European journal of pharmacology最新文献

{"title":"Fisetin alleviates osteoporosis by promoting osteogenesis and suppressing adipogenesis via the Wnt/β-catenin signaling pathway in mice","authors":"Jingjing Zhang,&nbsp;Jiawei Wang,&nbsp;Han Chen,&nbsp;Ruijie Zhang,&nbsp;Tiannan Huang,&nbsp;Xiaowen Jiang,&nbsp;Wei Zhang,&nbsp;Qinjiao Fu,&nbsp;Ziwan He,&nbsp;Mengrui Wu,&nbsp;Weixu Li,&nbsp;Zhihui Huang,&nbsp;Erman Chen","doi":"10.1016/j.ejphar.2026.178974","DOIUrl":"10.1016/j.ejphar.2026.178974","url":null,"abstract":"<div><div>Osteoporosis (OP) is characterized by an imbalance in which bone marrow mesenchymal stem cells (BMSCs) preferentially differentiate into adipocytes rather than osteoblasts. The natural polyhydroxyflavone fisetin functions as an antioxidant and multi-target signaling regulator with potential to modulate stem cell fate. However, its role and underlying mechanisms in OP remain unclear. This study investigated whether fisetin ameliorates OP by regulating osteogenic and adipogenic differentiation using integrated <em>in vitro</em> and <em>in vivo</em> models. The effects of fisetin on BMSC differentiation were assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, alkaline phosphatase (ALP)/Alizarin Red S staining, Oil Red O and lipid-droplet fluorescence staining, and immunofluorescence. RNA sequencing and network pharmacology were used to explore the underlying mechanisms, followed by validation using pharmacological and genetic approaches. The <em>in vivo</em> effects of fisetin were confirmed in an ovariectomy (OVX)-induced OP mouse model by micro-computed tomography (micro-CT) and bone histomorphometry. Fisetin dose-dependently promoted osteogenic differentiation and inhibited adipogenic differentiation in cultured BMSCs. Mechanistically, fisetin activated the canonical Wnt/β-catenin signaling pathway, which underpinned its pro-osteogenic and anti-adipogenic effects. In OVX-induced OP mice, fisetin treatment significantly attenuated trabecular bone loss and reduced bone marrow adiposity, demonstrating its anti-osteoporotic efficacy as evidenced by micro-CT and histomorphometric analyses. This study demonstrates that fisetin alleviates OVX-induced OP by mitigating trabecular bone loss and suppressing marrow adipogenesis via activation of the Wnt/β-catenin pathway, providing a mechanistic foundation for its development as a therapeutic agent.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 178974"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148224049","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":"Attenuated Salmonella typhimurium L-forms combined with lentiviral shRNA-HOTAIR suppress tumorigenicity and aggressiveness of murine breast cancer by inhibiting EGFR/Snail/MMP9 pathway","authors":"Ziqing Tang,&nbsp;Wei Zhao,&nbsp;Cuiping Yang,&nbsp;Qin Chen,&nbsp;Wenhui Yao,&nbsp;Yunjie Zhang,&nbsp;Yifan Chu,&nbsp;Jiyu Yang,&nbsp;Junru Chen,&nbsp;Dengyu Chen","doi":"10.1016/j.ejphar.2026.179090","DOIUrl":"10.1016/j.ejphar.2026.179090","url":null,"abstract":"<div><div>Breast cancer is a leading malignancy in women. HOTAIR promotes tumor proliferation, invasion, and EMT. This study evaluated combined therapy of attenuated <em>Salmonella typhimurium</em> (<em>ST</em>) L-forms and lentiviral shRNA-HOTAIR on triple-negative breast cancer in a murine model.</div></div><div><h3>Methodology</h3><div><em>ST</em> VNP20009 L-forms were induced by ceftriaxone. 4T1 cell invasion was assessed by Transwell Matrigel assay and apoptosis by Annexin V/PI flow cytometry <em>in vitro</em> and TUNEL <em>in vivo</em>. Tumorigenicity and aggressiveness were evaluated in a mouse breast cancer model. EGFR, Snail, and MMP9 expression in xenografts was detected by RT-qPCR and immunohistochemistry.</div></div><div><h3>Results</h3><div><em>ST</em> L-forms appeared as Gram-negative bacteria with irregular red staining and long filament bodies. Transwell invasion assay showed attenuated <em>ST</em> and its L-forms inhibited 4T1 cell invasion <em>in vitro</em>. Annexin V/PI and TUNEL assays revealed that combining <em>ST</em> L-forms with lentiviral shHOTAIR induced significantly greater apoptosis in 4T1 cells compared to control, <em>ST</em>, or <em>ST</em> L-forms alone <em>in vitro</em> and <em>in vivo</em>. Furthermore, this combination more effectively suppressed tumor growth and aggressiveness in murine breast cancer. IHC and RT-qPCR on xenografts showed that the combination more effectively suppressed expression of EGFR, Snail, and MMP9 compared to controls.</div></div><div><h3>Conclusion</h3><div>This study confirmed that the combination of attenuated <em>S. typhimurium</em> L-forms and lentiviral shRNA-HOTAIR significantly enhanced the suppression of tumor growth and aggressiveness in murine breast cancer. These findings supported the potential of this combined strategy of attenuated <em>ST</em> L-forms and lentiviral shHOTAIR as a novel and more effective bio-therapeutic approach for bacterial-mediated breast cancer therapy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179090"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148316426","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":"The protective effects and mechanisms of Erucic acid in allergic rhinitis via the MyD88/NF-κB pathway","authors":"Yingxuan Zhou,&nbsp;Jinbing Liu,&nbsp;Lifu Liu,&nbsp;Yintong Chen,&nbsp;Jiaqi Yan,&nbsp;Taotao Gao,&nbsp;Xiaoyan Deng,&nbsp;Zifeng Yang,&nbsp;Xiaoli Liang","doi":"10.1016/j.ejphar.2026.179086","DOIUrl":"10.1016/j.ejphar.2026.179086","url":null,"abstract":"<div><div>Allergic rhinitis (AR), a local inflammatory disease mediated by IgE in the nasal mucosa, presents a significant challenge to global health. Erucic acid (EA) is a monounsaturated fatty acid. Current research indicates EA possesses diverse biological activities, including anti-inflammatory, antioxidant, and immunomodulatory properties. However, its effects on AR remain unexplored. This study aims to investigate the therapeutic action and mechanism of EA in AR. The efficacy and mechanisms of EA were evaluated on the AR mouse model. Therapeutic outcomes were assessed through behavioral observations, measurements of various related cytokines in nasal mucosa and serum, and histopathological examination of nasal mucosa. An <em>in vitro</em> inflammatory model was established in RAW264.7 cells to investigate the anti-inflammatory effects and mechanisms of EA <em>via</em> RT-qPCR and Western blot. This study shows that, at a safe dose, EA significantly alleviates AR-associated behaviors such as rubbing and sneezing and reduces serum levels of histamine, Ovalbumin-specific IgE (OVA-sIgE), inflammatory cytokines, and chemokines. EA mitigated damage to the nasal mucosa tissue, including an increase of goblet cells, mast cells, and eosinophils. In the nasal tissue, EA also downregulated the mRNA levels of inflammation-related factors and epithelial barrier-related factors, as well as the protein levels of Myeloid Differentiation Primary Response Protein 88 (MyD88) and NF-κB. <em>In vitro</em>, EA suppressed Lipopolysaccharide (LPS)-induced expression of inflammatory cytokines and inhibited activation of the MyD88/NF-κB pathway. These findings demonstrate that EA exerts anti-inflammatory and epithelial barrier-restorative effects through inhibiting the MyD88/NF-κB pathway.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179086"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148327760","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":"Mitochondrial complex I inhibition remodels the PDAC fibrotic microenvironment via LOXL2 suppression to potentiate chemo-immunotherapy","authors":"Ziyi Qin,&nbsp;Yeting Xu,&nbsp;Yucheng Wang,&nbsp;Jinyang Ma,&nbsp;Jiaming Zou,&nbsp;Yingying Wang,&nbsp;Kaihan Zhang,&nbsp;Jiaxing Qiu,&nbsp;Rui Ju,&nbsp;Lei Guo","doi":"10.1016/j.ejphar.2026.179141","DOIUrl":"10.1016/j.ejphar.2026.179141","url":null,"abstract":"<div><h3>Purpose</h3><div>Pancreatic ductal adenocarcinoma (PDAC) exhibits a highly desmoplastic tumor microenvironment that contributes to therapeutic resistance. Cancer-associated fibroblasts (CAFs) are major drivers of extracellular matrix deposition. Considering CAF heterogeneity and plasticity, metabolic modulation may represent an alternative strategy to regulate stromal function. This study investigated whether targeting mitochondrial metabolism could attenuate CAF-mediated fibrosis and improve therapeutic responses in PDAC.</div></div><div><h3>Methods</h3><div>The effects of carboxyamidotriazole orotate (CTO), an oxidative phosphorylation inhibitor, were evaluated <em>in vitro</em> and in PDAC mouse models. LOXL2 expression, collagen deposition, and fibrosis-related gene signatures were analyzed using molecular and histological approaches. Combination treatments with anti-PD-1 therapy and gemcitabine were further assessed.</div></div><div><h3>Results</h3><div>CTO treatment reduced LOXL2 expression and downregulated collagen deposition-associated gene signatures in CAFs. In vivo, CTO attenuated stromal fibrosis and altered tumor microenvironmental features. Combination of CTO with anti-PD-1 therapy induced a pronounced anti-fibrotic phenotype. Integration of CTO into gemcitabine-based chemo-immunotherapy was associated with improved therapeutic responses and stromal remodeling.</div></div><div><h3>Conclusion</h3><div>Mitochondrial metabolic inhibition represents a feasible strategy to modulate CAF-mediated fibrosis in PDAC. CTO-mediated stromal reprogramming may enhance responses to chemo- and immunotherapy, providing a translational rationale for metabolism-based combination strategies.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179141"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148445175","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":"Poly(I:C)-stimulated alveolar macrophages modulate extracellular matrix turnover and fibroblast activation through cystatin 6 and cathepsin B","authors":"Chen-Ni Chang,&nbsp;Cheng-Fang Tsai,&nbsp;Yen-Chang Chen,&nbsp;Chao-Wei Chen,&nbsp;Yu-Wen Wang,&nbsp;Yu-Chi Chiou,&nbsp;Dah-Yuu Lu,&nbsp;Wei-Lan Yeh","doi":"10.1016/j.ejphar.2026.179149","DOIUrl":"10.1016/j.ejphar.2026.179149","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary fibrosis is characterized by persistent fibroblast activation and pathological extracellular matrix (ECM) deposition, driven by complex intercellular crosstalk within the lung microenvironment. While macrophages are recognized as central regulators of tissue repair and injury resolution, the specific molecular mechanisms by which they modulate fibroblast phenotypes remain to be fully elucidated.</div></div><div><h3>Methods</h3><div>Alveolar macrophages were stimulated with the viral mimic polyinosinic:polycytidylic acid [poly(I:C)], and their secretome was harvested as conditioned medium (CM). NIH/3T3 fibroblasts were then exposed to this CM to evaluate its effects on activation, migration, and fibrogenic responses.</div></div><div><h3>Results</h3><div>Poly(I:C)-stimulated macrophage CM significantly downregulated key pro-fibrotic markers (including collagen I, tissue transglutaminase, lysyl oxidase, α-smooth muscle actin, and connective tissue growth factor) and fibroblast activation-associated markers (vimentin, snail, and twist) in fibroblasts, while the cell adhesion marker αE-catenin was upregulated. Exposure to poly(I:C)-stimulated macrophage CM triggered a robust induction of cathepsin B in fibroblasts. Inhibition of cathepsin B effectively restores fibroblast activation and migratory capacity. In addition, poly(I:C) stimulation was found to reduce the secretion of cystatin 6 from macrophages. Neutralizing cystatin 6 in unstimulated macrophage CM raises the threshold required to trigger fibrogenesis, whereas the addition of recombinant cystatin 6 reversed the effects of poly(I:C)-stimulated macrophage CM.</div></div><div><h3>Conclusions</h3><div>These findings identify a novel macrophage cystatin 6-fibroblast cathepsin B axis that governs fibroblast behavior, fibrogenic response, and fibroblast activation. Understanding this regulatory pathway may provide important mechanistic insights into the resolution of fibrogenic responses.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179149"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454822","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":"Allicin is a potential hypolipidemic and antiatherogenic agent: Mechanisms of action and implicated signaling pathways","authors":"Sham A. Al Refaai,&nbsp;Mohammad A. Akram,&nbsp;Amin F. Majdalawieh","doi":"10.1016/j.ejphar.2026.179160","DOIUrl":"10.1016/j.ejphar.2026.179160","url":null,"abstract":"<div><div>Allicin, an organosulfur compound derived from garlic (<em>Allium sativum</em>), has been extensively studied for its cardiovascular benefits. Numerous reports highlight its lipid-lowering, antioxidant, and anti-atherogenic properties. The lipid-modulating effects reported for allicin-containing preparations are evidenced by reductions in plasma cholesterol and atherosclerotic lesion development. However, because intact allicin is highly unstable and rapidly degraded under physiological conditions, these effects should be interpreted as potentially reflecting the activity of allicin-derived organosulfur metabolites as well as allicin itself. Herein, we present a comprehensive summary of the reported anti-atherogenic effects of allicin. The impact of allicin on lipid metabolism, antioxidant defenses, and inflammatory processes is thoroughly evaluated. Studies demonstrating the ability of allicin to scavenge reactive oxygen species, prevent LDL oxidation, modulate thiol-dependent redox enzymes, and enhance endogenous antioxidant systems are outlined. Additionally, the molecular pathways underlying these effects, including NF-κB, NLRP3, MAPK, Nrf2, and PPARγ/LXRα signaling, are presented. Experimental evidence suggests that allicin and/or allicin-derived organosulfur metabolites may influence atherosclerosis-related processes through coordinated regulation of lipid metabolism, oxidative stress, and inflammatory responses. Nevertheless, the interpretation of these findings remains limited by poor allicin stability, uncertain systemic exposure to intact allicin, heterogeneity among garlic formulations, and inconsistent clinical outcomes. A deeper understanding of the relative contribution of intact allicin, allicin-generating formulations, and downstream metabolites is essential to evaluate their potential as natural or adjunctive therapeutic agents. Further research into its stability, bioavailability, and optimal dosage, particularly in humans, is warranted to ensure maximal therapeutic benefit towards the prevention and/or treatment of atherosclerosis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179160"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497241","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":"Bexarotene alleviates aberrant activation of microglia in early life by regulating the RXRα-PPARγ-NF-κB axis","authors":"Shijie Zhang,&nbsp;Xinqi Wang,&nbsp;Senyue Yang,&nbsp;Ziye Zang,&nbsp;Xiang Li,&nbsp;Jianhong Li","doi":"10.1016/j.ejphar.2026.179155","DOIUrl":"10.1016/j.ejphar.2026.179155","url":null,"abstract":"<div><div>The early developmental window is a critical period for the structural establishment and functional maturation of the central nervous system. During this stage, the proliferation, morphological remodeling, and phenotypic transformation of microglia are essential for neurogenesis, synaptic pruning, and refinement of neural circuits, and their dysregulation is implicated in multiple neurodevelopmental disorders. However, the molecular mechanisms governing early microglial development remain unclear. Retinoid X receptor α (RXRα), a nuclear receptor with key roles in development and immune regulation, has not been fully characterized in this context. Here, we used a mouse model of early-life stress (maternal separation) to assess its impact on hippocampal microglial development and inflammation, and to delineate the role of RXRα. Early-life stress reduced body weight and increased plasma corticosterone in juvenile mice, decreased microglial branching and induced aberrant activation, and elevated hippocampal IL-1β, IL-6, and NF-κB subunits P50 and P65. Treatment with the RXR agonist bexarotene upregulated hippocampal RXRα, partially restored microglial morphological complexity, and markedly suppressed pro-inflammatory cytokines and NF-κB pathway gene expression. In an in vitro microglial inflammation model, the anti-inflammatory effect of bexarotene was dependent on peroxisome proliferator-activated receptor γ (PPARγ), as inhibition of PPARγ attenuated its actions. These findings identify RXRα as a critical transcriptional regulator maintaining early microglial homeostasis and limiting inflammation and provide a theoretical basis for the application of bexarotene in the treatment of neuroinflammatory damage caused by early-life trauma.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179155"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469675","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":"Cerebrospinal fluid metabolites and brain imaging in epilepsy subtypes: Mendelian randomization and multi-omics analysis","authors":"Huaiyu Sun,&nbsp;Xuewei Li,&nbsp;Weixuan Zhao,&nbsp;Hongmei Meng,&nbsp;Wuqiong Zhang","doi":"10.1016/j.ejphar.2026.179095","DOIUrl":"10.1016/j.ejphar.2026.179095","url":null,"abstract":"<div><h3>Background</h3><div>Epilepsy is a complex neurological disorder significantly influenced by genetic factors. Observational studies can identify associations, but cannot establish causality. Mendelian randomization (MR) offers a robust tool for identifying etiology. Therefore, using multi-omics, we explored genetically proxied associations among cerebrospinal fluid metabolites, neuroimaging phenotypes, and epilepsy to prioritize candidate genes and potential therapeutic targets.</div></div><div><h3>Methods</h3><div>Leveraging data from genome-wide association studies, gene expression databases, and the UK Biobank, we performed two-sample MR analyses. Immune infiltration was assessed using multiple algorithms, transcription factors predicted using RcisTarget, and key genes prioritized through single-nucleotide polymorphism annotation and localization using single-cell RNA sequencing.</div></div><div><h3>Results</h3><div>We identified genetically proxied associations between 14 cerebrospinal fluid metabolites and focal epilepsy (11 protective, three risk-associated), with 13 confirmed using reverse MR. Additionally, 259 neuroimaging phenotypes showed significant associations with focal epilepsy. <em>DAB1</em>, <em>ITGA8</em>, and <em>RORA</em> were the top-ranked genes, localized to inhibitory neurons, oligodendrocyte precursor cells, and astrocytes, respectively.</div></div><div><h3>Discussion</h3><div>These findings demonstrate cell-specific pathology beyond standard neuronal activity. Mechanistically, <em>DAB1</em> contributes to defects in inhibitory circuits, potentially disrupting excitation–inhibition balance, <em>ITGA8</em> to matrix or myelin abnormalities in oligodendrocyte precursor cells, and <em>RORA</em> to astrocyte-mediated metabolic regulation and neuroinflammation. These robust metabolic and structural associations suggest that these features may represent early endophenotypes preceding clinical symptoms.</div></div><div><h3>Conclusion</h3><div>By integrating multi-omics data, we identified a candidate gene–metabolite–imaging feature network potentially involved in epileptogenesis. The prioritized glial and neuronal targets offer hypothesis-generating insights for future mechanistic studies, precision medicine approaches, and translational research in epilepsy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179095"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338354","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 ferulate prevents breast cancer metastasis by remodeling the bloodstream microenvironment","authors":"Mengting Lin,&nbsp;Shanshan He,&nbsp;Chunlian Zhong,&nbsp;Weiyu Wang,&nbsp;Yinyin Yao,&nbsp;Lin Luo,&nbsp;Jundan Xu,&nbsp;Lei Ma,&nbsp;Xinyi Zhao,&nbsp;Chengbin Fu,&nbsp;Mingqing Huang,&nbsp;Yusheng Lu","doi":"10.1016/j.ejphar.2026.179092","DOIUrl":"10.1016/j.ejphar.2026.179092","url":null,"abstract":"<div><div>Metastasis remains the leading cause of mortality in breast cancer, and effective prevention strategies are urgently needed. Sodium ferulate (SF), a bioactive compound derived from ferulic acid, has demonstrated diverse pharmacological activities, yet its role in suppressing cancer metastasis remains unclear. In this study, we demonstrate that SF significantly inhibits breast cancer metastasis through comprehensive modulation of the bloodstream microenvironment. At non-toxic concentrations, SF inhibited the migration and invasion of MCF-7 and MDA-MB-231 cells by suppressing the BMP4/Smad1/5/9 signaling pathway, reversing epithelial-mesenchymal transition (EMT), and disrupting cell cycle progression. SF also enhanced the sensitivity of breast cancer cells to paclitaxel. In addition, SF reduced tumor cell adhesion to endothelial cells by blocking TNF-α-induced expression of ICAM-1 and VCAM-1 through inhibition of NF-κB signaling cascade. Furthermore, SF attenuated platelet activation and angiogenesis, two key processes involved in metastatic dissemination and colonization. In 4T1 mouse metastasis model, SF treatment significantly decreased pulmonary metastatic nodules without causing organ toxicity. Immunohistochemical analysis further confirmed decreased expression of BMP4, PI3K, and N-cadherin in lung tissues following SF treatment. Additionally, SF enhanced systemic immunity by increasing the proportion of cytotoxic T cells and natural killer cells in peripheral blood. Collectively, these findings reveal that SF exerts potent anti-metastatic effects by modulating tumor-bloodstream-immune interactions rather than direct cytotoxicity. By remodeling the bloodstream microenvironment and enhancing immune defense, SF may represent a promising and safe candidate for the prevention of breast cancer metastasis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179092"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148327690","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":"Diammonium glycyrrhizinate attenuates neuroinflammation after intracerebral hemorrhage by suppressing VCAM-1 expression via the PI3K-Akt pathway","authors":"Mengzhao Feng,&nbsp;Kaiyuan Zhang,&nbsp;Fang Wang,&nbsp;Han Wu,&nbsp;Qi Qin","doi":"10.1016/j.ejphar.2026.179094","DOIUrl":"10.1016/j.ejphar.2026.179094","url":null,"abstract":"<div><div>Intracerebral hemorrhage (ICH) is a devastating stroke subtype with limited therapeutic options, and excessive neuroinflammation plays a critical role in secondary brain injury following ICH. Here, we investigated whether diammonium glycyrrhizinate (DG), a clinically approved anti-inflammatory agent, confers neuroprotection in a mouse model of ICH and explored the underlying mechanisms. Adult male C57BL/6J mice subjected to collagenase-induced ICH were treated with DG or vehicle, and we assessed neurological function, brain water content, hematoma volume, and blood–brain barrier (BBB) integrity at 3 days post-ICH. DG treatment significantly reduced brain edema, hematoma volume, and BBB leakage while improving neurological outcomes. RNA sequencing revealed that DG downregulated 94 genes, with enrichment in cell surface receptor activity pathways, and identified Vascular cell adhesion molecule-1 (VCAM-1) as a key downstream target. VCAM-1 upregulation in brain microvascular endothelial cells after ICH was markedly suppressed by DG, accompanied by reduced neutrophil infiltration, attenuated microglial M1 polarization, and decreased production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), matrix metalloproteinase-9, oxidative stress markers, and apoptotic factors. Mechanistically, DG activated the PI3K-Akt signaling pathway, and this activation was associated with suppression of VCAM-1 expression and subsequent attenuation of neuroinflammation. These findings demonstrate that DG attenuates neuroinflammation and secondary brain injury after ICH by activating the PI3K-Akt pathway to suppress VCAM-1 expression, thereby limiting peripheral immune cell infiltration and modulating microglial polarization. The PI3K-Akt/VCAM-1 axis represents a promising therapeutic target, and DG may serve as a potential candidate for ICH management.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179094"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338302","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}