European journal of pharmacology最新文献

{"title":"Effects of sitagliptin combined with GTS-21 on improving glycemic control and diabetic nephropathy by anti-apoptosis in Lepr^db/db mice.","authors":"Weikun Tian, Wenzhao Wang, Shuo Tang, Liye Su, Robert Cooney, Xinghan Tian, Qinghe Meng","doi":"10.1016/j.ejphar.2026.179426","DOIUrl":"10.1016/j.ejphar.2026.179426","url":null,"abstract":"<p><strong>Objective: </strong>Activation of α7 nicotinic acetylcholine receptor (α7nAChR) by GTS-21 engages the cholinergic anti-inflammatory pathway (CAP). This study investigated adding GTS-21 to sitagliptin, a DPP-4 inhibitor used to increase endogenous GLP-1, confers additional benefit over sitagliptin monotherapy on glycemic control and diabetic nephropathy (DN) in Leprdb/db mice, focusing on anti-apoptotic mechanisms.</p><p><strong>Methods: </strong>Leptin receptor-deficient (Lepr^db/db, 8-week-old) mice were randomized into control (saline), sitagliptin (20 mg/kg), or combination (sitagliptin 20 mg/kg + GTS-21 4 mg/kg) groups for 4 weeks. Oral glucose tolerance test (OGTT), serum creatinine (Scr), blood urea nitrogen (BUN), and IL-6 were measured. Renal histology was evaluated by H&E staining. Apoptosis was assessed by TUNEL staining and cleaved caspase-3 expression. In vitro, HK-2 cells exposed to high glucose (30 mM) were treated with liraglutide (100 nM) and/or GTS-21 (20 nM) to examine apoptosis.</p><p><strong>Results: </strong>Combination therapy significantly improved glucose tolerance at weeks 1 and 4 (AUC reduction, P = 0.0366 and P = 0.0435 vs control), whereas sitagliptin alone showed no effect. Both treatments reduced Scr (P = 0.0002 for combination; P = 0.0101 for monotherapy), but only combination therapy attenuated renal histological injury (P = 0.002) and decreased IL-6 in serum and kidney (P = 0.0433 and P = 0.0041). Renal apoptosis was also suppressed, with reduced TUNEL-positive cells (P = 0.0043) and cleaved caspase-3 (P = 0.0122). In HK-2 cells, high glucose increased cleaved caspase-3 (P = 0.0324), which was attenuated by liraglutide plus GTS-21 (P = 0.0320).</p><p><strong>Conclusions: </strong>Add-on GTS-21 to sitagliptin improved glycemic control and attenuated diabetic nephropathy beyond sitagliptin monotherapy in Leprdb/db mice, with reduced renal inflammation and suppressed apoptosis. These findings suggest that combined activation of GLP-1 receptor and α7nAChR signaling warrants further investigation as a renoprotective strategy in diabetic nephropathy.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"179426"},"PeriodicalIF":5.7,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180239","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":"Environmental enrichment preserves intestinal endocannabinoid signaling under LPS-inflammatory conditions.","authors":"Giovanna Rigillo, Cristina Benatti, Veronica Rivi, Miriam Ciani, Isabella Martusciello, Federico Imbeni, Joan Mc Blom, Luca Pani, Silvia Alboni, Fabio Tascedda","doi":"10.1016/j.ejphar.2026.179441","DOIUrl":"10.1016/j.ejphar.2026.179441","url":null,"abstract":"<p><p>Environmental factors critically influence intestinal homeostasis, yet the molecular mechanisms underlying these effects remain incompletely understood. The endocannabinoid system (ECS), a key regulator of immune, metabolic, and epithelial functions, has emerged as a promising pharmacological target in inflammatory disorders. However, whether environmental context influences intestinal ECS signaling and the coordinated mechanisms underlying intestinal homeostasis during inflammation remains unclear. This study investigated the impact of environmental enrichment (EE) on intestinal ECS regulation in the context of impaired intestinal homeostasis during lipopolysaccharide (LPS)-induced systemic inflammation. Adult male mice were housed under standard or enriched conditions for four weeks before LPS challenge (830 μg/kg, i.p., 24 h). ECS receptors (Cnr1, Cnr2), ECS-related targets (Trpv1, Pparγ), metabolic enzymes (Nape-pld, Dagl-β, Faah, Magl), inflammatory mediators (Tlr4, Tnf-α, Il-6), epithelial barrier markers (Ocln, Zo-1), endocannabinoid levels (AEA and 2-AG), selected bacterial taxa, and microbiota-derived metabolites were evaluated in the proximal colon. LPS induced coordinated changes in the intestinal ECS-related measures, endocannabinoid levels, inflammatory signaling, barrier-associated markers, and the selected microbial-metabolic profile. EE mitigated several of these changes, including ECS-related transcriptional and protein alterations and local inflammatory responses, while modulating tight-junction proteins, selected fecal bacterial taxa, microbiota-derived metabolites, and the integrated multivariate profile. Overall, EE modulates intestinal response profile consistent with greater resilience to inflammatory stress across ECS, inflammatory, barrier-associated, and microbial-metabolic measures. These findings suggest that ECS regulation may represent a context-dependent determinant of responsiveness to ECS-targeting pharmacological interventions.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"179441"},"PeriodicalIF":5.7,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180295","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":"Biased 5-HT_1A agonist NLX-101 improves executive function under NMDA receptor hypofunction and preferentially enhances cortical ERK2 phosphorylation.","authors":"Angelika Jagielska, Aleksandra Koszałka, Sameh Abouzahra, Klaudia Lustyk, Kinga Sałaciak, Jan Detka, Antonia Gurgone, Riccardo Pizzo, Maurizio Giustetto, Adrian Newman-Tancredi, Marcin Kołaczkowski, Karolina Pytka","doi":"10.1016/j.ejphar.2026.179439","DOIUrl":"10.1016/j.ejphar.2026.179439","url":null,"abstract":"<p><p>Cognitive inflexibility and working memory deficits are major contributors to functional impairment in neuropsychiatric disorders and remain insufficiently addressed by current treatments. NLX-101, a preferential postsynaptic 5-HT_1A receptor biased agonist, engages cortical serotonergic signaling and ERK1/2-related pathways, offering a mechanistically distinct approach to improving prefrontal cortex-dependent cognition. Here, we examined whether NLX-101 counteracts executive function deficits induced by NMDA receptor blockade in BALB/c mice. Working memory was assessed using the 8-arm radial maze, whereas cognitive flexibility was evaluated in a touchscreen-based visual discrimination/reversal learning task. Repeated oral administration of NLX-101 improved MK-801-induced working memory deficits and enhanced reversal learning performance, particularly during the later phase of contingency updating. These behavioral effects were accompanied by preferential enhancement of ERK2 phosphorylation in the prefrontal cortex, consistent with the biased signaling profile of NLX-101. In the touchscreen task, NLX-101 produced clearer improvement than vortioxetine under the dosing and timing conditions used here. Together, these findings identify NLX-101 as a promising pharmacological tool for improving executive dysfunction associated with impaired glutamatergic transmission and support further investigation of biased cortical 5-HT_1A receptor signaling as a therapeutic strategy for cognitive symptoms in neuropsychiatric disorders.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"179439"},"PeriodicalIF":5.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180282","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":"Epigenetic insights into anti-tuberculosis drug-induced liver injury: A systematic review of DNA methylation as a potential biomarker.","authors":"Hoang Dat Nguyen, Noppadol Chanhom, Jiraphun Jittikoon, Usa Chaikledkaew, Wanvisa Udomsinprasert","doi":"10.1016/j.ejphar.2026.179389","DOIUrl":"10.1016/j.ejphar.2026.179389","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) remains a major clinical challenge that may cause acute liver failure, chronic liver disease, and treatment discontinuation. DNA methylation, a key epigenetic mechanism regulating gene expression, has emerged as a potential biomarker of DILI susceptibility; however, clinical evidence is largely confined to anti-tuberculosis drug-induced liver injury (ATDILI). This systematic review evaluated associations between DNA methylation patterns and DILI risk, with emphasis on ATDILI. Searches of PubMed, Scopus, and Embase identified eight eligible case-control studies published between 2014 and 2024. ATDILI-associated hypermethylation was reported in N-acetyltransferase-2 (NAT2), cytochrome P450 family-2 subfamily E member-1 (CYP2E1), cytochrome P450 family-2 subfamily D member-6 (CYP2D6), cytochrome P450 family-1 subfamily A member-1 (CYP1A1), glutathione S-transferase pi-1 (GSTP1), hypoxia-inducible factor-1 alpha (HIF1α), and 5-aminolevulinate synthase-1 (ALAS1). Global hypomethylation of repetitive elements, including LINE-1, SINE, and ALU, was also associated with increased ATDILI risk. Genome-wide analyses identified potential markers in tetratricopeptide repeat, ankyrin repeat, and coiled-coil containing-1 (TANC1), solute carrier family-8 member A-2 (SLC8A2), proline-serine-threonine phosphatase-interacting protein-2 (PSTPIP2), and adenylate kinase-2 (AK2). These findings support DNA methylation as a potential biomarker of ATDILI susceptibility and personalized risk assessment. However, because all evidence derives from case-control studies, causal and temporal relationships remain uncertain. Prospective longitudinal studies, epigenome-wide analyses, multi-omics integration, mechanistic validation, and large-scale replication are needed to confirm these associations and establish their predictive and clinical utility.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"179389"},"PeriodicalIF":5.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180268","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":"Effectiveness and Safety of Target-Specific RNA-Based Lipid-Lowering Therapies: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.","authors":"Jordan Steven Widjaja, Arga Setyo Adji, Aufa Baraja, Alan Dharmasaputra, Ragil Nur Rosyadi, Intan Komalasari, Ali Mustofa, Chaq El Chaq Zamzam Multazam, Firas Farisi Alkaff, Pandit Bagus Tri Saputra","doi":"10.1016/j.ejphar.2026.179420","DOIUrl":"https://doi.org/10.1016/j.ejphar.2026.179420","url":null,"abstract":"<p><p>RNA-based therapies target distinct pathways involved in lipid metabolism and may therefore exhibit differential pharmacological effects according to their molecular targets. However, comparative evidence regarding the effectiveness and safety of these target-specific therapies remains limited. This study aimed to evaluate the effectiveness and safety of PCSK9-, APOC3-, and ANGPTL3-targeting RNA-based therapies in patients with hyperlipidemia or hypertriglyceridemia. We conducted a systematic review and meta-analysis of randomized controlled trials comparing inclisiran, olezarsen, plozasiran, or zodasiran with placebo. Treatment effects were expressed as mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs), and pooled analyses were stratified according to molecular target. Sixteen randomized controlled trials involving 6,982 participants were included. PCSK9-targeting therapy produced the greatest reductions in LDL-C (MD -53.01 mg/dL, 95% CI -57.56 to -48.45), ApoB (MD -39.59 mg/dL, 95% CI -43.33 to -35.85), and non-HDL-C (MD -44.62 mg/dL, 95% CI -47.73 to -41.51), whereas APOC3-targeting therapies produced the greatest reduction in triglycerides (MD -52.26 mg/dL, 95% CI -56.50 to -48.02). Total adverse events, serious adverse events, and adverse events leading to treatment discontinuation were comparable between RNA-based therapies and placebo. Overall, these findings indicate that RNA-based lipid-lowering therapies exhibit target-specific pharmacological effects, with PCSK9 inhibition predominantly reducing atherogenic lipoproteins and APOC3 inhibition producing greater triglyceride lowering. Although the overall safety profile was comparable with placebo, differences in individual adverse outcomes and the limited availability of long-term clinical outcome data highlights the need for further investigation.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"179420"},"PeriodicalIF":5.7,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164582","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":"Systemic Modulation of Group II mGluRs Increases Extracellular Lactate in the Rat Prefrontal Cortex.","authors":"Yujiro Ikegaki, Hiroko Itoh, Takanori Senoo, Daisuke Sumita, Tatsuya Nagasawa, Eiji Ikeda, Tsutomu Takahashi, Takashi Uehara","doi":"10.1016/j.ejphar.2026.179390","DOIUrl":"https://doi.org/10.1016/j.ejphar.2026.179390","url":null,"abstract":"<p><strong>Background: </strong>Lactate is increasingly recognized as a dynamic indicator of neuronal activity and brain energy metabolism and is closely linked to glutamatergic neurotransmission via the astrocyte-neuron lactate shuttle. Group II metabotropic glutamate receptors (mGluR2/3) regulate glutamate release and have been implicated in psychiatric disorders; however, their role in cortical lactate metabolism remains unclear.</p><p><strong>Methods: </strong>In this study, we examined the effects of pharmacological modulation of mGluR2/3 on extracellular lactate concentration (eLAC) in the medial prefrontal cortex of naïve rats using in vivo microdialysis. Systemic administration of an mGluR2/3 agonist (LY354740), an mGluR2 positive allosteric modulator (LY487379) and selective antagonists were evaluated. To explore the potential involvement of mGluR3 in cortical metabolism, we evaluated the effects of 2-PMPA, a glutamate carboxypeptidase II (GCP-II) inhibitor that increases endogenous levels of N-acetylaspartylglutamate (NAAG), which preferentially activates mGluR3 over mGluR2.</p><p><strong>Results: </strong>Systemic administration of LY354740 or LY487379 unexpectedly increased eLAC. These effects of LY354740 and LY487379 were prevented by the mGluR2 antagonist Ro 64-5229. In addition, systemic administration of 2-PMPA increased eLAC, and this effect was blocked by LY341495, an mGluR2/3 antagonist.</p><p><strong>Conclusions: </strong>These findings indicate that systemic modulation of group II mGluRs may engage indirect network-level mechanisms that influence cortical energy metabolism. These results provide new insight into the relationship between glutamatergic signaling and brain metabolic dynamics.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"179390"},"PeriodicalIF":5.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148261","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":"Farnesol mitigates post-infarction ventricular remodeling via pharmacological modulation of the SPHK2/S1P/SMAD3 axis.","authors":"Chanyuan Su, Hang Chen, Yuanming Yan, Beilei Li, Qin Chen, Zhaoyang Chen, Yukun Luo","doi":"10.1016/j.ejphar.2026.179343","DOIUrl":"https://doi.org/10.1016/j.ejphar.2026.179343","url":null,"abstract":"<p><p>Pathological ventricular remodeling following myocardial infarction (MI) is driven by dysregulated pro-fibrotic signaling and metabolic maladaptation. This study aimed to investigate whether farnesol, an endogenous mevalonate pathway intermediate with cardioprotective properties, mitigates post-MI fibrotic remodeling by pharmacologically modulating sphingolipid metabolism. MI was induced in C57BL/6 mice via permanent coronary artery ligation, followed by daily intragastric administration of farnesol (2 mg/kg) for 14 days. Cardiac structural and functional indices, alongside inflammatory and fibrotic cascades, were evaluated. The underlying molecular mechanisms were elucidated using transcriptomic and untargeted metabolomic profiling. In vivo target validation was achieved through pharmacological blockade of sphingosine kinase 2 (SPHK2) using opaganib. Farnesol treatment significantly preserved left ventricular systolic function and attenuated interstitial fibrosis. At the cellular level, farnesol facilitated inflammatory resolution by reducing acute neutrophil infiltration and promoting reparative M2 macrophage polarization, while restraining aberrant myofibroblast activation. Multi-omics integration revealed that farnesol modulated sphingolipid metabolism by selectively upregulating SPHK2 and increasing sphingosine-1-phosphate (S1P) synthesis. Activation of the SPHK2/S1P axis subsequently attenuated pro-fibrotic signaling via transforming growth factor-beta (TGF-β)/SMAD3. Crucially, targeted in vivo inhibition of SPHK2 with opaganib substantially reversed farnesol-induced suppression of SMAD3 and its downstream cardioprotective effects. These findings suggest that farnesol confers cardioprotection against post-MI remodeling, an effect closely associated with the pharmacological upregulation of the SPHK2/S1P axis and the subsequent attenuation of TGF-β/SMAD3-mediated fibrogenesis. Together, these findings highlight crosstalk between the mevalonate and sphingolipid pathways, supporting modulation of SPHK2 as a potential therapeutic strategy for the clinical management of post-MI heart failure.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"179343"},"PeriodicalIF":5.7,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982435","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":"Sodium butyrate alleviates neuronal ferroptosis after gas explosion-induced traumatic brain injury via regulation of JNK/P38 MAPK signaling pathway","authors":"Xinwen Dong,&nbsp;Zheng Luo,&nbsp;Cuiying Li,&nbsp;Jie Gao,&nbsp;Yue Ma,&nbsp;Xiaoran Ma,&nbsp;Jiahang Yang,&nbsp;Sanqiao Yao,&nbsp;Weidong Wu,&nbsp;Yichun Bai,&nbsp;Qunwei Zhang,&nbsp;Wenjie Ren","doi":"10.1016/j.ejphar.2026.179263","DOIUrl":"10.1016/j.ejphar.2026.179263","url":null,"abstract":"<div><div>This study investigated the neuroprotective effects of sodium butyrate (NaB) against gas explosion (GE)-induced traumatic brain injury (TBI), with particular emphasis on its modulation of ferroptosis. GE exposure was simulated using a shock tube <em>in vivo</em> and a shockwave therapy instrument <em>in vitro</em>. A comprehensive assessment was performed, including behavioral tests, histopathological examination, molecular analyses (c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK), solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4), and interleukin-6 (IL-6)/interleukin-10 (IL-10)/tumor necrosis factor-α (TNF-α)), and <em>in vitro</em> validation using a CTX TNA2 rat astrocyte/H19-7 rat hippocampal neuron/GMI-R1 rat microglia (CTX/H19-7/GMI-R) tri-culture system. Pharmacological inhibition with SP600125 (a JNK inhibitor), SB203580 (a p38 MAPK inhibitor), and ferrostatin-1 (Fer-1, a ferroptosis inhibitor) was employed to confirm pathway involvement. GE exposure induced profound neuropathological changes, characterized by mitochondrial cristae disruption, inflammatory cell infiltration, and locomotor deficits. At the molecular level, GE exposure activated the JNK/p38 MAPK pathway (as evidenced by increased JNK and p38 phosphorylation), triggered ferroptosis (elevated Fe²⁺ and malondialdehyde levels, with reduced GPX4 and SLC7A11 expression), and elicited a pro-inflammatory response (increased IL-6 and TNF-α, decreased IL-10). NaB administration effectively counteracted these deleterious effects by restoring redox homeostasis, suppressing JNK/p38 MAPK activation, and rebalancing inflammatory cytokine profiles. Notably, co-administration of pathway inhibitors potentiated the protective effects of NaB, further corroborating the involvement of JNK/p38 MAPK-mediated ferroptosis in GE-induced TBI. Collectively, these findings indicate that NaB attenuates GE-induced TBI and ferroptosis, likely through inhibition of the JNK/p38 MAPK signaling pathway.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1033 ","pages":"Article 179263"},"PeriodicalIF":5.7,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148780581","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":"Astragaloside IV attenuates atherosclerosis by regulating endothelial mitophagy and oxidative stress via the Nrf2/PINK1/Parkin pathway","authors":"Chang Chai,&nbsp;Dandan Liu,&nbsp;Yanjie Li,&nbsp;Yang Gao,&nbsp;Yiting Zhao,&nbsp;Hewei Qin","doi":"10.1016/j.ejphar.2026.179150","DOIUrl":"10.1016/j.ejphar.2026.179150","url":null,"abstract":"<div><div>Astragaloside IV (AS-IV) exhibits cardiovascular protective effects, but its role in mitochondrial quality control during atherosclerosis remains unclear. This study evaluated whether AS-IV attenuates atherosclerosis by regulating the nuclear factor erythroid 2-related factor 2 (Nrf2)–PTEN-induced putative kinase 1 (PINK1)/Parkin pathway. High-fat diet-fed apolipoprotein E-deficient (ApoE^−/−) mice and oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs) were used as in vivo and in vitro models. AS-IV reduced aortic plaque burden and alleviated endothelial injury in ApoE^−/− mice. In HUVECs, AS-IV decreased oxidative stress and improved mitochondrial function, accompanied by enhanced mitophagy. Mechanistically, AS-IV promoted Nrf2 nuclear translocation and upregulated the PINK1/Parkin axis. Silencing Nrf2 or PINK1, or pharmacological inhibition of Nrf2 with ML385, abolished the cytoprotective effects of AS-IV and suppressed mitophagy. Molecular docking and molecular dynamics simulations provided supportive structural context for a plausible AS-IV pose within the Kelch-like ECH-associated protein 1 (Keap1) pocket in the simulated system. Mechanistically, AS-IV appears to mitigate atherosclerotic progression by promoting Nrf2-driven, PINK1/Parkin-dependent mitophagy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179150"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal ketamine alleviates depressive-like behaviors in chronic unpredictable mild stress rats in association with hypothalamic NADH:Ubiquinone oxidoreductase subunit A10","authors":"Yongning Lv,&nbsp;Zihe Yang,&nbsp;Linjie Li,&nbsp;Yusen Xu,&nbsp;Yanjie Qin,&nbsp;Bin Deng,&nbsp;Xuejia Zhai","doi":"10.1016/j.ejphar.2026.179153","DOIUrl":"10.1016/j.ejphar.2026.179153","url":null,"abstract":"<div><div>Intranasal ketamine represents a rapid and minimally invasive antidepressant strategy, yet the molecular mechanisms underlying its antidepressant-like effects after intranasal administration remain incompletely understood. Male Sprague–Dawley rats were subjected to a 28-day chronic unpredictable mild stress (CUMS) paradigm and then received intranasal racemic ketamine at 8.58 mg/kg twice weekly for 14 days, with four administrations in total. Depressive-like behaviors were evaluated using the open-field, sucrose preference, and forced swimming tests. Hypothalamic histological alterations and synaptic and mitochondrial integrity were examined by Hematoxylin and eosin staining, Golgi-Cox staining, and transmission electron microscopy, and hypothalamic transcriptomics was combined with molecular validation. Intranasal ketamine improved CUMS-induced behavioral deficits, attenuated histological neuronal alterations in the hypothalamus, improved mitochondrial ultrastructure, increased synaptic density, and restored dendritic length and spine density. RNA sequencing highlighted oxidative phosphorylation-related changes and identified <em>Ndufa10</em>, encoding NADH:ubiquinone oxidoreductase subunit A10, as a ketamine-responsive mitochondrial complex I candidate; Real-time quantitative PCR and immunohistochemistry confirmed that, compared with the CUMS group, intranasal ketamine administration increased hypothalamic <em>Ndufa1</em>0 mRNA and NDUFA10 protein levels. Pharmacological inhibition of mitochondrial complex I with rotenone attenuated ketamine-associated behavioral improvement and restoration of NDUFA10 expression, supporting a potential contribution of mitochondrial complex I activity. α-Synuclein (SNCA) protein abundance changed in parallel, whereas <em>Snca</em> mRNA levels remained unchanged, suggesting an accompanying protein-level alteration rather than a primary transcriptional response. Together, these findings suggest that hypothalamic mitochondrial complex I activity may contribute to the antidepressant-like effects of intranasal ketamine, with NDUFA10 emerging as a ketamine-responsive candidate molecule that requires further functional validation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179153"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520047","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}