European journal of pharmacology最新文献

{"title":"Genetic and pharmacological evidence for a role of the ion channel TRPV2 as a regulator of actin-dependent functional traits in rat basophilic leukemia cells","authors":"Christine Herzog ,&nbsp;Pia Mülke ,&nbsp;Toni Stuhrhahn ,&nbsp;Julia A. Rocereta ,&nbsp;Ruth A. Pumroy ,&nbsp;Vera Moiseenkova-Bell ,&nbsp;Frank G. Echtermeyer ,&nbsp;Andreas Leffler","doi":"10.1016/j.ejphar.2025.178164","DOIUrl":"10.1016/j.ejphar.2025.178164","url":null,"abstract":"<div><div>The transient receptor potential ion channel TRPV2 is broadly expressed in cells originating from hematopoietic stem cells and is vital for an effective innate immunity. TRPV2 is expressed in mast cells, where it was suggested that physical stimuli activate TRPV2 to provoke physical urticaria. Given that only unselective pharmacological tools are available to study TRPV2, functional characterization of TRPV2 in mast cells remains imprecise. We studied mast cell-like rat basophilic leukemia (RBL-2H3) cells following CRISPR-Cas9-genetic deletion of TRPV2. Cells lacking TRPV2 fail to generate membrane currents induced by the nonselective TRPV-agonists 2-aminoethoxydiphenyl borate (2-APB) and probenecid (PBC), and they exhibit reduced proliferation, cell adhesion, migration and phagocytosis. While Transforming Growth Factor β1 (TGF-β1) reduces cortical actin in wildtype RBL2-2H3 cells, the basal level of cortical actin is reduced in TRPV2-knockout cells but not modified by TGF-β1. Deletion of TRPV2 reduces the numbers of membrane ruffles induced by TGF-β1, and it increases phosphorylated ERK (p-ERK) in both unstimulated and TGF-β1-treated cells. The release of β-hexosaminidase induced by IgE antigen-stimulation of FcεRI receptors does not depend on TRPV2. PBC applied alone or in combination with 2-APB, cannabidiol (CBD), or protons induce a TRPV2-dependent degranulation. The intracellular residues His165 and His521 are crucial for this pH-sensitive activation of rat TRPV2. Our data suggest that TRPV2 regulates actin-dependent mast cell-like properties of RBL2-2H3 cells. PBC can be used as a pharmacological tool to induce a TRPV2-dependent but IgE-independent degranulation, and it employs a novel molecular mechanism to activate TRPV2 in a proton-dependent manner.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178164"},"PeriodicalIF":4.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080034","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":"Molecular mechanisms and emerging therapeutics in pulmonary fibrosis: A recent update","authors":"Pragati Sharma ,&nbsp;Kajal Kumari ,&nbsp;Richa Yadav ,&nbsp;Kanika Verma ,&nbsp;Swati Paliwal ,&nbsp;Sarvesh Paliwal ,&nbsp;Swapnil Sharma","doi":"10.1016/j.ejphar.2025.178159","DOIUrl":"10.1016/j.ejphar.2025.178159","url":null,"abstract":"<div><div>Pulmonary fibrosis (PF) is a chronic, progressive, and fatal lung disorder characterized by injury to alveolar epithelial cells (AECs), the formation of activated fibroblast/myofibroblast foci, and an excessive buildup of extracellular matrix (ECM). Current treatment strategies include the administration of two main drugs, <em>viz.,</em> pirfenidone and nintedanib. However, there is no cure for PF; thus, there is a dire need to understand the pathophysiology of PF better and identify potential novel targets for PF. This review aims to provide a recent update on the signaling pathways contributing to the intricacies of cell signaling mechanisms driving fibrogenesis, including TGF-β, Hippo-YAP, NF-κB, inflammation, and Wnt/β-catenin. Additionally, the discussion covers emerging therapeutic strategies directed against such signaling networks, focusing on some of the most promising molecular strategies to halt or reverse fibrotic processes. Additionally, we discuss preclinical studies revealing the in vitro efficacy and safety, and the current clinical status of new therapeutic agents in PF. The synergy of preclinical and clinical studies' findings will allow this review to critically evaluate current therapeutic directions and emerging trends in PF management, shaping a future course of research and clinical application.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178159"},"PeriodicalIF":4.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079960","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":"2,5-Dimethoxy-4-methylamphetamine (DOM)-induced gait alterations in mice: Dissecting the role of 5-HT2A/2C receptor-mediated mechanisms","authors":"Bin Li,&nbsp;Shanshan Jiang,&nbsp;Yishan Yao,&nbsp;Gang Yu,&nbsp;Ruibin Su","doi":"10.1016/j.ejphar.2025.178170","DOIUrl":"10.1016/j.ejphar.2025.178170","url":null,"abstract":"<div><div>Psychedelics have demonstrated significant therapeutic potential in treating various psychiatric disorders; however, their effects on motor function remain poorly understood. This study investigated the impact of 2,5-dimethoxy-4-methylamphetamine (DOM), a classical phenethylamine psychedelic agent, on gait parameters in C57BL/6J mice using an active gait monitoring system. We found that 0.3–3 mg/kg DOM significantly increased locomotor velocity by enhancing stride frequency and length while reducing stance duration. These effects were accompanied by decreased plantar pressure and more concentrated paw placement patterns. High-dose DOM (10 mg/kg) suppressed voluntary locomotion, which was reversible by 5-HT_2C receptor antagonism. Pharmacological studies using subtype-selective serotonin receptor antagonists revealed that DOM's effects on gait parameters were primarily mediated through 5-HT_2A receptors. Pretreatment with 0.1 mg/kg MDL100907, but not 1 mg/kg SB242084, normalized DOM-induced gait alterations. Moreover, the antagonism of 5-HT_2A or 5-HT_2C receptor alone modified baseline gait parameters, suggesting the complex serotonergic regulation of locomotor function. These findings reveal alterations in fine gait parameters following DOM administration, expanding our understanding of the complicated effects of psychedelics.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178170"},"PeriodicalIF":4.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079962","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":"Modulation of HIF1α/CXCR4 by CDDP, acetazolamide, and salidroside in early lung injury caused by acute high-altitude hypoxia","authors":"Fei Wang ,&nbsp;Yiman Zhang ,&nbsp;Bing Liu ,&nbsp;Jia Liu ,&nbsp;Baochang Lai ,&nbsp;Pu Jia ,&nbsp;Junbo Zhang ,&nbsp;Qiang Ma ,&nbsp;Yan Meng ,&nbsp;Ye Zhao ,&nbsp;Tana Wuren ,&nbsp;Xiaohui Zheng ,&nbsp;Hongyan Tian ,&nbsp;Qian Yin","doi":"10.1016/j.ejphar.2025.178174","DOIUrl":"10.1016/j.ejphar.2025.178174","url":null,"abstract":"<div><h3>Background</h3><div>The inflammatory response of pulmonary vascular endothelial cells is critical in the pathogenesis of hypobaric hypoxia-induced acute lung injury. Elucidation of the underlying mechanisms and potential therapeutic interventions is crucial for both medical professionals and individuals exposed to high altitudes.</div></div><div><h3>Methods</h3><div>A murine model of acute lung injury was established by subjecting mice to hypobaric hypoxia at an altitude equivalent to 6000 m for 8 and 72 h. Histopathological and immunohistochemical analyses were performed using hematoxylin-eosin staining and immunohistochemistry to assess inflammation. Western blotting for Endothelial Nitric Oxide Synthase (eNOS) phosphorylation was used to evaluate endothelial injury. High-throughput RNA sequencing was employed to identify early inflammatory regulators, and the protein expression of Hypoxia inducible factor-1 (HIF1α), C-X-C chemokine receptor 4 (CXCR4) and Phospho-Endothelial Nitric Oxide Synthase (p-eNOS) was examined via western blotting. Additionally, the expression level of CXCR4 and selected cytokines were quantified by real-time Polymerase Chain Reaction.</div></div><div><h3>Results</h3><div>Lung tissues demonstrated marked inflammatory infiltration and lung injury after 8 h of hypobaric hypoxia exposure, peaking at 24 h. HIF1α expression was significantly upregulated at 8 h and gradually decreased thereafter. CXCR4, identified as a target gene of HIF1α, exhibited a similar expression pattern. Preventive treatment with compound Danshen dripping pills, acetazolamide and salidroside accelerated the suppression of HIF1α and CXCR4 expression compared to the natural response following 8 h of hypobaric hypoxia. Furthermore, these agents demonstrated enhanced protective effects against endothelial dysfunction and inflammation.</div></div><div><h3>Conclusions</h3><div>These findings indicate that the endothelial HIF1α/CXCR4 axis plays a pivotal role in the early phase of hypobaric hypoxia-induced acute lung injury. The downregulation of HIF1α/CXCR4 by compound Danshen dripping pills, acetazolamide and salidroside suggests promising therapeutic strategies for managing acute high-altitude hypoxic lung injury.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178174"},"PeriodicalIF":4.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079979","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":"Comparison of clopidogrel monotherapy versus prolonged DAPT based on the GRACE risk score in patients with acute coronary syndromes at high ischemic and bleeding risk: a subgroup analysis of the OPT-BIRISK randomized clinical trial","authors":"Shiyu Zhang ,&nbsp;Jing Li ,&nbsp;Miaohan Qiu ,&nbsp;Yi Li ,&nbsp;Xiaozeng Wang ,&nbsp;Zhifang Wang ,&nbsp;Shuhong Su ,&nbsp;Yaojun Zhang ,&nbsp;Aijun Liu ,&nbsp;Yaling Han","doi":"10.1016/j.ejphar.2025.178151","DOIUrl":"10.1016/j.ejphar.2025.178151","url":null,"abstract":"<div><h3>Objective</h3><div>This study assessed the effect of clopidogrel monotherapy versus extended Dual antiplatelet therapy (DAPT) on outcomes in patients with acute coronary syndromes (ACS) who have completed 9–12 months of DAPT after Percutaneous Coronary Intervention (PCI) and meet both high bleeding and high ischemia risk (birisk), stratified by Global Registry of Acute Coronary Events (GRACE) risk score.</div></div><div><h3>Methods</h3><div>In the OPT-BIRISK study, 7758 ACS Patients who completed 9–12 months of DAPT after PCI were randomized either to clopidogrel monotherapy or extended DAPT. This prespecified subgroup analysis categorized patients by GRACE score into intermediate-high-risk (&gt;88) and low-risk (≤88) groups. The primary endpoint of the study was BARC 2, 3, or 5 bleeding. The key secondary endpoint was the rate of major adverse cardio-cerebral events (MACCE; the composite of all-cause death, myocardial infarction, stroke or clinically driven revascularization).</div></div><div><h3>Findings</h3><div>In low-risk patients, BARC 2, 3, or 5 bleeding occurred in 49 (2.7 %) with clopidogrel monotherapy versus 69 (3.6 %) with extended DAPT (HR 0.73, 95 % CI 0.50–1.05; p = 0.088).In intermediate-high-risk patients, clopidogrel monotherapy versus extended DAPT showed comparable BARC 2, 3, or 5 bleeding (2.3 % vs. 3.0 %; HR 0.77, 95 % CI 0.52–1.14; p = 0.8377), but significantly reduced MACCE (2.9 % vs. 4.1 %; HR 0.69, 95 % CI 0.49–0.97; p = 0.0332). In the overall trial population, there was no significant interaction between the GRACE score and treatment group for the primary or key secondary endpoints (P &gt; 0.05 for all outcomes).</div></div><div><h3>Conclusions</h3><div>Among birisk patients with ACS, clopidogrel monotherapy was associated with lower incidence of all bleeding events (BARC 1–5) versus extended DAPT regardless of GRACE score, but showed no significant difference in BARC 2, 3, or 5 bleeding. Moreover, it was associated with lower MACCE incidence versus extended DAPT in intermediate-high-risk groups.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178151"},"PeriodicalIF":4.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069010","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":"Spotlight on membrane fluidity of normal and cancer cells: Implications for cancer diagnosis and treatment","authors":"Roberto Canaparo,&nbsp;Federica Foglietta,&nbsp;Carlo Della Pepa,&nbsp;Loredana Serpe","doi":"10.1016/j.ejphar.2025.178152","DOIUrl":"10.1016/j.ejphar.2025.178152","url":null,"abstract":"<div><div>Membrane fluidity is crucial for cellular function, signalling, and adaptation. Healthy cells maintain strict control over membrane fluidity through homeostatic mechanisms such as lipid-protein interactions, phospholipid asymmetry and cholesterol distribution. In contrast, cancer cells exhibit profound dysregulation. Altered lipid metabolism, increased incorporation of unsaturated fatty acids and disrupted cholesterol homeostasis create a more fluid and dynamic membrane environment, thereby enhancing oncogenic signalling, mechanotransduction and immune evasion. These changes are key drivers of cancer behaviours, including enhanced proliferation, resistance to apoptosis and metastasis.</div><div>This review explores the biophysical basis of membrane fluidity, examining its dual role as a diagnostic biomarker and a therapeutic target in cancer. Advanced imaging techniques, such as fluorescence recovery after photobleaching (FRAP), fluorescence lifetime imaging microscopy (FLIM) and electron spin resonance (ESR), enable precise measurement of membrane fluidity, revealing cancer-specific alterations. These tools provide high-resolution insights into lipid organization and protein mobility, facilitating improved cancer diagnostics and therapeutic response monitoring. Emerging therapeutic strategies exploit membrane fluidity to selectively induce cancer cell death. These strategies include modulating cholesterol levels, using lipid metabolism inhibitors, and activating sonosensitisers, intracellular responsive chemical agents that generate reactive oxygen species, using ultrasound by sonodynamic therapy.</div><div>Despite these advances, there are still challenges in translating membrane-targeted strategies into clinical practice, primarily due to tumour heterogeneity and the complex relationship between lipid dynamics and protein function. Future research must integrate lipidomics, biophysics, and oncology to exploit membrane fluidity as a biomarker and therapeutic target, paving the way for more precise cancer treatments.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178152"},"PeriodicalIF":4.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057384","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":"Mutational effects of the asparagine198 and glutamate223 residues on the human norepinephrine transporter on basal and HIV-1 Tat protein-induced inhibition of dopamine transport","authors":"Katherine Darby Porter ,&nbsp;Charles Adeniran ,&nbsp;Ana Catya Jimenez-Torres ,&nbsp;Karl Lee Pless ,&nbsp;Abagail Brenda Cirincione ,&nbsp;Harper Davenport ,&nbsp;Carolyn Chen ,&nbsp;Chang-Guo Zhan ,&nbsp;Jun Zhu","doi":"10.1016/j.ejphar.2025.178131","DOIUrl":"10.1016/j.ejphar.2025.178131","url":null,"abstract":"<div><div>HIV-1 transactivator of transcription (Tat) protein induces dopaminergic dysregulation, which plays a central role in HIV-1-associated neurocognitive disorders. Computational modeling predicts that asparagine 198 and glutamate 223 of the human norepinephrine transporter (hNET) are key residues involved in Tat binding. This study investigated the effects of N198A and E223A mutations on basal and Tat-induced inhibition of dopamine (DA) uptake via hNET in CHO cells expressing WT hNET or its mutants. Compared to WT hNET, E223A mutation increased the affinity for nisoxetine and cocaine in inhibiting [³H]DA uptake. However, N198A and E223A decreased the affinity for cocaine inhibiting [³H]WIN35,428 binding, without altering the [³H]WIN35,428 binding under control. Kinetic analysis of [³H]DA uptake revealed that N198A and E223A did not alter the affinity for DA uptake but reduced the maximal velocity compared to WT hNET. An optimization study using recombinant Tat_1-86 at 0.25–140 nM revealed a K_i of 3.4 nM for inhibiting hNET-mediated DA uptake, with inhibition plateauing at above 8.75 nM. Treatment with 140 nM recombinant Tat_1-86 resulted in a 34 % reduction in [³H]DA uptake in WT hNET, which was attenuated in the N198A mutant but remained unchanged in E223A. However, the inhibition of [³H]DA uptake by 8.75 nM rTat_1-86 in WT hNET was attenuated in N198A and E223A. Moreover, N198A and E223A altered transporter conformational dynamics, as evidenced by changing the efflux of [³H]DA and [³H]MPP+. Collectively, these findings support the role of asparagine198 and glutamate223 as essential recognition residues in Tat-induced inhibition of DA uptake through hNET.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178131"},"PeriodicalIF":4.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063824","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":"Effects of dibenzazepine compounds on Nav1.2 channels and neuronal network activity: A systematic comparison","authors":"Kunihiko Araki ,&nbsp;Merlin Felix Schwering-Sohnrey ,&nbsp;Griselda Marku ,&nbsp;Michael Wenzel ,&nbsp;Susanne Schoch ,&nbsp;Thoralf Opitz ,&nbsp;Heinz Beck","doi":"10.1016/j.ejphar.2025.178147","DOIUrl":"10.1016/j.ejphar.2025.178147","url":null,"abstract":"<div><div>Voltage-gated Na⁺ channels are critical therapeutic targets of anti-seizure medications. The anti-seizure medications such as carbamazepine (CBZ), oxcarbazepine (OXC) and eslicarbazepine acetate (ESL) of the dibenzazepine family are structurally similar, but a comparative analysis under identical conditions is lacking. Here, we rigorously compared their effects on biophysical properties of Na_v1.2 Na ⁺ channels and effects on network properties in primary neuron cultures. HEK 293T cells stably expressing human Na_v1.2 channels were employed to assess biophysical profiles using whole-cell patch clamp techniques. Additionally, the impact on neuronal networks in primary cortical neurons was evaluated using microelectrode array recordings. CBZ and OXC exhibited similar effects on voltage-dependent fast inactivation and recovery from inactivation. ESL and its active metabolite S-licarbazepine (S-Lic) also influenced fast inactivation, but their effects were less pronounced than those observed with CBZ. Notably, S-Lic exhibited comparatively small effects on use-dependent block. In these in vitro settings, all compounds had a subtle effect on slow inactivation. With regards to neuronal network activity, CBZ, OXC, and ESL induced substantial changes in spiking, bursting, and synchrony. S-Lic elicited significant and selective effects on network synchrony without effects on other parameters. In conclusion, CBZ, OXC and ESL exhibited similar activity profiles on properties of Na_v1.2 channels and neuronal networks. The structurally similar S-Lic showed significantly less use-dependent blocking effect, and a selective effect on distributed network bursts. These results emphasize that structurally similar dibenzazepine anti-seizure medications can exhibit substantial differences in activity on the ion channel and network level.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178147"},"PeriodicalIF":4.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060744","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":"Analysis of pulmonary adverse events associated with immune checkpoint inhibitors based on FAERS and VigiBase database","authors":"Zi-Mu Li ,&nbsp;Yi-Fan Zheng ,&nbsp;Pei-Hang Xu ,&nbsp;Ji-Yu Wang ,&nbsp;Rong-ling He ,&nbsp;Hui-Xia Li ,&nbsp;Yu -Kun Kuang ,&nbsp;Li-Hong Bai ,&nbsp;Ke-Jing Tang","doi":"10.1016/j.ejphar.2025.178156","DOIUrl":"10.1016/j.ejphar.2025.178156","url":null,"abstract":"<div><div>This study investigates pulmonary immune-related adverse events (pirAEs) in patients undergoing immune checkpoint inhibitors (ICIs), including anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies. Reports for pirAEs from the Food and Drug Administration Adverse Event Reporting System (FAERS) and the World Health Organization Global Database on Case Safety Reporting (VigiBase) between the first quarter of 2015 and the second quarter of 2020 were analyzed.16,372 and 7,943 individual case safety reports (ICSRs)were collected using FAERS database and VigiBase database, respectively. More than 50 % of pirAEs occurred within 60 days after treatment with ICIs, and their mortality was higher than that after 60 days. In each period after the use of ICIs, pirAEs with the highest incidence were interstitial lung disease, dyspnoea, and pneumonitis. The all-cause mortality of respiratory failure, pulmonary hemorrhage, acute interstitial pneumonitis, and stridor was over 25 %. The mortality of respiratory failure remained stable at a high level in each period after initiation of immunotherapy, of which the mortality was still 40 % after one year of initiation of immunotherapy. This study can better help physicians understand the types and mortality rate of pirAEs at each period after using such drugs, particularly during the initial 60 days of ICI therapy, so as to achieve early identification and treatment.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178156"},"PeriodicalIF":4.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063784","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":"Dual acting inhibitor of soluble epoxide hydrolase and Cyclooxygenase-2, attenuates glomerular injury in renal hypoplasia mice","authors":"Md Abdul Hye Khan ,&nbsp;Samaneh Goorani ,&nbsp;Anna Atamanchuk ,&nbsp;Wojceich Jankiewicz ,&nbsp;Michael M. Yeboah ,&nbsp;Scott D. Barnett ,&nbsp;John R. Falck ,&nbsp;Sung H. Hwang ,&nbsp;Bodgan Barnych ,&nbsp;Bruce D. Hammock ,&nbsp;Ashraf El-Meanawy ,&nbsp;John D. Imig","doi":"10.1016/j.ejphar.2025.178132","DOIUrl":"10.1016/j.ejphar.2025.178132","url":null,"abstract":"<div><div>Glomerular diseases like focal and segmental glomerulosclerosis (FSGS) are the leading cause of chronic and end-stage kidney diseases. Although FSGS is associated with high morbidity and mortality, available treatments are limited, which emphasizes the need for novel therapy. We developed a dual inhibitor, PTUPB, that concurrently acts as a soluble epoxide hydrolase (sEH) inhibitor and a cyclooxygenase-2 (COX-2) inhibitor. In the current study, we investigated renal actions of PTUPB in a genetic renal hypoplasia FSGS model, ROP <em>Os</em>/+ mice. ROP <em>Os</em>/+ mice developed albuminuria and glomerular injury between 16 and 20 weeks of age with an 8-fold higher albumin/Cr ratio than wild-type ROP +/+ mice. Three groups were assessed: 20-week-old ROP +/+ mice, ROP <em>Os</em>/+ mice treated with vehicle, and ROP <em>Os</em>/+ mice treated with PTUPB (10 mg/kg/d, i.p.). After 4 weeks, urine, blood, and kidney tissue were collected in the mice groups for biochemical, molecular, and histological analysis. ROP <em>Os</em>/+ mice had 10-fold higher albuminuria than ROP +/+ mice, and PTUPB treatment markedly attenuated albuminuria in ROP <em>Os</em>/+ mice by 69 %. ROP <em>Os</em>/+ mice developed a glomerular injury with a 3-fold higher glomerular injury score and 10-fold higher glomerular expression of sclerotic marker fibronectin than ROP +/+ mice, and PTUPB treatment attenuated these by 40–50 %. We further demonstrated that there was significantly lower renal mRNA expression of nephrin, podocin, podoplanin, synaptopodin, and glomerular WT1 immunopositive cells in ROP <em>Os</em>/+ mice which was improved by PTUPB treatment in these mice. Glomerular permeability studies in isolated glomeruli determined that COX-2 metabolites of 8,9-epoxyeicosatrienoic acid (EET) increased glomerular permeability. PTUPB, 8,9-EET, or 8,9-EET analogs prevented angiotensin II-induced glomerular permeability and mesangial cell proliferation. These findings demonstrate that COX-2 metabolites harm the glomerulus, whereas 8,9-EET improves glomerular function. Lastly, kidney fibrosis and inflammation were increased in ROP <em>Os</em>/+ mice compared to ROP +/+ mice. PTUPB treatment to ROP <em>Os</em>/+ mice decreased kidney fibrosis and inflammation. These findings demonstrate that the dual inhibitor PTUPB that concurrently inhibits sEH and COX-2 is a potential treatment for FSGS and related glomerular diseases.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178132"},"PeriodicalIF":4.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060745","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}