Pub Date : 2026-02-15Epub 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":"2026-02-15","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 : 2026-02-15Epub Date: 2026-01-23DOI: 10.1016/j.ejphar.2026.178601
Yuxiu Zhang , Panpan Lei , Jinna Liang , Sifan Xie , Xiaoyu Ma , Weina Ma
Non-small cell lung cancer (NSCLC) remains the leading contributor to cancer mortality, and its relentless progression is partly fueled by the overexpression of α1-type I collagen (COL1A1), an extracellular-matrix protein whose abundance herald dismal prognosis and shorter survival. Here, we establish COL1A1 as a bona fide oncogenic driver: genetic silencing attenuates NSCLC proliferation and migratory capacity, whereas enforced expression accelerates both phenotypes. Exploiting this vulnerability, we identify bufotalin (BT), a bufadienolide extracted from the traditional remedy Chansu, as a selective and potent inhibitor of COL1A1-high NSCLC. BT physically engages COL1A1, triggering its post-transcriptional down-regulation and concomitantly crippling malignant fitness. Mechanistically, BT simultaneously disables the PTEN/AKT/mTOR and Ras/MEK/ERK cascades, enforces G2–M arrest via Cyclin B1/CDK1 dysregulation, and quells epithelial-to-mesenchymal transition by restoring E-cadherin while repressing N-cadherin, MMP3, and MMP9. Beyond tumoricidal action, BT reshapes the tumor microenvironment: it suppresses TGF-β secretion, deactivates cancer-associated fibroblasts (CAFs), and severs the pro-tumorigenic COL1A1–integrin α11(ITGA11) paracrine circuit. Notably, COL1A1 reconstitution rescues CAF-induced tumor progression, underscoring COL1A1 dependency. Collectively, our findings position BT as a first-in-class COL1A1 antagonist that exerts dual cytotoxic and microenvironment-normalizing effects, providing a rational therapeutic avenue for NSCLC.
{"title":"Bufotalin targets COL1A1 to suppress non-small cell lung cancer growth and remodel the tumor microenvironment via dual inhibition of PI3K/AKT/mTOR and MAPK pathways","authors":"Yuxiu Zhang , Panpan Lei , Jinna Liang , Sifan Xie , Xiaoyu Ma , Weina Ma","doi":"10.1016/j.ejphar.2026.178601","DOIUrl":"10.1016/j.ejphar.2026.178601","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) remains the leading contributor to cancer mortality, and its relentless progression is partly fueled by the overexpression of α1-type I collagen (COL1A1), an extracellular-matrix protein whose abundance herald dismal prognosis and shorter survival. Here, we establish COL1A1 as a bona fide oncogenic driver: genetic silencing attenuates NSCLC proliferation and migratory capacity, whereas enforced expression accelerates both phenotypes. Exploiting this vulnerability, we identify bufotalin (BT), a bufadienolide extracted from the traditional remedy Chansu, as a selective and potent inhibitor of COL1A1-high NSCLC. BT physically engages COL1A1, triggering its post-transcriptional down-regulation and concomitantly crippling malignant fitness. Mechanistically, BT simultaneously disables the PTEN/AKT/mTOR and Ras/MEK/ERK cascades, enforces G2–M arrest via Cyclin B1/CDK1 dysregulation, and quells epithelial-to-mesenchymal transition by restoring E-cadherin while repressing N-cadherin, MMP3, and MMP9. Beyond tumoricidal action, BT reshapes the tumor microenvironment: it suppresses TGF-β secretion, deactivates cancer-associated fibroblasts (CAFs), and severs the pro-tumorigenic COL1A1–integrin α11(ITGA11) paracrine circuit. Notably, COL1A1 reconstitution rescues CAF-induced tumor progression, underscoring COL1A1 dependency. Collectively, our findings position BT as a first-in-class COL1A1 antagonist that exerts dual cytotoxic and microenvironment-normalizing effects, providing a rational therapeutic avenue for NSCLC.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178601"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046394","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 : 2026-02-15Epub 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":"2026-02-15","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}
Pub Date : 2026-02-15Epub Date: 2026-01-16DOI: 10.1016/j.ejphar.2026.178561
Ying-Qi Liu , Yi Zhang , Yu Song , Qin Yang , Guo-Wei He
Heart failure (HF) is often a result of cardiac hypertrophy, and it is still the main public health challenge. Although vericiguat has been proved to be effective in treating heart failure through soluble guanylate cyclase (sGC), its potential preventive effects on myocardial hypertrophy and the exact related mechanisms are still unclear. We aimed to investigate the mechanism of the effectiveness of vericiguat in treating HF, focusing on its multi-targets of therapeutic effect. Echocardiographic assessments performed after treatment of vericiguat revealed significant improvements in cardiac function compared to untreated controls (TAC + SS). Biochemically, vericiguat effectively reversed the decrease of cGMP levels observed in hypertrophic mice hearts. Histological analysis showed that hypertrophy and fibrosis were reduced, myofibril arrangement, mitochondrial function and autophagy were improved, and the swelling of the sarcoplasmic reticulum was reduced. This study for the first time demonstrates that in addition to the direct effect of cGMP signaling, vericiguat may target and regulate HDAC1 expression and may repair sarcoplasmic reticulum swelling and enhance autophagy in hypertrophic hearts. We conclude that the preventive effect of vericiguat on the HF through multiple mechanisms and the results emphasize the potential clinical usefulness of vericiguat in the prevention of the progress of HF.
{"title":"Vericiguat inhibits the progress of cardiac hypertrophy and prevents hypertrophy-induced heart failure by multiple mechanisms","authors":"Ying-Qi Liu , Yi Zhang , Yu Song , Qin Yang , Guo-Wei He","doi":"10.1016/j.ejphar.2026.178561","DOIUrl":"10.1016/j.ejphar.2026.178561","url":null,"abstract":"<div><div>Heart failure (HF) is often a result of cardiac hypertrophy, and it is still the main public health challenge. Although vericiguat has been proved to be effective in treating heart failure through soluble guanylate cyclase (sGC), its potential preventive effects on myocardial hypertrophy and the exact related mechanisms are still unclear. We aimed to investigate the mechanism of the effectiveness of vericiguat in treating HF, focusing on its multi-targets of therapeutic effect. Echocardiographic assessments performed after treatment of vericiguat revealed significant improvements in cardiac function compared to untreated controls (TAC + SS). Biochemically, vericiguat effectively reversed the decrease of cGMP levels observed in hypertrophic mice hearts. Histological analysis showed that hypertrophy and fibrosis were reduced, myofibril arrangement, mitochondrial function and autophagy were improved, and the swelling of the sarcoplasmic reticulum was reduced. This study for the first time demonstrates that in addition to the direct effect of cGMP signaling, vericiguat may target and regulate HDAC1 expression and may repair sarcoplasmic reticulum swelling and enhance autophagy in hypertrophic hearts. We conclude that the preventive effect of vericiguat on the HF through multiple mechanisms and the results emphasize the potential clinical usefulness of vericiguat in the prevention of the progress of HF.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178561"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997507","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 : 2026-02-15Epub Date: 2026-01-16DOI: 10.1016/j.ejphar.2026.178545
Min Xia , Bin Wang , Jincheng Lu , Yuan Liu , Tianyu Wang , Jinnian Duan , Zuodong Wang , Lingchao Li , Shao Li , Dongbai Li
Perioperative neurocognitive disorder (PND), a major contributor to poor postoperative outcomes and excessive healthcare costs, has been associated with isoflurane inhalation, although the underlying mechanisms remain poorly defined. Voltage-gated sodium channels (VGSCs or Nav) have been implicated in mediating the anesthetic effects of isoflurane. We previously reported that the Nav1.6 subtype modulates neural network activity and cognitive function. Here we investigated whether Nav1.6-mediated network disturbances contribute to isoflurane-induced PND. In the present study, we observed an increase in hippocampal Nav1.6 expression, accompanied by abnormal neural network excitability characterized by decreased β- and γ-band power on electroencephalogram (EEG) recordings. This dysfunction led to excessive glutamate release and subsequent cognitive impairment. Correspondingly, downregulation of Nav1.6 by lidocaine abolished both the abnormal network excitability and excessive glutamate release in isoflurane-exposed mice. In parallel, changes in excitatory synaptic proteins and excitatory amino acid transporters contributed to improved cognitive performance in isoflurane-inhaled mice. Taken together, isoflurane-induced increase in Nav1.6 evokes the abnormal network excitability, leading to excessive glutamate release and eventually cognitive decline. Our study offers a novel potential mechanism linking Nav1.6 to isoflurane-induced PND and suggests lidocaine as a potential therapeutic candidate.
{"title":"Sodium channel Nav1.6 involved in modulating isoflurane-induced perioperative cognitive disorder of mice","authors":"Min Xia , Bin Wang , Jincheng Lu , Yuan Liu , Tianyu Wang , Jinnian Duan , Zuodong Wang , Lingchao Li , Shao Li , Dongbai Li","doi":"10.1016/j.ejphar.2026.178545","DOIUrl":"10.1016/j.ejphar.2026.178545","url":null,"abstract":"<div><div>Perioperative neurocognitive disorder (PND), a major contributor to poor postoperative outcomes and excessive healthcare costs, has been associated with isoflurane inhalation, although the underlying mechanisms remain poorly defined. Voltage-gated sodium channels (VGSCs or Na<sub>v</sub>) have been implicated in mediating the anesthetic effects of isoflurane. We previously reported that the Na<sub>v</sub>1.6 subtype modulates neural network activity and cognitive function. Here we investigated whether Na<sub>v</sub>1.6-mediated network disturbances contribute to isoflurane-induced PND. In the present study, we observed an increase in hippocampal Na<sub>v</sub>1.6 expression, accompanied by abnormal neural network excitability characterized by decreased β- and γ-band power on electroencephalogram (EEG) recordings. This dysfunction led to excessive glutamate release and subsequent cognitive impairment. Correspondingly, downregulation of Na<sub>v</sub>1.6 by lidocaine abolished both the abnormal network excitability and excessive glutamate release in isoflurane-exposed mice. In parallel, changes in excitatory synaptic proteins and excitatory amino acid transporters contributed to improved cognitive performance in isoflurane-inhaled mice. Taken together, isoflurane-induced increase in Na<sub>v</sub>1.6 evokes the abnormal network excitability, leading to excessive glutamate release and eventually cognitive decline. Our study offers a novel potential mechanism linking Na<sub>v</sub>1.6 to isoflurane-induced PND and suggests lidocaine as a potential therapeutic candidate.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178545"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997509","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 : 2026-02-15Epub Date: 2025-12-16DOI: 10.1016/j.ejphar.2025.178481
Wenyan Zhou , Yan Tang , Lihua Xie , Yan Yi , Wenyu Cao , Xiaolin Zhong , Ling Chen
Diabetic patients often have intestinal dysfunction, such as diarrhea, constipation, abdominal pain, etc., and are accompanied by excessive inflammation. However, the underlying molecular mechanisms by which diabetes causes intestinal damage remain largely unclear. Here, we investigated the protective effect and detailed mechanism of Transient Receptor Potential vanilla protein 4 (TRPV4) agonist GSK1016790A in the treatment of diabetes-induced intestinal injury in mice. The in vivo efficacy of GSK1016790A was evaluated using a streptozotocin (STZ)-induced diabetic mouse model of intestinal injury. Jejunal and colon sections were analyzed to assess intestinal injury by hematoxylin and eosin (HE) staining, Alcian blue-periodic acid Schiff (AB-PAS) staining, and immunofluorescence. Western blotting was used to detect the changes in the expression levels of tight junction protein occludin, pro-inflammatory factor-related proteins, mucin MUC2, calmodulin-dependent protein kinase II (CAMKII) and glycogen synthase kinase 3β (GSK3β)-related protein in the intestinal tract of mice. The TRPV4 agonist GSK1016790A can significantly ameliorate intestinal mucosal structural disorder and decreased mucin secretion in diabetic mice, and downregulat the expression of pro-inflammatory factors. The underlying mechanism is to increase mucus synthesis through the mediated Ca2+/CAMKII/GSK3β pathway, thereby repairing diabetic intestinal injury. Therefore, the GSK1016790A therapy may have promising potential for the treatment of diabetic intestinal injury.
{"title":"TRPV4 agonist GSK1016790A increases mucus production and alleviates diabetic intestinal injury by activating the Ca2+/CAMKII/GSK3β pathway","authors":"Wenyan Zhou , Yan Tang , Lihua Xie , Yan Yi , Wenyu Cao , Xiaolin Zhong , Ling Chen","doi":"10.1016/j.ejphar.2025.178481","DOIUrl":"10.1016/j.ejphar.2025.178481","url":null,"abstract":"<div><div>Diabetic patients often have intestinal dysfunction, such as diarrhea, constipation, abdominal pain, etc., and are accompanied by excessive inflammation. However, the underlying molecular mechanisms by which diabetes causes intestinal damage remain largely unclear. Here, we investigated the protective effect and detailed mechanism of Transient Receptor Potential vanilla protein 4 (TRPV4) agonist GSK1016790A in the treatment of diabetes-induced intestinal injury in mice. The <em>in vivo</em> efficacy of GSK1016790A was evaluated using a streptozotocin (STZ)-induced diabetic mouse model of intestinal injury. Jejunal and colon sections were analyzed to assess intestinal injury by hematoxylin and eosin (HE) staining, Alcian blue-periodic acid Schiff (AB-PAS) staining, and immunofluorescence. Western blotting was used to detect the changes in the expression levels of tight junction protein occludin, pro-inflammatory factor-related proteins, mucin MUC2, calmodulin-dependent protein kinase II (CAMKII) and glycogen synthase kinase 3β (GSK3β)-related protein in the intestinal tract of mice. The TRPV4 agonist GSK1016790A can significantly ameliorate intestinal mucosal structural disorder and decreased mucin secretion in diabetic mice, and downregulat the expression of pro-inflammatory factors. The underlying mechanism is to increase mucus synthesis through the mediated Ca<sup>2+</sup>/CAMKII/GSK3β pathway, thereby repairing diabetic intestinal injury. Therefore, the GSK1016790A therapy may have promising potential for the treatment of diabetic intestinal injury.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178481"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780444","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 : 2026-02-15Epub Date: 2026-01-24DOI: 10.1016/j.ejphar.2026.178599
Lucía Garrido-Matilla , Alberto Marcos , Carlos León , Leonor Nozal , Natalia Puig-Martínez , Antonio L. Crego , Emilio Ambrosio
The combined use of cocaine and alcohol is highly prevalent and produces more severe effects than either drug alone. This study investigates this polysubstance abuse pattern by modelling the incubation of cocaine craving, both alone and in combination with ethanol.
To investigate the mechanisms underlying this phenomenon, we performed an untargeted plasma metabolomic analysis using High-Performance Liquid Chromatography coupled with a High-Resolution Hybrid Quadrupole-Orbitrap mass spectrometer. Both positive and negative ionization modes, and two complementary chromatographic methods, were employed to maximize compound detection. We analysed metabolite differences after 30 versus 2 days of withdrawal in rats that self-administered cocaine alone or with ethanol and then, identified the pathways in which these metabolites are involved to reveal the biological processes that could be affected during craving incubation.
Although all rats were exposed to cocaine, those that also consumed ethanol showed distinct metabolic pathway alterations. Both sexes exhibited changes in similar pathways, yet the specific metabolites affected differed, revealing clear sex dimorphism. Cocaine primarily altered tryptophan metabolism and the urea cycle, whereas the combination with ethanol mainly affected α-linolenic acid metabolism, bile acid synthesis, and arginine, proline, glycine, serine, and threonine metabolism.
This study provides insight into peripheral metabolomic alterations during the incubation of cocaine and cocaine plus ethanol seeking, offering a framework for further investigation of the affected pathways in peripheral tissues and within the central nervous system in both sexes.
{"title":"Metabolomic profiling of cocaine plus ethanol poly-consumption in young adult rats: Insights into the incubation of drug seeking","authors":"Lucía Garrido-Matilla , Alberto Marcos , Carlos León , Leonor Nozal , Natalia Puig-Martínez , Antonio L. Crego , Emilio Ambrosio","doi":"10.1016/j.ejphar.2026.178599","DOIUrl":"10.1016/j.ejphar.2026.178599","url":null,"abstract":"<div><div>The combined use of cocaine and alcohol is highly prevalent and produces more severe effects than either drug alone. This study investigates this polysubstance abuse pattern by modelling the incubation of cocaine craving, both alone and in combination with ethanol.</div><div>To investigate the mechanisms underlying this phenomenon, we performed an untargeted plasma metabolomic analysis using High-Performance Liquid Chromatography coupled with a High-Resolution Hybrid Quadrupole-Orbitrap mass spectrometer. Both positive and negative ionization modes, and two complementary chromatographic methods, were employed to maximize compound detection. We analysed metabolite differences after 30 versus 2 days of withdrawal in rats that self-administered cocaine alone or with ethanol and then, identified the pathways in which these metabolites are involved to reveal the biological processes that could be affected during craving incubation.</div><div>Although all rats were exposed to cocaine, those that also consumed ethanol showed distinct metabolic pathway alterations. Both sexes exhibited changes in similar pathways, yet the specific metabolites affected differed, revealing clear sex dimorphism. Cocaine primarily altered tryptophan metabolism and the urea cycle, whereas the combination with ethanol mainly affected α-linolenic acid metabolism, bile acid synthesis, and arginine, proline, glycine, serine, and threonine metabolism.</div><div>This study provides insight into peripheral metabolomic alterations during the incubation of cocaine and cocaine plus ethanol seeking, offering a framework for further investigation of the affected pathways in peripheral tissues and within the central nervous system in both sexes.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178599"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050968","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 : 2026-02-15Epub Date: 2026-01-23DOI: 10.1016/j.ejphar.2026.178600
Yuqing Li , Haoqi Li , Zijie Cheng , Huimin Li , Yupeng Zhong , Xin Dong , Dan Wu , Qingxun Hu
Cardiovascular disease (CVD) is a major public health issue causing high mortality rates worldwide. Its pathogenesis is complex and diverse, its treatment costs are high, and it represents a serious threat to human health. In recent years, changes in amino acid metabolism have drawn widespread attention as a key part of regulating CVD. Among these amino acids, glutamine (Gln)—the most abundant free amino acid in the body — has gradually shown important potential in the cardiovascular system, both in terms of its metabolic activity and its role in functional regulation. As new technologies like spatiotemporal metabolomics and single-cell metabolic imaging have developed, they have provided new ways to systematically analyze the dynamic distribution and regulatory mechanisms of Gln in the tissue microenvironment. This paper reviews Gln's metabolic pathways in the body and how it works in maintaining cardiovascular balance and in disease states, including ferroptosis, oxidative stress (OS), and inflammatory regulation. It also looks at, based on current research, how Gln might help treat different CVD models and its potential value in practical use. Finally, this paper suggests that future research should combine metabolomics methods with higher temporal and spatial resolution. This will help further identify the key metabolic nodes and pathways of Gln in CVD development, and provide theoretical support and technical ways to develop precise treatment plans based on regulating amino acid metabolism.
{"title":"The role of glutamine metabolism in cardiovascular diseases","authors":"Yuqing Li , Haoqi Li , Zijie Cheng , Huimin Li , Yupeng Zhong , Xin Dong , Dan Wu , Qingxun Hu","doi":"10.1016/j.ejphar.2026.178600","DOIUrl":"10.1016/j.ejphar.2026.178600","url":null,"abstract":"<div><div>Cardiovascular disease (CVD) is a major public health issue causing high mortality rates worldwide. Its pathogenesis is complex and diverse, its treatment costs are high, and it represents a serious threat to human health. In recent years, changes in amino acid metabolism have drawn widespread attention as a key part of regulating CVD. Among these amino acids, glutamine (Gln)—the most abundant free amino acid in the body — has gradually shown important potential in the cardiovascular system, both in terms of its metabolic activity and its role in functional regulation. As new technologies like spatiotemporal metabolomics and single-cell metabolic imaging have developed, they have provided new ways to systematically analyze the dynamic distribution and regulatory mechanisms of Gln in the tissue microenvironment. This paper reviews Gln's metabolic pathways in the body and how it works in maintaining cardiovascular balance and in disease states, including ferroptosis, oxidative stress (OS), and inflammatory regulation. It also looks at, based on current research, how Gln might help treat different CVD models and its potential value in practical use. Finally, this paper suggests that future research should combine metabolomics methods with higher temporal and spatial resolution. This will help further identify the key metabolic nodes and pathways of Gln in CVD development, and provide theoretical support and technical ways to develop precise treatment plans based on regulating amino acid metabolism.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178600"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046328","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 : 2026-02-15Epub Date: 2026-01-23DOI: 10.1016/j.ejphar.2026.178591
Marie H. Deventer , Silvia Mori , Marcus Angermann , Michael Decker , Christophe P. Stove
The excitatory neuropeptides orexin-A and -B interact with their target G protein-coupled receptors (GPCRs), the orexin 1 and orexin 2 (OX1 and OX2) receptors, which are widely expressed throughout the central nervous system. The orexin system plays a critical role in regulating several physiological processes such as sleep-wake cycles, feeding behaviour, and arousal, and is implicated in a variety of (neurological) disorders. In particular dysregulation of the orexin system is linked to sleep disorders such as narcolepsy (often associated with orexin deficiency) and insomnia (characterized by an overactivity of sleep-wake regulation). This has prompted a growing interest in orexin-targeting therapeutics. This study is the first to report the development of four OX1 and OX2 receptor luminescence bioassays based on functional complementation of a split-nanoluciferase enzyme, capable of monitoring β-arrestin 2 (βarr2) and Gαq recruitment to activated OX1 and OX2 receptors. These assays were successfully applied to evaluate the pharmacological profiles of both agonists and antagonists, including the endogenous ligands orexin-A and -B, the clinically approved small molecule antagonists suvorexant and daridorexant, as well as EMPA (N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) and four other compounds described in literature to act at orexin receptors. The obtained receptor activation patterns and selectivity profiles were consistent with literature data, indicating the reliability and robustness of the assay systems. Overall, the newly developed assays expand the toolkit for orexin receptor research by allowing the characterization of both agonists and antagonists, thereby contributing to the functional characterization of potential new drug candidates for various pathological conditions.
{"title":"Sleep, wake, and signaling: Functional profiling of orexin agonists and antagonists using newly developed orexin β-arrestin 2 and miniGαq recruitment assays","authors":"Marie H. Deventer , Silvia Mori , Marcus Angermann , Michael Decker , Christophe P. Stove","doi":"10.1016/j.ejphar.2026.178591","DOIUrl":"10.1016/j.ejphar.2026.178591","url":null,"abstract":"<div><div>The excitatory neuropeptides orexin-A and -B interact with their target G protein-coupled receptors (GPCRs), the orexin 1 and orexin 2 (OX<sub>1</sub> and OX<sub>2</sub>) receptors, which are widely expressed throughout the central nervous system. The orexin system plays a critical role in regulating several physiological processes such as sleep-wake cycles, feeding behaviour, and arousal, and is implicated in a variety of (neurological) disorders. In particular dysregulation of the orexin system is linked to sleep disorders such as narcolepsy (often associated with orexin deficiency) and insomnia (characterized by an overactivity of sleep-wake regulation). This has prompted a growing interest in orexin-targeting therapeutics. This study is the first to report the development of four OX<sub>1</sub> and OX<sub>2</sub> receptor luminescence bioassays based on functional complementation of a split-nanoluciferase enzyme, capable of monitoring β-arrestin 2 (βarr2) and Gα<sub>q</sub> recruitment to activated OX<sub>1</sub> and OX<sub>2</sub> receptors. These assays were successfully applied to evaluate the pharmacological profiles of both agonists and antagonists, including the endogenous ligands orexin-A and -B, the clinically approved small molecule antagonists suvorexant and daridorexant, as well as EMPA (<em>N</em>-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-<em>N</em>-pyridin-3-ylmethyl-acetamide) and four other compounds described in literature to act at orexin receptors. The obtained receptor activation patterns and selectivity profiles were consistent with literature data, indicating the reliability and robustness of the assay systems. Overall, the newly developed assays expand the toolkit for orexin receptor research by allowing the characterization of both agonists and antagonists, thereby contributing to the functional characterization of potential new drug candidates for various pathological conditions.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178591"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046377","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 : 2026-02-15Epub Date: 2026-01-22DOI: 10.1016/j.ejphar.2026.178594
Nicola Benvenuto , Filippo Mearelli , Gianni Biolo , Filippo Giorgio Di Girolamo , Erik Roman-Pognuz , Abbas Yadegar , Annalisa Serio , Saveria Lory Crocè , Mauro Giuffrè , Paolo De Cristofaro , Nina Grasselli Kmet , Maria Vittoria Micioni Di Bonaventura , Verena Zerbato , Stefano Di Bella
Sepsis remains a major global health problem and is responsible for millions of deaths annually despite significant progress in antimicrobial therapy and organ support. Increasing evidence highlights the role of the gut–immune axis in shaping host responses during sepsis, with particular interest in microbiota-derived metabolites such as short-chain fatty acids (SCFAs). Among these, butyrate has emerged as a promising candidate due to its anti-inflammatory, immunomodulatory, and intestinal barrier–preserving properties. This narrative review summarizes current evidence regarding the biological activities of butyrate and its potential therapeutic relevance in sepsis and septic shock.
A comprehensive literature search of PubMed and additional sources up to April 2025 identified experimental and clinical studies evaluating butyrate supplementation in sepsis. Preclinical studies show that butyrate improves function across organ systems (neurologic, hepatic, intestinal, cardiac, pulmonary, and renal) mainly by reducing inflammation, oxidative stress, and epithelial barrier disruption. In models like cecal ligation and puncture (CLP) or endotoxemia, survival improved by 20–40 % with butyrate administration. Human data are limited: an observational study found higher circulating β-hydroxybutyrate levels in sepsis survivors, while a randomized trial reported fewer gastrointestinal complications and ventilator-associated pneumonia in patients with synbiotic-induced butyrate increases.
Overall, current evidence suggests that butyrate may modulate key pathophysiological pathways in sepsis and holds potential as an adjunctive therapy. Nonetheless, dedicated early-phase clinical trials are required to clarify safety, optimal dosing, pharmacodynamics, and clinical effectiveness.
{"title":"Therapeutic potential of butyrate supplementation in sepsis: a review of preclinical evidence and translational perspectives","authors":"Nicola Benvenuto , Filippo Mearelli , Gianni Biolo , Filippo Giorgio Di Girolamo , Erik Roman-Pognuz , Abbas Yadegar , Annalisa Serio , Saveria Lory Crocè , Mauro Giuffrè , Paolo De Cristofaro , Nina Grasselli Kmet , Maria Vittoria Micioni Di Bonaventura , Verena Zerbato , Stefano Di Bella","doi":"10.1016/j.ejphar.2026.178594","DOIUrl":"10.1016/j.ejphar.2026.178594","url":null,"abstract":"<div><div>Sepsis remains a major global health problem and is responsible for millions of deaths annually despite significant progress in antimicrobial therapy and organ support. Increasing evidence highlights the role of the gut–immune axis in shaping host responses during sepsis, with particular interest in microbiota-derived metabolites such as short-chain fatty acids (SCFAs). Among these, butyrate has emerged as a promising candidate due to its anti-inflammatory, immunomodulatory, and intestinal barrier–preserving properties. This narrative review summarizes current evidence regarding the biological activities of butyrate and its potential therapeutic relevance in sepsis and septic shock.</div><div>A comprehensive literature search of PubMed and additional sources up to April 2025 identified experimental and clinical studies evaluating butyrate supplementation in sepsis. Preclinical studies show that butyrate improves function across organ systems (neurologic, hepatic, intestinal, cardiac, pulmonary, and renal) mainly by reducing inflammation, oxidative stress, and epithelial barrier disruption. In models like cecal ligation and puncture (CLP) or endotoxemia, survival improved by 20–40 % with butyrate administration. Human data are limited: an observational study found higher circulating β-hydroxybutyrate levels in sepsis survivors, while a randomized trial reported fewer gastrointestinal complications and ventilator-associated pneumonia in patients with synbiotic-induced butyrate increases.</div><div>Overall, current evidence suggests that butyrate may modulate key pathophysiological pathways in sepsis and holds potential as an adjunctive therapy. Nonetheless, dedicated early-phase clinical trials are required to clarify safety, optimal dosing, pharmacodynamics, and clinical effectiveness.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178594"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043959","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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