Pub Date : 2026-01-13DOI: 10.1016/j.ejphar.2026.178552
Ning Liu , Shuang Zhao , Yuhan Ao , Jianan Su , Zimeng Liu , Pingxi Zhou , Shuwen Pang , Jing Li
Atherosclerosis (AS) is a major underlying cause of cardiovascular diseases, with hypercholesterolemia, inflammatory responses, and macrophage polarization being established key contributors. The roles of NLRP3 inflammasome activation and macrophage polarization in AS pathogenesis have garnered significant research interest. This study investigated the therapeutic potential of Schisandrol B (Sol B) against AS using an in vivo model of ApoE−/− mice fed a high-fat diet and an in vitro foam cell model. Network pharmacology and analysis of the GEO database were employed to predict potential targets and pathways of Sol B, which were further validated by molecular docking. In vivo, Sol B treatment significantly attenuated atherosclerotic plaque formation, as assessed by Oil Red O and EVG staining, improved serum lipid profiles, and modulated macrophage polarization. Furthermore, Sol B suppressed the activation of the NLRP3 inflammasome. In vitro, Sol B reduced lipid accumulation and inhibited NLRP3 inflammasome activation in foam cells. These results suggest that the anti-atherosclerotic effects of Sol B are mediated through the regulation of macrophage polarization and the inhibition of pyroptosis. Our findings indicate that Sol B is a.
NLRP3 inhibitor for AS therapy and warrant further investigation into its detailed mechanisms and clinical potential.
{"title":"Schisandrol B alleviates the progression of atherosclerosis by inhibiting the NLRP3-pyroptosis signaling axis driven by M1-type macrophage polarization","authors":"Ning Liu , Shuang Zhao , Yuhan Ao , Jianan Su , Zimeng Liu , Pingxi Zhou , Shuwen Pang , Jing Li","doi":"10.1016/j.ejphar.2026.178552","DOIUrl":"10.1016/j.ejphar.2026.178552","url":null,"abstract":"<div><div>Atherosclerosis (AS) is a major underlying cause of cardiovascular diseases, with hypercholesterolemia, inflammatory responses, and macrophage polarization being established key contributors. The roles of NLRP3 inflammasome activation and macrophage polarization in AS pathogenesis have garnered significant research interest. This study investigated the therapeutic potential of Schisandrol B (Sol B) against AS using an in vivo model of ApoE<sup>−/−</sup> mice fed a high-fat diet and an in vitro foam cell model. Network pharmacology and analysis of the GEO database were employed to predict potential targets and pathways of Sol B, which were further validated by molecular docking. <em>In vivo</em>, Sol B treatment significantly attenuated atherosclerotic plaque formation, as assessed by Oil Red O and EVG staining, improved serum lipid profiles, and modulated macrophage polarization. Furthermore, Sol B suppressed the activation of the NLRP3 inflammasome. <em>In vitro</em>, Sol B reduced lipid accumulation and inhibited NLRP3 inflammasome activation in foam cells. These results suggest that the anti-atherosclerotic effects of Sol B are mediated through the regulation of macrophage polarization and the inhibition of pyroptosis. Our findings indicate that Sol B is a.</div><div>NLRP3 inhibitor for AS therapy and warrant further investigation into its detailed mechanisms and clinical potential.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1014 ","pages":"Article 178552"},"PeriodicalIF":4.7,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.ejphar.2026.178556
Mei Yang , Ziyi Zhang , Xin Su , Jiayu Li , Haoran Liu , Siqi Wang , Waleed Yousuf , Yingqiu Zhang , Shuang Guo , Dawei Li , Shuyan Liu
Nasopharyngeal carcinoma (NPC) is characterized by high metastatic potential and invasiveness, posing significant therapeutic challenges. Existing treatment methods remain limited, and new therapeutic strategies are urgently needed. Brusatol, a natural quinoline-derived compound, exhibits broad pharmacological activities, including anti-cancer effects. Ferroptosis is a unique mode of regulated cell death and is closely associated with tumorigenesis. However, the effects of brusatol on ferroptosis in NPC cells have not been reported. This study aimed to investigate how brusatol regulates ferroptosis in NPC and its underlying mechanisms. Our results showed that brusatol inhibited NPC cell growth and downregulated the expression of nuclear factor erythroid-2-related factor 2 (Nrf2). The combination of brusatol with RAS-selective lethal 3 (RSL3) significantly enhanced ferroptosis in NPC cells, accompanied by increased levels of cellular reactive oxygen species (ROS) and lipid peroxidation. These effects were further confirmed in NPC xenograft mouse models, as demonstrated by reduced tumor volumes, decreased Ki-67 and Nrf2 staining, and increased expression of cyclooxygenase-2 (COX2). In conclusion, brusatol promotes ferroptotic cell death in NPC cells by inducing Nrf2 degradation and enhancing lipid peroxidation, suggesting its promising therapeutic potential for the treatment of NPC.
{"title":"Brusatol enhances ferroptosis susceptibility in nasopharyngeal carcinoma by downregulating Nrf2 expression","authors":"Mei Yang , Ziyi Zhang , Xin Su , Jiayu Li , Haoran Liu , Siqi Wang , Waleed Yousuf , Yingqiu Zhang , Shuang Guo , Dawei Li , Shuyan Liu","doi":"10.1016/j.ejphar.2026.178556","DOIUrl":"10.1016/j.ejphar.2026.178556","url":null,"abstract":"<div><div>Nasopharyngeal carcinoma (NPC) is characterized by high metastatic potential and invasiveness, posing significant therapeutic challenges. Existing treatment methods remain limited, and new therapeutic strategies are urgently needed. Brusatol, a natural quinoline-derived compound, exhibits broad pharmacological activities, including anti-cancer effects. Ferroptosis is a unique mode of regulated cell death and is closely associated with tumorigenesis. However, the effects of brusatol on ferroptosis in NPC cells have not been reported. This study aimed to investigate how brusatol regulates ferroptosis in NPC and its underlying mechanisms. Our results showed that brusatol inhibited NPC cell growth and downregulated the expression of nuclear factor erythroid-2-related factor 2 (Nrf2). The combination of brusatol with RAS-selective lethal 3 (RSL3) significantly enhanced ferroptosis in NPC cells, accompanied by increased levels of cellular reactive oxygen species (ROS) and lipid peroxidation. These effects were further confirmed in NPC xenograft mouse models, as demonstrated by reduced tumor volumes, decreased Ki-67 and Nrf2 staining, and increased expression of cyclooxygenase-2 (COX2). In conclusion, brusatol promotes ferroptotic cell death in NPC cells by inducing Nrf2 degradation and enhancing lipid peroxidation, suggesting its promising therapeutic potential for the treatment of NPC.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178556"},"PeriodicalIF":4.7,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.ejphar.2026.178553
Wen-Hung Wang , Chun-Yu Lin , Syun Huang , Yu-Te Tsai , Sheng-Fan Wang , Tzu-Chuan Ho , Yen-Hsu Chen
Vascular leakage is the defining pathological hallmark of severe dengue, including dengue hemorrhagic fever and dengue shock syndrome. Despite its clinical importance, the mechanisms linking dengue virus infection to endothelial dysfunction remain incompletely understood, and no medicine is currently available. Emerging evidence implicates dysregulation of the host fibrinolytic system in dengue-induced vascular leakage, but its mechanistic role has not been evaluated. Here, we show that dengue virus infection activates endothelial fibrinolytic pathways to drive plasmin-mediated vascular leakage and viral propagation. This fibrinolytic pathway can be targeted with tranexamic acid (TXA). We integrated patient cohort analyses with endothelial cell and mouse models. Serum from dengue patients were profiled for fibrinolytic markers, and human microvascular endothelial cells were used to assess the impact of dengue virus and NS1 on tissue-type and urokinase-type plasminogen activators (tPA, uPA) and plasmin activity. Serum tPA and uPA levels were markedly elevated and correlated with dengue severity. In endothelial cells, dengue virus infection and NS1 exposure induced a pro-fibrinolytic state with increased tPA/uPA expression and plasminogen activation. Plasmin acted as a pathogenic amplifier, promoting viral replication and disrupting endothelial barrier function. Pharmacological blockade of fibrinolysis with the approved antifibrinolytic drug TXA reduced dengue virus replication, preserved endothelial integrity, and mitigated thrombocytopenia, liver injury, and vascular leakage in infected mice. These findings identify a previously unrecognized NS1-fibrinolysis-plasmin axis as a critical driver of dengue vascular pathology and support TXA as a promising adjunctive strategy to reduce hemorrhagic complications in severe dengue.
{"title":"Dengue virus modulates the fibrinolytic system to drive vascular leakage and serves as a therapeutic target for tranexamic acid","authors":"Wen-Hung Wang , Chun-Yu Lin , Syun Huang , Yu-Te Tsai , Sheng-Fan Wang , Tzu-Chuan Ho , Yen-Hsu Chen","doi":"10.1016/j.ejphar.2026.178553","DOIUrl":"10.1016/j.ejphar.2026.178553","url":null,"abstract":"<div><div>Vascular leakage is the defining pathological hallmark of severe dengue, including dengue hemorrhagic fever and dengue shock syndrome. Despite its clinical importance, the mechanisms linking dengue virus infection to endothelial dysfunction remain incompletely understood, and no medicine is currently available. Emerging evidence implicates dysregulation of the host fibrinolytic system in dengue-induced vascular leakage, but its mechanistic role has not been evaluated. Here, we show that dengue virus infection activates endothelial fibrinolytic pathways to drive plasmin-mediated vascular leakage and viral propagation. This fibrinolytic pathway can be targeted with tranexamic acid (TXA). We integrated patient cohort analyses with endothelial cell and mouse models. Serum from dengue patients were profiled for fibrinolytic markers, and human microvascular endothelial cells were used to assess the impact of dengue virus and NS1 on tissue-type and urokinase-type plasminogen activators (tPA, uPA) and plasmin activity. Serum tPA and uPA levels were markedly elevated and correlated with dengue severity. In endothelial cells, dengue virus infection and NS1 exposure induced a pro-fibrinolytic state with increased tPA/uPA expression and plasminogen activation. Plasmin acted as a pathogenic amplifier, promoting viral replication and disrupting endothelial barrier function. Pharmacological blockade of fibrinolysis with the approved antifibrinolytic drug TXA reduced dengue virus replication, preserved endothelial integrity, and mitigated thrombocytopenia, liver injury, and vascular leakage in infected mice. These findings identify a previously unrecognized NS1-fibrinolysis-plasmin axis as a critical driver of dengue vascular pathology and support TXA as a promising adjunctive strategy to reduce hemorrhagic complications in severe dengue.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178553"},"PeriodicalIF":4.7,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976247","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}
Cellular senescence plays a contributory role in the development and progression of diabetic kidney disease (DKD). Melatonin shows potent anti-senescent and anti-inflammatory effects, with demonstrated benefits in DKD. Delineation of the mechanisms through which melatonin delays cellular senescence to ameliorate the progression of DKD will enhance our understanding and ability to treat the disease. Therefore, to elucidate the effects and underlying mechanisms of melatonin, we established streptozotocin (STZ)-induced diabetic mouse models and high glucose (HG)-stimulated human renal cortical proximal tubule epithelial (HK-2) cell models. Cellular senescence was assessed by western blotting, quantitative real-time PCR (qPCR), and β-galactosidase (SA-β-gal) staining. Renal histopathological injury was evaluated by hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining, along with renal function measurements. The results showed that melatonin administration significantly improved renal function and attenuated histopathological damage in diabetic mice. Furthermore, melatonin effectively reduced the levels of cellular senescence marker proteins (p53, p21, p16INK4A, and γ-H2AX), decreased the SA-β-gal positive staining area, and suppressed senescence-associated secretory phenotype (SASP) expression. Mechanistically, melatonin potently inhibited the upregulation of key proteins in the Wnt/β-catenin signaling pathway, including Wnt3a, β-catenin, p-GSK-3β, c-Myc, and Cyclin-D1, with an efficacy comparable to that of the Wnt inhibitor XAV-939. Notably, experiments in HK-2 cells further demonstrated that treatment with the Wnt/β-catenin activator BML-284 abrogated the protective effects of melatonin. Overall, these findings demonstrate that melatonin suppresses cellular senescence in DKD by inhibiting the Wnt/β-catenin pathway.
{"title":"Melatonin suppresses cellular senescence in diabetic kidney disease though the Wnt/β-catenin signaling pathway","authors":"Wenjun Fan, Jinhua Huang, Ziyang Guo, Ailing Zhong, Xin Tong, Xiang Li, Wei Li, Yiming Chen, Yanyi Chen, Xiaotong Lin, Jingyu Xu, Danmei Huang, Yanmei Zhang, Bin Wang","doi":"10.1016/j.ejphar.2026.178541","DOIUrl":"10.1016/j.ejphar.2026.178541","url":null,"abstract":"<div><div>Cellular senescence plays a contributory role in the development and progression of diabetic kidney disease (DKD). Melatonin shows potent anti-senescent and anti-inflammatory effects, with demonstrated benefits in DKD. Delineation of the mechanisms through which melatonin delays cellular senescence to ameliorate the progression of DKD will enhance our understanding and ability to treat the disease. Therefore, to elucidate the effects and underlying mechanisms of melatonin, we established streptozotocin (STZ)-induced diabetic mouse models and high glucose (HG)-stimulated human renal cortical proximal tubule epithelial (HK-2) cell models. Cellular senescence was assessed by western blotting, quantitative real-time PCR (qPCR), and β-galactosidase (SA-β-gal) staining. Renal histopathological injury was evaluated by hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining, along with renal function measurements. The results showed that melatonin administration significantly improved renal function and attenuated histopathological damage in diabetic mice. Furthermore, melatonin effectively reduced the levels of cellular senescence marker proteins (p53, p21, p16<sup>INK4A</sup>, and γ-H2AX), decreased the SA-β-gal positive staining area, and suppressed senescence-associated secretory phenotype (SASP) expression. Mechanistically, melatonin potently inhibited the upregulation of key proteins in the Wnt/β-catenin signaling pathway, including Wnt3a, β-catenin, p-GSK-3β, c-Myc, and Cyclin-D1, with an efficacy comparable to that of the Wnt inhibitor XAV-939. Notably, experiments in HK-2 cells further demonstrated that treatment with the Wnt/β-catenin activator BML-284 abrogated the protective effects of melatonin. Overall, these findings demonstrate that melatonin suppresses cellular senescence in DKD by inhibiting the Wnt/β-catenin pathway.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178541"},"PeriodicalIF":4.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145969413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1016/j.ejphar.2026.178544
Wenying Fu , Ying Yan , Chongchong Shu , Chenxin Xu , Yinghua Chen , Yiqun Xia , Jundixia Chen , Yunzhi Chen , Ri Cui , Peng Zou , Daoyong Ni
6-Methoxydihydrosanguinarine is a natural alkaloid derived from medicinal plants that exhibits significant antitumor activity, making it a promising candidate for cancer therapy. However, the exact molecular mechanisms underlying its effects require further investigation. In this study, we investigated the cytotoxicity and underlying mechanisms of 6-Methoxydihydrosanguinarine in human non-small cell lung cancer (NSCLC) cells. Our findings reveal that reactive oxygen species (ROS) accumulation is the key driver of its antitumor activity. Mechanistically, 6-Methoxydihydrosanguinarine activates the JNK signaling pathway and induces endoplasmic reticulum (ER) stress, both of which can be reversed by the ROS scavenger N-acetylcysteine (NAC). Interestingly, 6-Methoxydihydrosanguinarine also activates autophagy, and inhibition of autophagy reverses the JNK and ER stress pathway activation induced by 6-Methoxydihydrosanguinarine. Notably, 6-Methoxydihydrosanguinarine synergistically enhances cisplatin-induced NSCLC cell death, and this synergistic effect is abolished by NAC, highlighting the critical role of ROS accumulation in their combined efficacy. This study systematically elucidates the molecular mechanisms of 6-Methoxydihydrosanguinarine against NSCLC, revealing that, in addition to the JNK and autophagy pathways, ER stress also mediates its antitumor effects. Moreover, our data establish a rationale for exploring 6-Methoxydihydrosanguinarine in NSCLC therapy and highlight its combination with cisplatin as a potentially effective strategy.
{"title":"6-Methoxydihydrosanguinarine synergizes with cisplatin to enhance lung cancer cell death via ROS-mediated autophagy, ER stress, and JNK activation","authors":"Wenying Fu , Ying Yan , Chongchong Shu , Chenxin Xu , Yinghua Chen , Yiqun Xia , Jundixia Chen , Yunzhi Chen , Ri Cui , Peng Zou , Daoyong Ni","doi":"10.1016/j.ejphar.2026.178544","DOIUrl":"10.1016/j.ejphar.2026.178544","url":null,"abstract":"<div><div>6-Methoxydihydrosanguinarine is a natural alkaloid derived from medicinal plants that exhibits significant antitumor activity, making it a promising candidate for cancer therapy. However, the exact molecular mechanisms underlying its effects require further investigation. In this study, we investigated the cytotoxicity and underlying mechanisms of 6-Methoxydihydrosanguinarine in human non-small cell lung cancer (NSCLC) cells. Our findings reveal that reactive oxygen species (ROS) accumulation is the key driver of its antitumor activity. Mechanistically, 6-Methoxydihydrosanguinarine activates the JNK signaling pathway and induces endoplasmic reticulum (ER) stress, both of which can be reversed by the ROS scavenger N-acetylcysteine (NAC). Interestingly, 6-Methoxydihydrosanguinarine also activates autophagy, and inhibition of autophagy reverses the JNK and ER stress pathway activation induced by 6-Methoxydihydrosanguinarine. Notably, 6-Methoxydihydrosanguinarine synergistically enhances cisplatin-induced NSCLC cell death, and this synergistic effect is abolished by NAC, highlighting the critical role of ROS accumulation in their combined efficacy. This study systematically elucidates the molecular mechanisms of 6-Methoxydihydrosanguinarine against NSCLC, revealing that, in addition to the JNK and autophagy pathways, ER stress also mediates its antitumor effects. Moreover, our data establish a rationale for exploring 6-Methoxydihydrosanguinarine in NSCLC therapy and highlight its combination with cisplatin as a potentially effective strategy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1014 ","pages":"Article 178544"},"PeriodicalIF":4.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1016/j.ejphar.2026.178551
Sobhan Nardast , Ali Asadirad , Kowsar Bavarsad , Alireza Sarkaki , Amir Shojaei , Samireh Ghafouri
Introduction
Hypoxia-induced neonatal seizures (HINS) lead to long-term cognitive deficits and increased epilepsy risk in later life. This study examined the therapeutic potential of mesenchymal stem cell-derived exosomes (MSC-derived exosomes) in rat model of HINS.
Methods
Eighty-two male and female rats were divided into four groups: hypoxia + exosome, hypoxia + saline, control + exosome, and control + saline. On postnatal day 10 (P10), hypoxia groups underwent seizure induction via 5 % oxygen exposure. The hypoxia + exosome and control + exosome groups received intraperitoneal bone marrow MSC-derived exosomes injection (30 μg/100 μl) for 12 consecutive days, while the two other groups received saline. Outcomes included weight gain, behavioral tests (Y-maze, elevated plus maze (EPM) and open field (OF) at P60 and P90), hippocampal gene expression of NR2A subunit of N-methyl-D-aspartate (NMDA) receptor, GluR2 subunit of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and γ2 subunit of Gamma-aminobutyric acid (GABAA) receptor via RT-PCR at P60, pentylenetetrazol (PTZ)-induced acute seizure, and local field potential (LFP) recordings at P90.
Results
MSC-derived exosomes treatment in hypoxic rats restored normal weight gain, improved spatial-working memory, and reduced anxiety-like behaviors in both genders. Hypoxia-induced dysregulation of hippocampal NR2A, GluR2, and γ2 gene expression was reversed by exosome injection. However, exosome therapy did not significantly alter PTZ-induced seizure susceptibility. In addition, LFP power did not show any significant difference between the different experimental groups.
Conclusion
Our findings suggest that MSC-derived exosomes mitigate long-term cognitive impairments following HINS, likely through hippocampal gene expression modulation. This study highlights the potential of exosome therapy in addressing HINS related neurodevelopmental deficits.
缺氧引起的新生儿癫痫发作（HINS）会导致长期认知缺陷，并增加以后生活中癫痫的风险。本研究探讨了间充质干细胞衍生外泌体（MSC-derived exosomes）对HINS大鼠模型的治疗潜力。方法：将82只雌雄大鼠分为缺氧+外泌体组、缺氧+生理盐水组、对照组+外泌体组、对照组+生理盐水组。在出生后第10天（P10），缺氧组通过5%的氧气暴露诱导癫痫发作。缺氧+外泌体组和对照组+外泌体组连续12天腹腔注射骨髓间充质干细胞外泌体（30 μg/100μl），其余两组注射生理盐水。结果包括体重增加、P60和P90时的行为测试（y-迷宫、升高+迷宫（EPM）和开放野区（OF））、P60时海马n -甲基- d -天冬氨酸（NMDA）受体NR2A亚基、α-氨基-3-羟基-5-甲基-4-异氧唑丙酸（AMPA）受体GluR2亚基和γ -氨基丁酸（GABAA）受体γ2亚基的RT-PCR表达、P90时戊四氮唑（PTZ）诱导的急性发作和局部场电位（LFP）记录。结果：在缺氧大鼠中，骨髓间质干细胞衍生的外泌体治疗恢复了正常的体重增加，改善了空间工作记忆，减少了男女的焦虑样行为。外泌体注射可逆转缺氧诱导的海马NR2A、GluR2和γ - 2基因表达失调。然而，外泌体治疗并没有显著改变ptz诱导的癫痫易感性。此外，LFP功率在不同实验组之间没有显着差异。结论：我们的研究结果表明，msc来源的外泌体可能通过海马基因表达调节来减轻HINS后的长期认知障碍。这项研究强调了外泌体治疗在解决HINS相关神经发育缺陷方面的潜力。
{"title":"Long term cognitive impairments following hypoxia-induced neonatal seizure restored by MSC-derived exosomes injection: Role of glutamatergic and GABAergic receptors","authors":"Sobhan Nardast , Ali Asadirad , Kowsar Bavarsad , Alireza Sarkaki , Amir Shojaei , Samireh Ghafouri","doi":"10.1016/j.ejphar.2026.178551","DOIUrl":"10.1016/j.ejphar.2026.178551","url":null,"abstract":"<div><h3>Introduction</h3><div>Hypoxia-induced neonatal seizures (HINS) lead to long-term cognitive deficits and increased epilepsy risk in later life. This study examined the therapeutic potential of mesenchymal stem cell-derived exosomes (MSC-derived exosomes) in rat model of HINS.</div></div><div><h3>Methods</h3><div>Eighty-two male and female rats were divided into four groups: hypoxia + exosome, hypoxia + saline, control + exosome, and control + saline. On postnatal day 10 (P10), hypoxia groups underwent seizure induction via 5 % oxygen exposure. The hypoxia + exosome and control + exosome groups received intraperitoneal bone marrow MSC-derived exosomes injection (30 μg/100 μl) for 12 consecutive days, while the two other groups received saline. Outcomes included weight gain, behavioral tests (Y-maze, elevated plus maze (EPM) and open field (OF) at P60 and P90), hippocampal gene expression of NR2A subunit of N-methyl-D-aspartate (NMDA) receptor, GluR2 subunit of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and γ2 subunit of Gamma-aminobutyric acid (GABA<sub>A)</sub> receptor via RT-PCR at P60, pentylenetetrazol (PTZ)-induced acute seizure, and local field potential (LFP) recordings at P90.</div></div><div><h3>Results</h3><div>MSC-derived exosomes treatment in hypoxic rats restored normal weight gain, improved spatial-working memory, and reduced anxiety-like behaviors in both genders. Hypoxia-induced dysregulation of hippocampal NR2A, GluR2, and γ2 gene expression was reversed by exosome injection. However, exosome therapy did not significantly alter PTZ-induced seizure susceptibility. In addition, LFP power did not show any significant difference between the different experimental groups.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that MSC-derived exosomes mitigate long-term cognitive impairments following HINS, likely through hippocampal gene expression modulation. This study highlights the potential of exosome therapy in addressing HINS related neurodevelopmental deficits.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178551"},"PeriodicalIF":4.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984809","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}
Chemotherapy is an important means of cancer treatment, but multidrug resistance (MDR) is a key factor in chemotherapy failure. The mechanisms responsible for MDR are complex. The overexpression of P-glycoprotein (P-gp) is the main driving factor. P-gp significantly reduces efficacy through efflux chemotherapy drugs. Inhibition of P-gp efflux has become one of the main strategies to reverse MDR. Over the past few decades, researchers have designed and developed a large number of P-gp inhibitors. This article reviews the P-gp inhibitors that have been widely reported in recent years and evaluates their pharmacological characteristics, mechanisms of action and clinical studies. Although numerous studies have shown that most P-gp inhibitors exhibit excellent reversal activity in vitro trials, they have not significantly improved patient conditions in clinical trials, indicating that there are currently no safe and effective drugs available in clinical practice. In recent years, structure-activity relationship (SAR) studies suggest that the quinoline ring or tetrahydroisoquinoline ring can serve as the core pharmacological factors (active mother rings) that inhibit P-gp efflux and structural modification is an important pathway to enhance reversal activity. Based on this, the article aims to provide reference for the development of new efficient and low toxicity inhibitors, and promote the clinical translation of MDR reversal strategies.
{"title":"Research progress on the mechanisms of action, pharmacological activities and clinical application of P-glycoprotein inhibitors","authors":"Di Gu, Jianhua Wang, Yuna Fu, Ruifeng Hao, Qiuyue Xie, Letian Zhang","doi":"10.1016/j.ejphar.2026.178546","DOIUrl":"10.1016/j.ejphar.2026.178546","url":null,"abstract":"<div><div>Chemotherapy is an important means of cancer treatment, but multidrug resistance (MDR) is a key factor in chemotherapy failure. The mechanisms responsible for MDR are complex. The overexpression of P-glycoprotein (P-gp) is the main driving factor. P-gp significantly reduces efficacy through efflux chemotherapy drugs. Inhibition of P-gp efflux has become one of the main strategies to reverse MDR. Over the past few decades, researchers have designed and developed a large number of P-gp inhibitors. This article reviews the P-gp inhibitors that have been widely reported in recent years and evaluates their pharmacological characteristics, mechanisms of action and clinical studies. Although numerous studies have shown that most P-gp inhibitors exhibit excellent reversal activity in vitro trials, they have not significantly improved patient conditions in clinical trials, indicating that there are currently no safe and effective drugs available in clinical practice. In recent years, structure-activity relationship (SAR) studies suggest that the quinoline ring or tetrahydroisoquinoline ring can serve as the core pharmacological factors (active mother rings) that inhibit P-gp efflux and structural modification is an important pathway to enhance reversal activity. Based on this, the article aims to provide reference for the development of new efficient and low toxicity inhibitors, and promote the clinical translation of MDR reversal strategies.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178546"},"PeriodicalIF":4.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984755","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 “Synergistic anticancer effects of doxorubicin in combination with tilorone in breast cancer” [European J. Pharmacol. 1008 (2025) 178249]","authors":"Abu Sufiyan Chhipa , Margherita Gallicchio , Valentina Boscaro , Snehal Patel","doi":"10.1016/j.ejphar.2026.178525","DOIUrl":"10.1016/j.ejphar.2026.178525","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1014 ","pages":"Article 178525"},"PeriodicalIF":4.7,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-10DOI: 10.1016/j.ejphar.2026.178539
Hailin Zhang , Hongzhuang Wang , Kai Kang , Shuaijie Chen , Yong Chu , Weiqiang Liu , Wenxiang Zhao , Zhongxing Zhou , Ruming Shen , Xiaoyan Lin , Jinxiu Lin , Dajun Chai
Background
Myocardial infarction (MI) remains a leading cause of cardiovascular mortality. While ketone bodies show cardioprotective potential, their role in regulating cardiomyocyte autophagy post-MI is unclear.
Methods
A rat MI model was established and treated with 1,3-butanediol (1,3-BD, 10 mg/100 g/day), a ketone precursor. Cardiac structure and function were assessed alongside autophagy and apoptosis levels. In vitro, hypoxia-induced cardiomyocytes were treated with β-hydroxybutyrate (β-HB) and phosphatidylinositol 3-kinase (PI3K) inhibitor. Mechanisms were explored via transcriptomics/metabolomics and validated by immunoblotting.
Results
1,3-BD treatment for 4 weeks significantly elevated serum β-HB, improved cardiac structure and function,and reduced cardiomyocyte apoptosis in MI rats, a finding corroborated in vitro where β-HB attenuated hypoxia-induced apoptosis in primary neonatal rat cardiomyocytes. The number of autophagic vesicles and LC3 fluorescence intensity in the infarct border zone decreased in the MI group compared with the control group, whereas 1,3-BD significantly increased autophagy levels in cardiomyocytes. In vitro, both β-HB and the PI3K inhibitor increased autophagy. However, the combination did not have an additional effect on regulating autophagy. Multi-omics analysis revealed 1,3-BD enriched the autophagy and PI3K-Akt-FOXO3 pathways. MI activated PI3K-Akt signaling and suppressed FOXO3, downregulating autophagy proteins (Atg7, Atg13, Beclin1, ULK1, LC3II/LC3I). 1,3-BD intervention reversed these changes.
Conclusion
1,3-BD improves post-MI cardiac remodeling by inhibiting cardiomyocyte apoptosis and enhancing autophagy, the latter mediated via suppression of the PI3K/Akt/FOXO3 pathway. Ketone supplementation represents a promising strategy against ischemic cardiomyopathy.
{"title":"1,3-Butanediol enhances autophagy via PI3K/Akt/FOXO3 pathway to ameliorate cardiac remodeling post-myocardial infarction","authors":"Hailin Zhang , Hongzhuang Wang , Kai Kang , Shuaijie Chen , Yong Chu , Weiqiang Liu , Wenxiang Zhao , Zhongxing Zhou , Ruming Shen , Xiaoyan Lin , Jinxiu Lin , Dajun Chai","doi":"10.1016/j.ejphar.2026.178539","DOIUrl":"10.1016/j.ejphar.2026.178539","url":null,"abstract":"<div><h3>Background</h3><div>Myocardial infarction (MI) remains a leading cause of cardiovascular mortality. While ketone bodies show cardioprotective potential, their role in regulating cardiomyocyte autophagy post-MI is unclear.</div></div><div><h3>Methods</h3><div>A rat MI model was established and treated with 1,3-butanediol (1,3-BD, 10 mg/100 g/day), a ketone precursor. Cardiac structure and function were assessed alongside autophagy and apoptosis levels. In vitro, hypoxia-induced cardiomyocytes were treated with β-hydroxybutyrate (β-HB) and phosphatidylinositol 3-kinase (PI3K) inhibitor. Mechanisms were explored via transcriptomics/metabolomics and validated by immunoblotting.</div></div><div><h3>Results</h3><div>1,3-BD treatment for 4 weeks significantly elevated serum β-HB, improved cardiac structure and function,and reduced cardiomyocyte apoptosis in MI rats, a finding corroborated <em>in vitro</em> where β-HB attenuated hypoxia-induced apoptosis in primary neonatal rat cardiomyocytes. The number of autophagic vesicles and LC3 fluorescence intensity in the infarct border zone decreased in the MI group compared with the control group, whereas 1,3-BD significantly increased autophagy levels in cardiomyocytes. In vitro, both β-HB and the PI3K inhibitor increased autophagy. However, the combination did not have an additional effect on regulating autophagy. Multi-omics analysis revealed 1,3-BD enriched the autophagy and PI3K-Akt-FOXO3 pathways. MI activated PI3K-Akt signaling and suppressed FOXO3, downregulating autophagy proteins (Atg7, Atg13, Beclin1, ULK1, LC3II/LC3I). 1,3-BD intervention reversed these changes.</div></div><div><h3>Conclusion</h3><div>1,3-BD improves post-MI cardiac remodeling by inhibiting cardiomyocyte apoptosis and enhancing autophagy, the latter mediated via suppression of the PI3K/Akt/FOXO3 pathway. Ketone supplementation represents a promising strategy against ischemic cardiomyopathy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178539"},"PeriodicalIF":4.7,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951314","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}
Sirtuin 1 (SIRT1) is a nicotinamide adenosine dinucleotide-dependent deacetylase regulating various cellular processes. Yes-associated protein (YAP) is a transcription cofactor of the Hippo pathway which is implicated in cardiac remodelling. However, the effects of SIRT1 and YAP on diabetic cardiomyopathy (DCM)-induced cardiac hypertrophy remain unclear. In this study, the relationship of SIRT1 and YAP on cardiac hypertrophy in DCM was investigated using an overexpressing rat model and overexpression/knockdown H9c2 cardiomyocytes. We found that in DCM rat hearts and high glucose-induced H9c2 cardiomyocytes, SIRT1 expression significantly decreased, YAP expression significantly increased, and the overexpression of SIRT1 decreased the acetylation level of YAP and reduced its nuclear translocation, thus alleviating myocardial hypertrophy. Furthermore, in the H9c2 cardiomyocytes model, YAP downregulation attenuated high glucose-induced H9c2 cardiomyocyte hypertrophy by inhibiting the PI3K/AKT pathway. Our findings suggest that YAP is closely associated with cardiac hypertrophy in DCM through the PI3K-Akt signalling pathway, and its acetylation modification influences the nuclear translocation of YAP; SIRT1 overexpression alleviated cardiac hypertrophy in DCM by mediating YAP deacetylation.
{"title":"SIRT1-mediated YAP deacetylation suppresses myocardial hypertrophy in diabetic cardiomyopathy","authors":"Hongwei Ye , Linlin Zhang , Anbo Zhao , Rui Zhang , Mengjie Yu , Shicheng Xia , Jiahui Wang , Qin Gao","doi":"10.1016/j.ejphar.2026.178538","DOIUrl":"10.1016/j.ejphar.2026.178538","url":null,"abstract":"<div><div>Sirtuin 1 (SIRT1) is a nicotinamide adenosine dinucleotide-dependent deacetylase regulating various cellular processes. Yes-associated protein (YAP) is a transcription cofactor of the Hippo pathway which is implicated in cardiac remodelling. However, the effects of SIRT1 and YAP on diabetic cardiomyopathy (DCM)-induced cardiac hypertrophy remain unclear. In this study, the relationship of SIRT1 and YAP on cardiac hypertrophy in DCM was investigated using an overexpressing rat model and overexpression/knockdown H9c2 cardiomyocytes. We found that in DCM rat hearts and high glucose-induced H9c2 cardiomyocytes, SIRT1 expression significantly decreased, YAP expression significantly increased, and the overexpression of SIRT1 decreased the acetylation level of YAP and reduced its nuclear translocation, thus alleviating myocardial hypertrophy. Furthermore, in the H9c2 cardiomyocytes model, YAP downregulation attenuated high glucose-induced H9c2 cardiomyocyte hypertrophy by inhibiting the PI3K/AKT pathway. Our findings suggest that YAP is closely associated with cardiac hypertrophy in DCM through the PI3K-Akt signalling pathway, and its acetylation modification influences the nuclear translocation of YAP; SIRT1 overexpression alleviated cardiac hypertrophy in DCM by mediating YAP deacetylation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1014 ","pages":"Article 178538"},"PeriodicalIF":4.7,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959019","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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