European journal of pharmacology最新文献

{"title":"Inhibition of soluble epoxide hydrolase ameliorates hyperhomocysteinemia-induced perivascular adipose tissue dysfunction: Revealing epoxyeicosatrienoic acid as a perivascular adipose tissue-derived relaxing factor","authors":"Jia-Hui Wei ,&nbsp;Hang Qi ,&nbsp;Xiang-Chong Wang ,&nbsp;Hai-Tao Hou ,&nbsp;Guo-Wei He ,&nbsp;Qin Yang","doi":"10.1016/j.ejphar.2025.178181","DOIUrl":"10.1016/j.ejphar.2025.178181","url":null,"abstract":"<div><h3>Objectives</h3><div>Hyperhomocysteinemia harms vascular endothelium and smooth muscle. We recently reported that homocysteine also impairs perivascular adipose tissue (PVAT) function but the mechanisms remain poorly elucidated. This study aimed to advance mechanistic understanding of hyperhomocysteinemia-induced PVAT dysfunction through revealing the role of epoxyeicosatrienoic acids (EETs) in the anticontractile/vasorelaxing activity of PVAT. Further, the effect of targeting soluble epoxide hydrolase (sEH) against hyperhomocysteinemia-induced PVAT dysfunction was explored.</div></div><div><h3>Methods</h3><div>Methionine diet-induced hyperhomocysteinemic rat model and in vitro homocysteine-incubation model were used. PVAT and endothelium-intact (PVAT + E+) or both denuded (PVAT-E−), either PVAT (PVAT-E+) or endothelium-denuded (PVAT + E−) aortic rings were studied for vasoreactivity. Aortic PVAT was measured for EETs, sEH expression and activity, and transferred to skeletonized aorta for vasoreactivity regulation study.</div></div><div><h3>Results</h3><div>Both in vivo and in vitro studies showed that homocysteine augments vasocontractile responses to phenylephrine and KCl and attenuates vasorelaxant response to acetylcholine in PVAT-intact rat aortas with or without endothelium. EETs in the aortic PVAT were decreased in hyperhomocysteinemic rats (8,9-, 11,12-, 14,15-EET) and after homocysteine-exposure (11,12-, 14,15-EET), associating with an increased expression and activity of sEH. Treating in vivo and in vitro models with sEH inhibitor TPPU suppressed sEH activity and increased EETs in the PVAT, accompanied by a restored anticontractile/vasorelaxing capacity of PVAT. PVAT from TPPU-treated hyperhomocysteinemic rat suppressed the contractility of hyperhomocysteinemic rat aorta. Both 11,12- and 14,15-EET evoked relaxation in PVAT-E− aorta.</div></div><div><h3>Conclusions</h3><div>EETs are PVAT-derived relaxing factors. Inhibition of sEH prevents homocysteine-induced EETs loss in PVAT, thereby improving the anticontractile/vasorelaxing activity of PVAT.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178181"},"PeriodicalIF":4.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145097455","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":"Quercetin attenuates busulfan-induced testicular and epididymal toxicity via modulation of oxidative stress, inflammatory cytokines, and apoptotic markers in rats","authors":"Dalia Ibrahim El-wafaey ,&nbsp;Aliaa Talaat ,&nbsp;Nanees F. El-Malkey ,&nbsp;Amira Mohamed Abdelhamid ,&nbsp;Fatma Ibrahim ,&nbsp;Ahmed Mohammed Zaazaa ,&nbsp;Eman Faruk","doi":"10.1016/j.ejphar.2025.178177","DOIUrl":"10.1016/j.ejphar.2025.178177","url":null,"abstract":"<div><h3>Background</h3><div>Busulfan, an alkylating chemotherapeutic agent, is associated with male reproductive toxicity, including impaired spermatogenesis and hormonal imbalance. This study aimed to investigate the protective effects of quercetin, a natural antioxidant flavonoid, against busulfan-induced testicular and epididymal damage in adult male rats.</div></div><div><h3>Methods</h3><div>Forty adult male albino rats were randomly divided into four groups: Control, Quercetin (70 mg/kg), Busulfan (10 mg/kg), and Quercetin + Busulfan. Treatments were administered orally for four weeks. Testicular and epididymal tissues were evaluated histologically, and sperm parameters, oxidative stress markers (MDA, SOD), inflammatory cytokines (TNF-α, IL-10), apoptotic proteins (caspase-3, Bax), antiapoptotic (BCL-2) and serum sex hormones (testosterone, LH,and FSH) were assessed.</div></div><div><h3>Results</h3><div>Busulfan significantly impaired testicular architecture, reduced sperm count and motility, increased MDA levels, and decreased SOD activity. It also elevated pro-inflammatory cytokines and pro-apoptotic markers while suppressing serum testosterone, LH, and FSH levels (p &lt; 0.05). Co-administration of quercetin markedly alleviated histopathological damage, restored sperm quality, reduced oxidative and inflammatory markers, and normalized hormone levels.</div></div><div><h3>Conclusion</h3><div>Quercetin demonstrates significant protective effects against busulfan-induced testicular and epididymal toxicity, likely through its antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. These findings support the potential use of quercetin as an adjuvant therapy to mitigate chemotherapy-induced male infertility.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178177"},"PeriodicalIF":4.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102786","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":"TGF-β1 mediates epithelial-mesenchymal transition in interstitial cystitis through the regulation of ROCK","authors":"Xuezhi Long ,&nbsp;Bangxian Yu ,&nbsp;Ming Chen ,&nbsp;Qi Zhang ,&nbsp;Yubo Wang ,&nbsp;Yueting Huang ,&nbsp;Jianhao Wu ,&nbsp;Peibin Cen ,&nbsp;Hongyu Lan ,&nbsp;Jun Long ,&nbsp;Zhixiong Zhang ,&nbsp;Jinghua Zhong ,&nbsp;Xiaolu Duan ,&nbsp;Qingfeng Yu ,&nbsp;Di Gu","doi":"10.1016/j.ejphar.2025.178184","DOIUrl":"10.1016/j.ejphar.2025.178184","url":null,"abstract":"<div><div>Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition characterised by bladder pain, urinary frequency, and urgency, which impacts quality of life. The pathogenesis remains unclear, though bladder fibrosis resulting from epithelial-mesenchymal transition (EMT) plays a key role. Transforming growth factor-β1 (TGF-β1) is a critical inducer of EMT and has been implicated in IC/BPS, although the molecular mechanisms are not fully understood. Rho-associated kinase (ROCK), a downstream effector of TGF-β1, may be involved in this process. This study aimed to explore the role of TGF-β1 in regulating EMT through ROCK in IC/BPS. An interstitial cystitis model in rats was established by intraperitoneal injection of cyclophosphamide (CYP). EMT in SV-HUC-1 cells was induced with recombinant TGF-β1 and modulated by treatment with the TGF-β receptor inhibitor SB505124 and the ROCK inhibitor Y-27632. Mechanical pain sensitivity was assessed using the Von Frey test, and serum TGF-β1 levels were measured by ELISA. Fibrosis markers in bladder tissue and cell were analyzed by H&amp;E staining, Masson's trichrome, Western blotting, immunohistochemistry, and immunofluorescence. Results showed CYP-induced rats exhibited mechanical pain, elevated serum TGF-β1, and aggravated bladder fibrosis. In addition, TGF-β1, ROCK, and fibrosis-related proteins (vimentin, N-cadherin, fibroblast-specific protein 1, α-smooth muscle actin) were upregulated, while E-cadherin was reduced. Inhibition of TGF-β1 and ROCK reversed these changes, though the ROCK inhibitor did not affect TGF-β1 levels. This study demonstrates that TGF-β1 mediates EMT in bladder epithelial cells via ROCK, contributing to IC/BPS pathogenesis, and suggests that TGF-β1 and ROCK inhibitors may offer potential therapeutic strategies for IC/BPS.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178184"},"PeriodicalIF":4.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145097366","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":"Transcriptomic profiling unveils novel therapeutic options for drug-resistant temporal lobe epilepsy","authors":"Patricia Sánchez-Jiménez ,&nbsp;Lola Alonso-Guirado ,&nbsp;Laura Cerrada-Gálvez ,&nbsp;Marcos Elizalde-Horcada ,&nbsp;Inmaculada Granero-Cremades ,&nbsp;Paolo Maietta ,&nbsp;Antonio Gómez-Martín ,&nbsp;Francisco Abad-Santos ,&nbsp;Cristina Virginia Torres-Díaz ,&nbsp;Maria de Toledo ,&nbsp;Natalia Frade-Porto ,&nbsp;Patricia Gonzalez-Tarno ,&nbsp;Paloma Pulido ,&nbsp;María C. Ovejero-Benito","doi":"10.1016/j.ejphar.2025.178146","DOIUrl":"10.1016/j.ejphar.2025.178146","url":null,"abstract":"<div><h3>Background</h3><div>Epilepsy drug treatments fail in 25–30 % of patients, leading to drug resistance. Temporal lobe epilepsy is the most prevalent subtype associated with drug resistance. Classical drug discovery is a long and extremely costly process with a high failure rate in clinical trials. Drug repurposing is a more cost- and time-effective strategy. Hence, the main objective of this study is to propose drug candidates for the treatment of drug-resistant temporal lobe epilepsy (DR-TLE) through drug repurposing based on transcriptomic profiling.</div></div><div><h3>Methods</h3><div>Total RNA-sequencing (RNA-Seq) was performed on 45 formalin-fixed paraffin-embedded (FFPE) hippocampi of DR-TLE patients and 36 FFPE hippocampi of post-mortem biobank donors. RNA-Seq was carried out on an Illumina NovaSeq 6000 platform in 100bp paired-end. Drug repurposing based on transcriptomic analysis top candidates was performed against these databases: Pandrugs2, PharmOmics, DGIdb, ToppGene, L1000CDS² and Connectivity Map.</div></div><div><h3>Results</h3><div>We identified 887 genes differentially expressed between DR-TLE patients and post-mortem controls. We observed 74 potential drug candidates in at least two independent databases. Of these, we selected only the 11 which can cross the blood-brain barrier: cobimetinib, panobinostat, melphalan, rucaparib, alectinib, ponatinib, danazol, carboplatin, vandetanib, erlotinib, and gefitinib. After analyzing their mechanisms to modulate epileptogenesis, their safety and efficacy profiles from previous publications, we provide a list of the top 5 candidates.</div></div><div><h3>Conclusion</h3><div>Based on differential RNA-Seq profiling, we therefore propose erlotinib, danazol, rucaparib, ponatinib, and panobinostat.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178146"},"PeriodicalIF":4.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102801","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":"Procyanidin B2 alleviates LPS-induced acute lung injury by regulating M1 macrophage polarization and inhibiting pyroptosis via the NF-κB/JAK2/STAT1 signaling pathway","authors":"Hui Wan ,&nbsp;Yuxin Zhang ,&nbsp;Zhicheng Gao ,&nbsp;Guanyue Shan ,&nbsp;Jianing Yin ,&nbsp;Haijun Li","doi":"10.1016/j.ejphar.2025.178149","DOIUrl":"10.1016/j.ejphar.2025.178149","url":null,"abstract":"<div><div>Acute lung injury (ALI) has attracted considerable attention because of its high mortality rate. Procyanidin B2 (PCB2) is widely present in various dietary foods and plants. However, the effects of PCB2 on lung macrophages in LPS-induced ALI and the underlying molecular mechanisms have not yet been reported. The objective of the present study was to examine the effects of PCB2 on LPS-induced ALI and macrophages and the related mechanisms. Immunofluorescence, ELISA, qRT‒PCR, H&amp;E staining and Western blotting were used for in vivo and in vitro experiments. The outcomes showed that PCB2 effectively alleviated ALI by reducing the lung wet‒dry (W/D) ratio, improving histopathological changes, decreasing the levels of IL-1β, TNF-α, IL-6 and reducing M1 polarization of lung macrophages. Both in vitro and in vivo, PCB2 inhibited the activation of the NF-κB and JAK2/STAT1 signaling pathways, suppressed the expression of Caspase-1, NLRP3, ASC proteins, and the expression of CD80, CD86, and iNOS, while increasing the expression of CD206. Our findings suggested that PCB2 inhibited the activation of the NF-κB and JAK2/STAT1 signaling pathways, thereby alleviating macrophage pyroptosis and M1 polarization in LPS-caused ALI. PCB2 holds considerable promise as a potential therapeutic option for ALI.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178149"},"PeriodicalIF":4.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102776","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":"Forskolin alleviates cholestatic liver disease by inhibiting the Hippo/YAP-mediated ductular reaction and fibrosis progression","authors":"Walaa H. El-Maadawy ,&nbsp;Ehab Hafiz ,&nbsp;Amr Mostafa ,&nbsp;Abdelrahman A. Hassany ,&nbsp;Nesma S. Shafie ,&nbsp;Ahmed W. Lethy ,&nbsp;Eman El-Ahwany ,&nbsp;Marwa Amer","doi":"10.1016/j.ejphar.2025.178182","DOIUrl":"10.1016/j.ejphar.2025.178182","url":null,"abstract":"<div><div>Cholestatic liver disease (CLD) results from impaired bile flow, involving dysregulated Hippo/YAP signaling driving pathogenic ductular reaction (DR), inflammation, and fibrosis. Although ursodeoxycholic acid (UDCA) remains first-line therapy, most patients show inadequate response. Our computational screening identified forskolin (FSK), adenylate cyclases (ADCY1–10) activator, as a potential Hippo/YAP pathway modulator through cAMP elevation. Molecular docking confirmed FSK's stable binding across all human ADCY isoforms, supporting upstream cAMP's activation. Cholestatic injury was induced in rats via bile duct ligation (BDL). BDL-rats were treated with either FSK or UDCA. Relative to UDCA, FSK significantly improved liver function (ALT, AST, ALP, GGT) and cholestasis (bilirubin, bile acids) parameters. FSK markedly reduced inflammation markers (IL-6, IL-1β, CXCL1, and CXCL2) and attenuated fibrosis, as evidenced by restored Hydroxyproline levels, COL1A1, and α-SMA expressions. Histological analysis revealed that FSK preserved hepatic architecture, suppressed DR, and downregulated CK19/EpCAM expressions, whereas UDCA showed only partial improvement. Although UDCA significantly modulated Hippo/YAP signaling, FSK substantially activated the pathway through LATS1/2 and YAP1 phosphorylation, suppressing YAP/TEAD transcriptional activity, mediated through cAMP elevation. These findings indicate FSK's multi-target therapeutic actions, mitigating inflammation, DR, and fibrosis mediated by ADCY-cAMP-Hippo/YAP axis modulation. Given its superior efficacy over UDCA, FSK represents a promising therapeutic candidate for clinical translation in CLD.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178182"},"PeriodicalIF":4.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102809","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":"Cardiac hypertrophy at the crossroads: Mechanistic insights and emerging multimodal therapeutic strategies","authors":"Dharshini Kannan ,&nbsp;Sheeja Rajasingh ,&nbsp;Parani Madasamy ,&nbsp;Johnson Rajasingh","doi":"10.1016/j.ejphar.2025.178179","DOIUrl":"10.1016/j.ejphar.2025.178179","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for approximately 17.9 million deaths annually. Among their diverse manifestations, cardiac hypertrophy is a clinically significant condition that predisposes patients to heart failure, arrhythmias, and and sudden cardiac death. Clinically, hypertrophy can be classified into three forms: physiological (adaptive) hypertrophy, which supports cardiac performance and is reversible, pathological hypertrophy most often secondary to hypertension, valvular disease, hemodynamic stress, or sustained neurohumoral activation; and hypertrophic cardiomyopathy (HCM) represents a primary genetic disorder, most often caused by mutations in sarcomeric proteins. These distinct etiologies have important therapeutic implications, as they determine how efficiently pharmacological agents can target underlying mechanisms. Conventional pharmacological treatments are widely used in clinical practice, yet they provide limited reversal of established remodeling. This therapeutic gap has driven the development of innovative modalities such as RNA-based therapeutics, exosome-mediated interventions, stem cell–derived therapies, and genome-editing technologies, which aim to modulate maladaptive signaling and restore myocardial integrity. This review integrates clinical perspectives with mechanistic insights, delineating the drivers of pathological hypertrophy while evaluating both established therapies and emerging strategies that hold promise for precision cardiology and improved patient outcomes.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178179"},"PeriodicalIF":4.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091487","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":"Role of C/EBPβ/STAT3/AP-1 transcriptional complex formation in thrombin-induced connective tissue growth factor expression in human lung fibroblasts","authors":"Hung-Sheng Hua ,&nbsp;Yi-Ting Huang ,&nbsp;Hong-Sheng Lee ,&nbsp;Chia-Hao Liu ,&nbsp;Wei Chao ,&nbsp;Bing-Chang Chen ,&nbsp;Chien-Huang Lin","doi":"10.1016/j.ejphar.2025.178178","DOIUrl":"10.1016/j.ejphar.2025.178178","url":null,"abstract":"<div><div>CCAAT/enhancer-binding protein-β (C/EBPβ) may play a key role in idiopathic pulmonary fibrosis progression. Despite this, the mechanism through which the formation of the transcriptional complex comprising C/EBPβ, signal transducer and activator of transcription 3 (STAT3), and activator protein-1 (AP-1) impacts the regulation of connective tissue growth factor (CTGF) production by thrombin in human lung fibroblasts (WI-38) is not well understood. In this study, C/EBPβ knockdown suppressed thrombin-stimulated CTGF production and CTGF-luciferase activity. The phosphorylation and cytosol-to-nucleus translocation of C/EBPβ were enhanced by thrombin. C/EBPβ knockdown attenuated thrombin-induced STAT3-and AP-1-luciferase activity. Upon thrombin stimulation, the C/EBPβ/STAT3/AP-1 complex was bound to the CTGF promoter. Both the phosphatidylinositol 3-kinase (PI3K) inhibitor and the dominant negative mutant of Akt inhibited thrombin-stimulated CTGF production, C/EBPβ phosphorylation, and C/EBPβ-luciferase activity. Furthermore, co-inhibition of the Akt, c-Jun N-terminal kinase (JNK), and Janus kinase 2 (JAK2) did not further reduce thrombin-induced C/EBPβ-luciferase activity compared to inhibition of each pathway alone. In bleomycin-induced pulmonary fibrosis, the phosphorylation of C/EBPβ, STAT3, and c-Jun in lung tissue was higher than the control group. In addition, the protein levels of C/EBPβ and CTGF, but not of c-Jun and STAT3, were higher than those in the control group. In conclusion, thrombin activates the PI3K/Akt pathway to activate C/EBPβ, which in turn induces CTGF expression in human lung fibroblasts. C/EBPβ/STAT3/AP-1 transcriptional complex formation plays an essential role in thrombin-triggered CTGF production. C/EBPβ upregulation and C/EBPβ/STAT3/AP-1 complex formation may play crucial roles in lung fibrosis and have potential for use as therapeutic targets.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178178"},"PeriodicalIF":4.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091436","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":"Tetramethylpyrazine ameliorates 5-fluorouracil-Induced cardiotoxicity by inhibiting PANoptosis and suppressing the p38 MAPK/JNK/ERK signaling pathway","authors":"Yi Xie ,&nbsp;Aling Shen ,&nbsp;Huiyun Lin ,&nbsp;Huifang Zheng ,&nbsp;Guosheng Lin ,&nbsp;Youqin Chen ,&nbsp;Ying Zhong ,&nbsp;Hongshu Liu ,&nbsp;Ying Cheng ,&nbsp;Meizhu Wu ,&nbsp;Lihui Wei ,&nbsp;Qingquan Li ,&nbsp;Jun Peng","doi":"10.1016/j.ejphar.2025.178180","DOIUrl":"10.1016/j.ejphar.2025.178180","url":null,"abstract":"<div><div>Cardiac injury is a severe complication of 5-fluorouracil (5-FU) treatment in patients with gastrointestinal tumors, underscoring the urgent need for effective therapeutic strategies. Tetramethylpyrazine (TMP), a bioactive compound derived from traditional Chinese medicine, has demonstrated promising potential for alleviating 5-FU-induced cardiotoxicity. However, the precise mechanisms underlying its cardioprotective effects remain poorly understood. This study aimed to investigate the cardioprotective effects of TMP on 5-FU-induced cardiac injury and elucidate the underlying molecular mechanisms. TMP intervention significantly alleviated 5-FU-induced cardiac injury in both <em>in vivo</em> and <em>in vitro</em> models, as evidenced by improved cardiac function, reduced histological damage, and decreased levels of injury markers (creatine kinase MB (CKMB), cardiac Troponin I (cTn-I), N-terminal pro-B-type natriuretic peptide (NT-proBNP)). RNA sequencing revealed that TMP suppressed the activation of the p38 MAPK/JNK/ERK signaling pathway in cardiac tissue following 5-FU treatment. Further <em>in vivo</em> and <em>in vitro</em> experiments confirmed that TMP treatment reduced 5-FU-induced PANoptosis in cardiomyocytes and inhibited the activation of p38 MAPK/JNK/ERK signaling pathway. The protective effects of TMP on PANoptosis were reversed by pathway activators. In conclusion, TMP alleviates 5-FU-induced cardiac injury and reduces cardiomyocyte PANoptosis via suppressing the p38 MAPK/JNK/ERK signaling pathway. These findings suggest that TMP is a promising therapeutic candidate for managing chemotherapy-induced cardiotoxicity.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178180"},"PeriodicalIF":4.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091459","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":"Liposomes-loaded miR-128-3p exert neuroprotective effects in hypoxia-ischemia injury by targeting Rgs1 in neonatal mice","authors":"Luyao Zhang ,&nbsp;Yahong Cheng ,&nbsp;Yijing Zhao ,&nbsp;Wenqiang Chen ,&nbsp;Dexiang Liu ,&nbsp;Zhen Wang","doi":"10.1016/j.ejphar.2025.178153","DOIUrl":"10.1016/j.ejphar.2025.178153","url":null,"abstract":"<div><div>Perinatal brain injury due to severe hypoxia-ischemia (HI) is a significant cause of neonatal mortality and high prevalence of long-term chronic disease on a global scale, whose clinical treatment is still limited to therapeutic hypothermia with limited efficacy. MiRNA-128 is a brain-enriched microcoding RNA that is highly expressed in the central nervous system. In this study, we found that miR-128-3p expression, a predicted down-regulated microRNA (miRNA) in GSE213067, was significantly reduced in ipsilateral cortical tissues after HI injury in pups. Then we successfully constructed a well-dispersed and uniformly sized liposome-encapsulated miR-128-3p nanoparticle (miR-128-3p@Lipo), with exhibited good stability and biosafety. Moreover, the use of a miR-128-3p@Lipo nanoparticle delivery system could simultaneously deliver miR-128-3p to neuron via a non-invasive intranasal route. Up-regulation of miR-128-3p levels in the ipsilateral cortical tissues via miR-128-3p@Lipo significantly ameliorated cerebral infarcts, apoptosis, neuroinflammation, and reactive oxygen species levels and facilitated the recovery of neurological function after HI injury in neonatal mice. Further mechanistic exploration revealed that miR-128-3p may exert neuroprotective effects by inhibiting the expression of the downstream target gene Regulating G protein signaling 1 (<em>Rgs1</em>). This work suggests that miRNAs offer a therapeutic potential to mitigate HI brain damage in neonatal mice.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178153"},"PeriodicalIF":4.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091407","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}