerbates brain damage through various mechanisms, including oxidative stress, neuroinflammation, blood-brain barrier (BBB) disruption, and cell death, which in turn affects patient prognosis and long-term recovery. Isoflurane (ISO), a commonly used inhalational anesthetic, has demonstrated significant neuroprotective effects in preclinical studies in recent years. The mechanisms of action include inhibition of oxidative stress, reduction of neuroinflammation, stabilization of BBB, regulation of cell death pathways, attenuation of excitotoxicity, and promotion of neurological recovery. Additionally, studies have shown that isoflurane provides long-term neuroprotection in rats with brain ischemia. These promising findings suggest that isoflurane could play a role in improving both short-term and long-term outcomes for ischemic stroke patients. However, despite the promising neuroprotective effects of isoflurane in preclinical studies, its clinical application in ischemic stroke patients still requires further validation to determine the optimal anesthesia protocol for improving long-term patient outcomes. This review aims to summarize the potential neuroprotective effects of isoflurane in ischemic stroke, elucidate its mechanisms of action, and provide a theoretical basis for its clinical application. Such insights could lead to improved therapeutic strategies and better patient prognoses in ischemic stroke management.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1013 ","pages":"Article 178497"},"PeriodicalIF":4.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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