European journal of pharmacology最新文献_第2页

Agomelatine and empagliflozin synergistically protect against diabetic cardiomyopathy via nrf2/HO-1 signaling. 阿戈美拉汀和恩格列净通过Nrf2/HO-1信号协同预防糖尿病性心肌病

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-08-09 DOI: 10.1016/j.ejphar.2025.178054

Nada A Elbaik, Shimaa M Elshazly, Atef El-Gharbawy, Mahmoud H Elbatreek

{"title":"Agomelatine and empagliflozin synergistically protect against diabetic cardiomyopathy via nrf2/HO-1 signaling.","authors":"Nada A Elbaik, Shimaa M Elshazly, Atef El-Gharbawy, Mahmoud H Elbatreek","doi":"10.1016/j.ejphar.2025.178054","DOIUrl":"10.1016/j.ejphar.2025.178054","url":null,"abstract":"<p><p>Diabetic cardiomyopathy (DCM) is a serious complication of diabetes with limited therapeutic options. This study investigated the potential synergistic cardioprotective effects of combining agomelatine (AGM), a melatonergic agonist, with empagliflozin (EMPA), an SGLT2 inhibitor, in a mouse model of DCM. Diabetes was induced in mice using streptozotocin. Animals were treated with AGM (20 mg/kg/day), EMPA (20 mg/kg/day), a low-dose combination of AGM and EMPA (10 mg/kg/day each), or vehicle for 6 weeks. Cardiac function, biochemical markers, histopathology, and protein expression related to oxidative stress, inflammation, fibrosis, and apoptosis were assessed. The low-dose combination of AGM and EMPA significantly attenuated hyperglycemia (reducing plasma glucose levels from approximately 20 mM-10 mM), improved cardiac function, and reduced myocardial injury and hypertrophy compared to monotherapy. Histopathological analysis revealed reduced cardiac fibrosis, inflammation, and myocyte damage in the combination group. Furthermore, the combination therapy synergistically enhanced endogenous antioxidant capacity by increasing Nrf2 and HO-1 expression and SOD activity, while decreasing MDA levels. It also effectively suppressed myocardial inflammation, fibrosis, and apoptosis, as evidenced by reduced NF-κB, TGF-β, and caspase-3 expression. These findings demonstrate the synergistic cardioprotective effects of combining AGM and EMPA in DCM, suggesting that this low-dose combination therapy may offer a promising new therapeutic strategy for managing this challenging condition.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178054"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820966","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}

引用次数: 0

A diet-based Drosophila melanogaster model for the in vivo pharmacological evaluation of α-glucosidase inhibitors. 以饮食为基础的黑腹果蝇模型对α-葡萄糖苷酶抑制剂的体内药理学评价。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-08-05 DOI: 10.1016/j.ejphar.2025.178028

Kai Lüersen, Sandra Nevermann, Melanie Nebendahl, Katherine Olabanjo Olufolabo, Samuel Ayoolu Oguntimehin, Jones Olanrewaju Moody, Gerald Rimbach

{"title":"A diet-based Drosophila melanogaster model for the in vivo pharmacological evaluation of α-glucosidase inhibitors.","authors":"Kai Lüersen, Sandra Nevermann, Melanie Nebendahl, Katherine Olabanjo Olufolabo, Samuel Ayoolu Oguntimehin, Jones Olanrewaju Moody, Gerald Rimbach","doi":"10.1016/j.ejphar.2025.178028","DOIUrl":"10.1016/j.ejphar.2025.178028","url":null,"abstract":"<p><p>The intestinal α-glucosidases maltase and sucrase break down the dietary disaccharides maltose and sucrose respectively into their monosaccharides for absorption by the body. These enzymes are therefore drug targets for hyperglycaemia-associated metabolic diseases. Here, we tested whether the fruit fly Drosophila melanogaster is a suitable in vivo model for evaluating the efficacy, specificity and tolerability of α-glucosidase inhibitors. To this end, we fed flies with different obesity-inducing high-sugar diets based on glucose, fructose, maltose and sucrose, respectively. The different types of dietary sugar allow the distinction between processes that require maltase or sucrase activity and those that are not related to α-glucosidase activity. Accordingly, administration of the established general α-glucosidase inhibitor acarbose reduced the triacylglyceride levels only in disaccharide-based diets. This was associated with a delayed larval development, a shortened lifespan and reduced spontaneous locomotor activity. Similar effects were not observed with monosaccharide-based diets. We conclude that acarbose is effective, selective, and well tolerated by the fly. By applying the same method approach, the root bark of the African mulberry Morus mesozygia was proved to be a potent in vivo inhibitor of maltase without side effects on the development and lifespan of D. melanogaster. We suggest that this convenient diet-based in vivo model is valuable even via non-invasive methods for evaluating novel drugs and bioactives with α-glucosidase inhibitory activity.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178028"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783849","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}

引用次数: 0

Cholesterol sulfate alleviates functional dyspepsia in juvenile mice via modulating the gut microbiota-derived lactate. 硫酸胆固醇通过调节肠道微生物来源的乳酸来减轻幼年小鼠的功能性消化不良。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-08-06 DOI: 10.1016/j.ejphar.2025.178051

Aitong Liu, Guangtao Yan, Jun Xie, Zichen He, Tianhao Yang, Xiaodan Huang, Jianhui Xie, Qingfeng Xie, Ziren Su, Yuhong Liu

{"title":"Cholesterol sulfate alleviates functional dyspepsia in juvenile mice via modulating the gut microbiota-derived lactate.","authors":"Aitong Liu, Guangtao Yan, Jun Xie, Zichen He, Tianhao Yang, Xiaodan Huang, Jianhui Xie, Qingfeng Xie, Ziren Su, Yuhong Liu","doi":"10.1016/j.ejphar.2025.178051","DOIUrl":"10.1016/j.ejphar.2025.178051","url":null,"abstract":"<p><p>The overall global pooled prevalence of functional dyspepsia (FD) was 8.4 %, affecting 3-27 % of children. Currently, no specific medication exists for FD, especially in pediatric cases. Cholesterol sulfate (CHS), a bioactive compound derived from sea cucumber, shows potential in protecting the gastrointestinal tract, but its effects on pediatric FD remain unknown. This study assessed the pharmacological effects of CHS using a juvenile mice model of FD induced by repeated low-dose cisplatin. Results indicated that CHS significantly enhanced gastrointestinal motility and alleviated inflammation, marked by increased serum gastrin (GAS) and motilin (MTL), elevated interleukin-4 (IL-4), and reduced interleukin-1β (IL-1β) in intestines of FD juvenile mice. CHS restrained FD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidotas (F/B) ratio and suppressing Lactobacillus dominance. Notably, CHS decreased lactate and lactate dehydrogenase (LDH) levels in serum and the intestines of FD juvenile mice. Elevated lactate suppresses ghrelin production through G protein-coupled receptor (GPR81) receptor signaling, impairing intestinal motility, which highlights the significance of reducing lactate levels. Ghrelin enhances gastrointestinal motility by activating intestinal cholinergic neurons and potentiating serotonin (5-HT) signaling. After CHS treatment, GPR81 expression was downregulated while acetylcholinesterase (AChE) expression, ghrelin and 5-HT levels were upregulated in intestines, as well as heightened serum AChE activity. The co-administration of CHS with antibiotics(ABX) significantly attenuated its therapeutic efficacy, confirming that CHS alleviates FD in juvenile mice by inhibiting gut microbiota-derived lactate metabolism. In conclusion, our study provides evidence to support the utilization of CHS for regulating gastrointestinal motility for pediatric FD patients.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178051"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803908","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}

引用次数: 0

The effect of exenatide (GLP-1a) and sitagliptin (DPP-4i) on paraoxonase 1 (PON1) activity and expression in normal and fructose-fed rats. 艾塞那肽（GLP-1a）和西格列汀（DPP-4i）对正常和果糖喂养大鼠对氧磷酶1 （PON1）活性和表达的影响。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-01 DOI: 10.1016/j.ejphar.2025.178197

G Wójcicka, A Pradiuch, L Guz, M Wójciak, M Rusek, A Jamroz-Wiśniewska, G Czechowska, S Marciniak, A Góralczyk, J Bełtowski

{"title":"The effect of exenatide (GLP-1a) and sitagliptin (DPP-4i) on paraoxonase 1 (PON1) activity and expression in normal and fructose-fed rats.","authors":"G Wójcicka, A Pradiuch, L Guz, M Wójciak, M Rusek, A Jamroz-Wiśniewska, G Czechowska, S Marciniak, A Góralczyk, J Bełtowski","doi":"10.1016/j.ejphar.2025.178197","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.178197","url":null,"abstract":"<p><p>Although low level of high-density lipoprotein (HDL) cholesterol inversely corelates with atherosclerotic cardiovascular disease (ASCVD) risk, there is an increasing awareness that HDL quality may be more important than HDL quantity. Low activity of liver-derived HDL associated paraoxonase 1 (PON1), which determines the antioxidant and antiatherosclerotic capabilities of HDL, is considered to be novel nontraditional risk factor for development of ASCVD. The aim of this study was to determine whether the antiatherogenic properties of incretin-based antidiabetic drugs may be related to their ability to impact on HDL-PON1 activity and expression in the fructose-fed rats. Control and fructose-fed (8 wk.) rats were treated (4 wk.) with exenatide (5.0/10.0 μg/kg s.c.) or sitagliptin (5.0/10 mg/kg p.o.). Plasma and liver PON1 activity was measured calorimetrically. Plasma PON1 protein was determined by ELISA. Liver PON1 protein and mRNA expression were assayed by western blot and real-time PCR, respectively. Unexpectedly, chronic exenatide administration into fructose-fed rats at low and high dose reduced PON1 arylesterase activity (P<0.001) and decreased plasma enzyme concentration (P<0.001), without affecting plasma PON1 paraoxonase and thiolactonase activity. In the liver a high dose of exenatide reduced PON1 protein expression (P<0.001) without affecting PON1 gene expression. Whereas sitagliptin in these animals had no effect on plasma PON1 activity and concentration as well as on liver activity and expression of the enzyme. The known anti-atherosclerotic effect of incretin drugs is not related to their positive effect on PON1 activity and expression.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178197"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225107","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}

引用次数: 0

Insights into the role of gut microbiota modulation in the management of various cardiovascular diseases: A new approach for improving the efficacy of current cardiovascular medications 肠道菌群调节在各种心血管疾病管理中的作用：提高当前心血管药物疗效的新方法

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-01 DOI: 10.1016/j.ejphar.2025.178210

Lamiaa A. Ahmed , Khaled F. Al-Massri

{"title":"Insights into the role of gut microbiota modulation in the management of various cardiovascular diseases: A new approach for improving the efficacy of current cardiovascular medications","authors":"Lamiaa A. Ahmed , Khaled F. Al-Massri","doi":"10.1016/j.ejphar.2025.178210","DOIUrl":"10.1016/j.ejphar.2025.178210","url":null,"abstract":"<div><div>Gut microbiome is an emerging contributor to various cardiovascular diseases (CVDs) where gut dysbiosis increases the risk of development and progression of atherosclerosis, coronary artery diseases, hypertension, and heart failure. Microbiota can also affect the metabolism of medications including cardiovascular drugs, resulting in alteration of their pharmacokinetics and pharmacodynamics or producing metabolites which can interfere with response of these drugs. Importantly, CVDs require prolonged pharmacological interventions with medications which may have impacts on the diversity and composition of gut microbiota. Gut microbiota modulation using diets, prebiotics, probiotics, fecal microbiota transplantation, antibiotics, and microbial trimethylamine-lyase inhibitors, has also shown benefits in the management of CVDs where gut microbiota and their metabolites have recently been studied as potential targets for the management of these diseases. Specifically, using innovative microbiota therapies in combination with traditional pharmacological agents have been evaluated for additional benefits in various CVDs. However, assessing the interactions among host factors, gut microbiome, and drug response will be essential for the development of new therapeutic targets for cardiovascular disorders, ultimately hoping better prognosis and patient's quality of life for those affected with CVDs.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1007 ","pages":"Article 178210"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145219067","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}

引用次数: 0

Statins activate temperature-gated transient receptor potential ion channels 他汀类药物激活温度门控瞬时受体电位离子通道

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-01 DOI: 10.1016/j.ejphar.2025.178206

George Oprita , Dan Domocos , Tudor Selescu , Adelina Paduraru , Sorin Tunaru , Andreas Leffler , Alexandru Babes , Ramona-Madalina Babes

{"title":"Statins activate temperature-gated transient receptor potential ion channels","authors":"George Oprita , Dan Domocos , Tudor Selescu , Adelina Paduraru , Sorin Tunaru , Andreas Leffler , Alexandru Babes , Ramona-Madalina Babes","doi":"10.1016/j.ejphar.2025.178206","DOIUrl":"10.1016/j.ejphar.2025.178206","url":null,"abstract":"<div><div>Statins are HMG-CoA reductase inhibitors administered to decrease levels of LDL cholesterol and to lower the risk of cardiovascular disease. Although statins are relatively well tolerated, adverse effects such as myalgia and painful peripheral neuropathy have been reported. While the underlying cause has not been fully elucidated, accumulating evidence shows that statins have numerous pleiotropic effects including anti-inflammatory and analgesic actions in several animal pain models. Here we report that some of the most extensively used statins activate members of the temperature-gated transient receptor potential (TRP) ion channel subfamily expressed in heterologous systems. All tested statins (simvastatin, atorvastatin and rosuvastatin) activate human TRPA1 and, in addition, simvastatin activates human TRPV1 and rosuvastatin activates human TRPM8. The activation of TRPV1 by simvastatin is abolished in a capsaicin-insensitive mutant. Furthermore, the sensitivities of both TRPV1 and TRPA1 to simvastatin are diminished in triple cysteine mutants known to exhibit a reduced sensitivity to reactive oxygen species. Rosuvastatin-induced activation of TRPM8 seems to involve an aspartate residue which is essential for sensitivity to the synthetic TRPM8-agonist icilin. In mouse dorsal root ganglion (DRG) neurons, simvastatin activates a subpopulation of neurons which also respond to the TRPV1-agonist capsaicin or the TRPA1-agonist allyl isothiocyanate. In addition, TRPM8 plays an important role for the activation of a small population of DRG neurons by rosuvastatin. Taken together, these results indicate that statins activate thermo-sensitive TRP channels expressed in nociceptive sensory neurons. This property may explain some of the pleiotropic effects of these widely used drugs.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178206"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217876","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}

引用次数: 0

Bone marrow MSCs-derived exosomes (BM-MSCs-Exo) expressed mir-181, mir-24, mir-9, mir-29, mir-338, and mir-486 ameliorated hepatic fibrosis in male rats via altering the expression of Menin-1/TGF-β/Smad pathway. 骨髓间充质干细胞来源的外泌体（bm - msc - exo）表达mir-181、mir-24、mir-9、mir-29、mir-338和mir-486通过改变Menin-1/TGF-β/Smad通路的表达改善雄性大鼠肝纤维化。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-01 DOI: 10.1016/j.ejphar.2025.178209

Tarek Khamis, Asmaa A Ibrahim, Lashin Saad Ali, Amal S El-Shal, Somaia H Abdallah, Asma Alanazi, Hussein Abdellatif, Wed Salah, Faisal A Kashgari, Noha Mohamed Halloull, Nehal E Refaay, Mohamed M M Metwally, Huda F Ebian, Fatma Alzahraa M Gomaa, Smuleac Laura, Muselin Florin, Pascalau Raul, Ahmed Hamed Arisha, Mamdouh Eldesoqui, Sally M Shalaby, Walaa M Sarhan

{"title":"Bone marrow MSCs-derived exosomes (BM-MSCs-Exo) expressed mir-181, mir-24, mir-9, mir-29, mir-338, and mir-486 ameliorated hepatic fibrosis in male rats via altering the expression of Menin-1/TGF-β/Smad pathway.","authors":"Tarek Khamis, Asmaa A Ibrahim, Lashin Saad Ali, Amal S El-Shal, Somaia H Abdallah, Asma Alanazi, Hussein Abdellatif, Wed Salah, Faisal A Kashgari, Noha Mohamed Halloull, Nehal E Refaay, Mohamed M M Metwally, Huda F Ebian, Fatma Alzahraa M Gomaa, Smuleac Laura, Muselin Florin, Pascalau Raul, Ahmed Hamed Arisha, Mamdouh Eldesoqui, Sally M Shalaby, Walaa M Sarhan","doi":"10.1016/j.ejphar.2025.178209","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.178209","url":null,"abstract":"<p><p>Bone marrow mesenchymal stem cells derived exosomes (BM-MSC-Exo) expressed a variety of microRNAs in their secretome however their role in alleviating hepatic fibrosis remains elusive. Thus, the present study was designed to investigate the role of the miRNAs conveyed by BM-MSC-Exo in reversing hepatic fibrosis in male rats. Seventy-five adult male Sprague Dawley rats were allocated into 5 equal groups 15 rats each, control, fibrosis, fibrosis + conditioned media (CM), fibrosis + EX, and fibrosis + BM-MSCs. The expression levels of mir-181a-2-3p, mir-24, mir-181a-5p, mir-9a-5p, mir-29a, mir-338-5p, and mir-486 in BM-MSCs, EX, CM, and hepatic tissue of the experimental animals were analyzed. Moreover, their impact on modulating hepatic: Menin-1 - TGF-β/ Smad fibrotic signaling pathway, inflammation, apoptosis, and angiogenesis was investigated. The results revealed a significant upregulation in the expression of mir-181a-2-3p, mir-24, mir-181a-5p, mir-9a-5p, mir-29a, mir-338-5p, and mir-486 in BM-MSCs-Exo and its treated rats' group than BM-MSCs, CM, and their rat treated groups. Moreover, there were significant improvements in hepatic: Menin-1 - TGF-β/ Smad fibrotic signaling pathway oxidative stress, apoptosis, and angiogenesis in the Exo-treated group than the other experimental group. It could be concluded that BM-MSCs-Exo alleviates hepatic fibrosis more than BM-MSCs by conveying a higher cargo of miRNAs.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178209"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225089","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}

引用次数: 0

Asiaticoside alleviates migraine-induced cognitive impairment via TLR4-Mediated apoptosis regulation 积雪草苷通过tlr4介导的细胞凋亡调节缓解偏头痛引起的认知障碍。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-09-30 DOI: 10.1016/j.ejphar.2025.178204

Wei Jiang , Xue-Min Feng , Peng Yu , Li-Xi Zhang , Meng-Tan Cai , Kang Qu , Yu Yang , Ming Dong

{"title":"Asiaticoside alleviates migraine-induced cognitive impairment via TLR4-Mediated apoptosis regulation","authors":"Wei Jiang , Xue-Min Feng , Peng Yu , Li-Xi Zhang , Meng-Tan Cai , Kang Qu , Yu Yang , Ming Dong","doi":"10.1016/j.ejphar.2025.178204","DOIUrl":"10.1016/j.ejphar.2025.178204","url":null,"abstract":"<div><div>Migraine, a prevalent neurological disorder, is often accompanied by cognitive impairment that significantly reduces patients' quality of life. This study explored the therapeutic potential of Asiaticoside, a neuroprotective compound derived from <em>Centella asiatica</em>, in alleviating migraine-associated cognitive deficits. Using network pharmacology, we identified putative molecular targets of Asiaticoside and cross-referenced them with migraine- and cognitive impairment-related targets from GeneCards and OMIM databases. Protein–protein interaction networks were constructed, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. In vivo validation was conducted using a nitroglycerin (NTG)-induced migraine mouse model, incorporating behavioral assessments alongside biochemical and molecular analyses. Network analysis highlighted the TLR4 signaling pathway and apoptosis as key mechanisms underlying Asiaticoside's therapeutic effects. Consistently, Asiaticoside dose-dependently alleviated NTG-induced nociceptive hypersensitivity and cognitive impairments. Mechanistically, Asiaticoside markedly inhibited the TLR4-MyD88-NF-κB signaling cascade and reduced the expression of pro-inflammatory cytokines and CGRP in the spinal trigeminal nucleus caudalis, prefrontal cortex, and hippocampus. Additionally, Asiaticoside attenuated neuronal apoptosis by modulating the balance of BCL-2 family proteins and suppressing Caspase-3 activation. Co-administration of the TLR4 inhibitor TAK-242 further enhanced Asiaticoside's protective effects. These findings collectively support that Asiaticoside alleviates migraine-induced cognitive impairments by modulating TLR4-mediated neuroinflammation and apoptosis, highlighting its promise as a potential therapeutic agent for migraine and its associated cognitive impairment.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1007 ","pages":"Article 178204"},"PeriodicalIF":4.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212042","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}

引用次数: 0

Spinal blockade with intrathecal spiradoline and buprenorphine in rats 大鼠脊髓鞘内螺旋喹啉和丁丙诺啡阻滞。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-09-30 DOI: 10.1016/j.ejphar.2025.178205

An-Kuo Chou , Chong-Chi Chiu , Li-Kai Wang , Yu-Wen Chen , Ching-Hsia Hung , Jhi-Joung Wang

{"title":"Spinal blockade with intrathecal spiradoline and buprenorphine in rats","authors":"An-Kuo Chou , Chong-Chi Chiu , Li-Kai Wang , Yu-Wen Chen , Ching-Hsia Hung , Jhi-Joung Wang","doi":"10.1016/j.ejphar.2025.178205","DOIUrl":"10.1016/j.ejphar.2025.178205","url":null,"abstract":"<div><div>This study aimed to evaluate <u>the spinal blockade effects of κ-opioid receptor ligands (spiradoline, U-50488H, and buprenorphine) compared with mepivacaine, and used isobolographic analysis to assess the interaction between spiradoline and mepivacaine.</u></div><div>Rats received intrathecal injections of spiradoline, U-50488, buprenorphine, or mepivacaine, followed by neurobehavioral assessments of motor function and nociception. Spiradoline and mepivacaine were co-administered at a fixed dose ratio to assess their interaction using isobolographic analysis. We showed that intrathecal administration of spiradoline, U-50488, and buprenorphine induced spinal motor and nociceptive blockade at an equal concentration of 30 mM. In dose-dependent studies, spiradoline exhibited significantly greater potency (<em>P</em> < 0.01) than mepivacaine for spinal motor and nociceptive blockade. At equipotent doses (ED<sub>25</sub>, ED<sub>50</sub>, and ED<sub>75</sub>), spiradoline produced a significantly longer duration of spinal motor and nociceptive blockade compared to mepivacaine (<em>P</em> < 0.001). Co-administration of spiradoline and mepivacaine resulted in an additive effect on spinal blockade of motor function and nociception. We concluded that spiradoline demonstrated the highest potency and most extended duration of action among drugs, whereas U-50488 and buprenorphine exhibited similar or lower potency than mepivacaine. Spiradoline elicited a longer duration of action than mepivacaine. The combination of spiradoline and mepivacaine produced an additive effect on spinal blockade, resembling the interaction observed with two local anesthetics.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178205"},"PeriodicalIF":4.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212039","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}

引用次数: 0

Research progress of lung organoids in infectious respiratory diseases 传染性呼吸系统疾病中肺类器官的研究进展。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-09-27 DOI: 10.1016/j.ejphar.2025.178201

Jun Li , Wendong Yang , Xiaoli Liu , Keda Yang , Jialin Zhou , Xiaochun Yang

{"title":"Research progress of lung organoids in infectious respiratory diseases","authors":"Jun Li , Wendong Yang , Xiaoli Liu , Keda Yang , Jialin Zhou , Xiaochun Yang","doi":"10.1016/j.ejphar.2025.178201","DOIUrl":"10.1016/j.ejphar.2025.178201","url":null,"abstract":"<div><div>Infectious respiratory diseases are common epidemics that often exhibit phased outbreaks, increasing the healthcare burden. Past research models for these diseases were relatively simplistic, but the emergence of organoids has transformed this landscape. Organoids, three-dimensional in vitro tissue analogs that recapitulate specific spatial organ structures derived from stem cell culture, have advanced significantly over the decade since their inception. Compared to conventional animal models, organoids circumvent interspecies variations, enabling a more precise representation of human physiological and pathological traits. Relative to two-dimensional cell cultures, organoids exhibit enhanced complexity, incorporating diverse cell types and maintaining stable genomes, which facilitates a more faithful simulation of cellular interactions within the extracellular microenvironment. Consequently, as a three-dimensional in vitro model, lung organoids are pivotal for investigating lung organ development, infectious disease pathogenesis, and drug screening. Although SARS-CoV-2 is receding from the spotlight, advancing lung organoid development for addressing infectious respiratory diseases like influenza remains a priority. This review demonstrated the differentiation culture process of lung organoids and outlined advancements in utilizing organoids to elucidate pathogenic infection mechanisms, reveal virus-host interactions and screen therapeutic drugs over the past seven years. Additionally, we have summarized the advances in lung organoid model technologies and outlined their developmental directions.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178201"},"PeriodicalIF":4.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185072","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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