PhytomedicinePub Date : 2025-03-20DOI: 10.1016/j.phymed.2025.156675
Jingchen Xie , Suhui Xiong , Jiahui Yu , Xinyi Ma , Feng Xiang , Yang Chen , Bohou Xia , Yamei Li , Zhimin Zhang , Duanfang Liao , Limei Lin
{"title":"Prunella vulgaris polyphenols alleviate liver injury-uveitis comorbidity by regulating acylcarnitine via the S100A9-PP2A-AMPK pathway","authors":"Jingchen Xie , Suhui Xiong , Jiahui Yu , Xinyi Ma , Feng Xiang , Yang Chen , Bohou Xia , Yamei Li , Zhimin Zhang , Duanfang Liao , Limei Lin","doi":"10.1016/j.phymed.2025.156675","DOIUrl":"10.1016/j.phymed.2025.156675","url":null,"abstract":"<div><h3>Background</h3><div>Liver injury and uveitis pose severe threats to human health. Owing to the close relationship of physiology and pathology between the liver and the eyes, cases in which both conditions occur simultaneously are not uncommon in clinical settings, significantly complicating treatment. However, no suitable comorbid animal model has been reported, and research on the pathological mechanisms of this comorbidity is lacking. <em>Prunella vulgaris</em> L., a well-known traditional Chinese medicine renowned for its liver-clearing and eye-brightening properties. <em>Prunella vulgaris</em> polyphenols (PVPs) hold promise for improving liver injury and uveitis. However, research exploring their dual therapeutic effects within a single organism remains lacking, leaving the key active components and mechanisms of action largely uninvestigated.</div></div><div><h3>Purpose</h3><div>This exploratory study aimed to establish a rat model of liver injury combined with uveitis and investigated its pathological mechanisms, evaluating the therapeutic efficacy of PVPs in alleviating liver injury combined with uveitis in rats. Additionally, it explored the mechanism of action and identified key active ingredients of PVPs, offering potential new directions for the development of clinical therapeutic drugs.</div></div><div><h3>Methods</h3><div>A rat model of liver injury with uveitis was established through intraperitoneal d-GalN/LPS injection. Metabolomics and proteomics were applied to investigate pathological mechanisms, followed by validation using acylcarnitine and S100A9 inhibitors. PVPs were administered to evaluate therapeutic effects and explore mechanisms involved in alleviating liver injury and uveitis. Network pharmacology combined with molecular docking identified critical active components in PVPs. Subsequent animal experiments verified the efficacy of the representative component in improving liver injury and uveitis.</div></div><div><h3>Results</h3><div>d-GalN/LPS (150 mg/kg : 1 mg/kg) induced significant liver injury and uveitis in rats. Metabolomics analysis pointed to acylcarnitine as a key metabolite, and its inhibition reduced inflammation. Proteomics analysis implicated S100A9 in inflammation and immunity. Then, we intervened with S100A9 inhibitors in the model rats. The results suggested that the pathological mechanism of liver injury and uveitis caused by d-GalN/LPS involved the upregulation of S100A9 expression, an increase in PP2A activity, the inhibition of AMPK phosphorylation, and the downregulation of CPT1A, leading to the accumulation of acylcarnitine and promoting the inflammatory response in the liver and retina. Further, experiments involving PVPs demonstrated dose-dependent improvements in liver injury and uveitis caused by d-GalN/LPS. The underlying mechanism of action involved suppression of S100A9 expression, reduction of PP2A activity, activation of AMPK, upregulation of CPT1A, and subsequent reduction in a","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"141 ","pages":"Article 156675"},"PeriodicalIF":6.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-03-20DOI: 10.1016/j.phymed.2025.156674
Mengting Zhou , Rui Li , Guiyun Lian , Mengni Yang , Li Li , Zhujun Yin , Guiyu Li , Junning Zhao , Ruirong Tan
{"title":"Tetrahydrocurcumin alleviates colorectal tumorigenesis by modulating the SPP1/CD44 axis and preventing M2 tumor-associated macrophage polarization","authors":"Mengting Zhou , Rui Li , Guiyun Lian , Mengni Yang , Li Li , Zhujun Yin , Guiyu Li , Junning Zhao , Ruirong Tan","doi":"10.1016/j.phymed.2025.156674","DOIUrl":"10.1016/j.phymed.2025.156674","url":null,"abstract":"<div><h3>Background</h3><div>Recent studies show that secreted phosphoprotein 1 (SPP1) is linked to the progression of various cancers, including colorectal cancer (CRC). SPP1 also promotes M2 macrophage polarization, contributing to immune evasion in the tumor microenvironment. Tetrahydrocurcumin (THC) has been reported to alleviate CRC, but the mechanism remains unclear.</div></div><div><h3>Purpose</h3><div>The study aimed to explore how THC modulated the SPP1/CD44 axis to inhibit M2 polarization and suppress CRC development.</div></div><div><h3>Methods</h3><div>Azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mouse model was used to assess the anti-CRC effects of THC. Transcriptome sequencing was conducted to identify the key targets of THC in CRC. The effects of THC on CRC cells were evaluated by CCK-8, colony formation, migration assays, immunofluorescence staining and flow cytometry. Human monocytic cells, THP-1, and colon cancer cell line, HCT116, were co-cultured, both directly or indirectly, to mimic the tumor-macrophage interactions, and investigate the role of SPP1/CD44 axis and the intervention effect of THC.</div></div><div><h3>Results</h3><div>THC significantly inhibited CRC carcinogenesis in mice and improved pathologic symptoms, serum inflammatory markers, and intestinal barrier integrity. THC inhibited CRC cell proliferation, migration and colony formation, while promoting apoptosis. Transcriptome analysis identified SPP1 as a key target of THC against CRC. SPP1 facilitated CRC progression by activating the ERK signaling pathway and maintaining the M2-like phenotype of macrophage, which further exacerbated this response. THC inhibited CRC development by targeting the SPP1/CD44 axis, rather than the integrin pathway.</div></div><div><h3>Conclusions</h3><div>SPP1 played a crucial role in maintaining the M2 phenotype of macrophage and promoting CRC cells proliferation. THC inhibited the activation of ERK signals in CRC cells and phenotypic transformation of M2-like macrophages through the SPP1/CD44 axis, thereby regulating the tumor immune microenvironment to exert anti-CRC effect.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"141 ","pages":"Article 156674"},"PeriodicalIF":6.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-03-20DOI: 10.1016/j.phymed.2025.156677
Yinhua Ni , Wenlong Yang , Sisi Wang , Yuxiang Pan , Haimei Du , Liujie Zheng , Cheguo Cai , Zhengwei Fu , Qiang He , Juan Jin , Peipei Zhang
{"title":"Modified huangfeng decoction alleviates diabetic nephropathy by activating autophagy and regulating the gut microbiota","authors":"Yinhua Ni , Wenlong Yang , Sisi Wang , Yuxiang Pan , Haimei Du , Liujie Zheng , Cheguo Cai , Zhengwei Fu , Qiang He , Juan Jin , Peipei Zhang","doi":"10.1016/j.phymed.2025.156677","DOIUrl":"10.1016/j.phymed.2025.156677","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic nephropathy (DN) is one of the complications with the highest mortality among diabetes patients and can lead to renal failure. Modified Huangfeng decoction (MHD) has been widely applied in the clinical treatment of kidney diseases. However, the mechanism by which MHD affects DN has not been fully elucidated.</div></div><div><h3>Purpose</h3><div>To investigate the impact of MHD on DN in mice and the underlying mechanism.</div></div><div><h3>Methods</h3><div>The main ingredients of MHD were identified by liquid chromatography‒mass spectrometry. A high-fat diet- and streptozotocin (STZ)-induced DN mouse model was constructed and treated with MHD for 6 weeks. The serum and urine parameters were measured, and the tissue sections were histologically stained. The mRNA and protein levels of metabolism-, inflammation-, fibrosis-, and autophagy-related markers were examined by qPCR and western blotting. The microbial composition and metabolites of cecal contents were analyzed through full-length 16S rRNA sequencing and nontargeted metabolomics.</div></div><div><h3>Results</h3><div>MHD alleviated insulin resistance in DN mice and ameliorated changes in lipid metabolism and inflammation in the liver and fat. In addition, MHD reduced the levels of kidney injury markers in the serum and urine and attenuated inflammation and fibrosis in the kidney. These results were accompanied by enhanced gut barrier function and a markedly altered microbiota composition and metabolites, with an increased abundance of beneficial bacterial species and metabolites. Moreover, MHD itself and the microbial metabolite spermidine reduced podocyte damage by activating autophagy via the PI3K/AKT/mTOR pathway.</div></div><div><h3>Conclusions</h3><div>MHD potentially ameliorated DN by activating podocyte autophagy via the PI3K/AKT/mTOR pathway and modulating the gut microbiota and its metabolites. Our findings provide a more comprehensive understanding of the mechanism of MHD and the involvement of the gut‒kidney interaction in the progression of DN, laying a theoretical foundation for the clinical application of MHD in DN treatment.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"141 ","pages":"Article 156677"},"PeriodicalIF":6.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143683115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-03-20DOI: 10.1016/j.phymed.2025.156671
Cheng Tan , Zixuan Xiang , Shuo Wang , Haodong He , Xiangyun Li , Miao Xu , Xingzhou Guo , Yu Pu , Junhai Zhen , Weiguo Dong
{"title":"Diosmin alleviates colitis by inhibiting PANoptosis of intestinal epithelial cells and regulating gut microbiota and metabolites","authors":"Cheng Tan , Zixuan Xiang , Shuo Wang , Haodong He , Xiangyun Li , Miao Xu , Xingzhou Guo , Yu Pu , Junhai Zhen , Weiguo Dong","doi":"10.1016/j.phymed.2025.156671","DOIUrl":"10.1016/j.phymed.2025.156671","url":null,"abstract":"<div><h3>Background</h3><div>Inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), is a chronic inflammatory disorder characterized by an unclear etiology, often linked to gut microbiota dysbiosis and immune dysregulation. Existing UC therapies are constrained by suboptimal efficacy and adverse effects, underscoring the necessity for novel therapeutic strategies. Diosmin (DIO), a naturally occurring flavonoid, has demonstrated anti-inflammatory and antioxidant potential, yet its precise mechanisms and therapeutic role in colitis remain poorly understood.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate the therapeutic efficacy and mechanistic underpinnings of DIO in dextran sulfate sodium (DSS)-induced colitis, with a focus on its effects on intestinal epithelial cell PANoptosis, gut microbiota composition, fecal metabolites, and an in vitro inflammatory model using human colonic epithelial cells.</div></div><div><h3>Study Design</h3><div>A controlled experimental design was employed, utilizing a DSS-induced murine colitis model and an LPS-induced inflammatory model in human colonic epithelial cells (NCM460). Mice were allocated into four groups: normal control, DSS-induced colitis, low-dose DIO (DIO-L, 100 mg/kg), and high-dose DIO (DIO-H, 200 mg/kg). In vitro experiments involved treating NCM460 cells with varying DIO concentrations post-LPS stimulation to assess its impact on inflammation and epithelial barrier integrity.</div></div><div><h3>Methods</h3><div>Mice were administered DIO orally at 100 mg/kg or 200 mg/kg daily. Therapeutic outcomes were evaluated through body weight monitoring, Disease Activity Index (DAI) scoring, and histopathological examination. Gut microbiota composition was analyzed via 16S rRNA sequencing, while untargeted metabolomics was employed to profile fecal metabolites. Data integration was performed using O2PLS and WGCNA to identify microbiota-metabolite correlations. In vitro, immunofluorescence staining and Western blotting were utilized to evaluate the expression of tight junction proteins (ZO-1, E-cadherin, and Occludin).</div></div><div><h3>Results</h3><div>DIO administration significantly ameliorated colitis symptoms in mice, as evidenced by attenuated weight loss, reduced DAI scores, and preserved colon length. Histopathological analysis confirmed diminished inflammation and tissue damage in DIO-treated groups. Mechanistically, DIO suppressed the expression of PANoptosis-associated genes and proteins, including ZBP1 and Caspase-1, while maintaining epithelial barrier integrity in vitro. Furthermore, DIO modulated gut microbiota composition, promoting beneficial taxa such as Ruminococcus and reducing pathogenic Proteobacteria. Metabolomic profiling revealed alterations in key metabolic pathways, including flavonoid and steroid hormone biosynthesis, which correlated with microbiota changes.</div></div><div><h3>Conclusion</h3><div>DIO effectively mitigates DSS-induced colit","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"141 ","pages":"Article 156671"},"PeriodicalIF":6.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-03-20DOI: 10.1016/j.phymed.2025.156678
Danli Zhu , Jinghan Zhang , Xiaochun Huang , Na Wei , Jinxiu Jiang , Jiayao Li , Li Liu , Yulin Liu , Jun Zhou , Jing Jia
{"title":"Integrated network pharmacology and experimental validation to elucidate the mechanism of celastrol in mitigating sepsis-induced acute lung injury in mice","authors":"Danli Zhu , Jinghan Zhang , Xiaochun Huang , Na Wei , Jinxiu Jiang , Jiayao Li , Li Liu , Yulin Liu , Jun Zhou , Jing Jia","doi":"10.1016/j.phymed.2025.156678","DOIUrl":"10.1016/j.phymed.2025.156678","url":null,"abstract":"<div><h3>Background</h3><div>Sepsis is an acute, life-threatening condition that precipitates multiple organ failure, including acute lung injury (ALI), characterized by a complex pathophysiological process and elevated mortality rates. Celastrol, a pentacyclic triterpenoid quinone derived from traditional Chinese medicine, exhibits diverse pharmacological properties, including immunomodulatory, anti-inflammatory, anticancer, and antifibrotic effects, and has demonstrated favorable safety profiles in vivo. However, the precise mechanism by which CSL contributes to sepsis-induced ALI remains to be elucidated.</div></div><div><h3>Purpose</h3><div>The study aimed to explore the mechanisms by which celastrol mitigates sepsis-induced ALI using network pharmacology, followed by experimental validation of its regulatory effects on sepsis-induced ALI.</div></div><div><h3>Methods</h3><div>Utilizing a network pharmacology analysis, the potential targets and pathways of celastrol were identified. To explore celastrol's therapeutic effects on ALI, a rat model of sepsis was induced via cecal ligation and puncture, followed by assessment through hematoxylin-eosin staining, Real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting. Further investigation involved evaluating celastrol's influence on LPS-stimulated A549 and Raw264.7 cells, employing RT-qPCR, Western blotting, and immunofluorescence techniques.</div></div><div><h3>Results</h3><div>Network pharmacological analysis identified 10 core targets and 31 pathways relevant to sepsis-induced ALI, with STAT3, TLR4, HIF-1α, and NF-κB1 emerging as central targets. Animal experiments demonstrated that celastrol treatment significantly reduced lung tissue inflammation, as evidenced by immunohistochemistry, Western blot, and RT-qPCR results, in comparison to the cecal ligation and puncture group. Notably, the levels of IL-1β, TNF-α, HIF-1α, STAT3, and NF-κB1 proteins and mRNA in the celastrol treatment group were significantly reduced compared to those in the cecal ligation and puncture (CLP) group and the LPS-treated group. Additionally, Western blot and immunofluorescence analyses confirmed the activation of the NF-κB pathway in vitro.</div></div><div><h3>Conclusion</h3><div>This study indicates that celastrol significantly suppresses the expression of inflammatory factors in sepsis-induced ALI by inhibiting the NF-κB/HIF-1α pathway in both in vivo and in vitro models, highlighting its therapeutic potential for modulating inflammation. These findings provide valuable evidence for future clinical research and drug development.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"141 ","pages":"Article 156678"},"PeriodicalIF":6.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143683112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-03-19DOI: 10.1016/j.phymed.2025.156667
Ziyao Wu , Kang Ding , Wenli Liu , Hong He , Meiyun Chen , Mingxin Chen , Liwen Zhang , Chunyan Wang , Weiku Zhang , Lin Li
{"title":"Wikstrol B reactivates latent human immunodeficiency virus (HIV-1) via the nuclear factor-κB (NF-κB) pathway","authors":"Ziyao Wu , Kang Ding , Wenli Liu , Hong He , Meiyun Chen , Mingxin Chen , Liwen Zhang , Chunyan Wang , Weiku Zhang , Lin Li","doi":"10.1016/j.phymed.2025.156667","DOIUrl":"10.1016/j.phymed.2025.156667","url":null,"abstract":"<div><h3>Background</h3><div>Combination antiretroviral therapy (cART) and latency-reversing agents (LRAs) have not achieved a successful cure of HIV infection, due to latent HIV reservoir for the former, and insufficient efficacy and adverse side effects for the latter. Therefore, candidate LRAs with high antiviral efficacy and low cytotoxicity are critical for achieving a functional cure of HIV-1 infection.</div></div><div><h3>Purpose</h3><div>To identify promising flavonoids with dual functions in reactivating latent HIV-1 and inhibiting viral infection, and to explore the mechanisms involved therein.</div></div><div><h3>Methods</h3><div>We screened 21 flavonoids from <em>Stellera chamaejasme</em> and selected wikstrol B as a promising LRA candidate. The effects of the candidate on latent HIV-1 reactivation were assessed using enzyme-linked immunosorbent assay (ELISA), reverse-transcription quantitative PCR (RT-qPCR), and flow cytometry. Its cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry, western blot (WB) analysis, confocal microscopy and chromatin immunoprecipitation (ChIP) assay were applied for mechanism exploration. Anti-HIV-1 activity was assessed with ELISA, and the effect of wikstrol B on the Vif/hA3G complex was evaluated by co-immunoprecipitation (Co-IP) assay. Additionally, synergy of wikstrol B with cART drugs or other LRAs were also tested.</div></div><div><h3>Results</h3><div>Wikstrol B effectively reversed HIV-1 latency in both latently infected cell lines and primary CD4<sup>+</sup> T cells at low micromolar concentrations with minimal cytotoxicity. As for mechanisms, wikstrol B specifically induced HIV-1 long terminal repeat (LTR) transactivation and reactivated latent HIV-1 transcription by modulating the NF-κB signaling pathway. Additionally, wikstrol B demonstrated potent inhibitory activity against the laboratory-adapted HIV-1<sub>IIIB</sub> strain by blocking Vif-mediated degradation.</div></div><div><h3>Conclusion</h3><div>Wikstrol B is capable of both reactivating latent HIV-1 and inhibiting HIV-1 infection with few adverse effects, and may be applied, preferably in synergistic combination with cART drugs and other LRAs, in the “shock and kill” strategy for treating Acquired Immune Deficiency Syndrome (AIDS).</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"141 ","pages":"Article 156667"},"PeriodicalIF":6.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-03-19DOI: 10.1016/j.phymed.2025.156663
Mengdi Gu, Zheng Pang
{"title":"Luteolin inhibits inflammation and M1 macrophage polarization in the treatment of Pseudomonas aeruginosa-induced acute pneumonia through suppressing EGFR/PI3K/AKT/NF-κB and EGFR/ERK/AP-1 signaling pathways","authors":"Mengdi Gu, Zheng Pang","doi":"10.1016/j.phymed.2025.156663","DOIUrl":"10.1016/j.phymed.2025.156663","url":null,"abstract":"<div><h3>Background</h3><div>The opportunistic pathogen <em>Pseudomonas aeruginosa</em> primarily causes infections in immunocompromised individuals. Luteolin, a natural flavonoid, is widely present in plants, which exerts various pharmacological activities, including anti-inflammatory and antimicrobial activities.</div></div><div><h3>Purpose</h3><div>This study aimed to explore the therapeutic efficacy of luteolin and the underlying molecular mechanisms in treating the <em>P. aeruginosa</em>-induced acute pneumonia.</div></div><div><h3>Methods</h3><div>Network pharmacology was utilized to identify the core targets of luteolin for treating acute <em>P. aeruginosa</em> pneumonia. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to dissect the potential effects of luteolin and the involved signaling pathways. Surface plasmon resonance (SPR) assay and molecular docking were employed for studying the binding affinities of luteolin with the key targets. Furthermore, we applied a mouse model of bacterial pneumonia for assessing the therapeutic effects of luteolin <em>in vivo</em>, and an <em>in vitro</em> infection model for specifically investigating the effects of luteolin on macrophages as well as the underlying mechanisms upon <em>P. aeruginosa</em> infection.</div></div><div><h3>Results</h3><div>Network pharmacology identified TNF, IL-6, EGFR and AKT1 as the key targets of luteolin for treating acute <em>P. aeruginosa</em> pneumonia. Moreover, as revealed by GO and KEGG enrichment analysis, EGFR, MAPK and PI3K/AKT pathways were the potential pathways regulated the <em>P. aeruginosa</em>-induced inflammatory response. According to the <em>in vivo</em> results, luteolin effectively mitigated the <em>P. aeruginosa</em>-induced acute lung injury through reducing the pulmonary permeability, neutrophil infiltration, proinflammatory cytokine production (IL-1β, IL-6, TNF and MIP-2) and bacterial burden in lung tissues, which led to increased survival rate of mice. Furthermore, the luteolin-treated mice had diminished EGFR, PI3K, AKT, IκBα, NF-κB p65, ERK, c-Jun and c-Fos phosphorylation, down-regulated M1 macrophage marker levels (iNOS, CD86 and IL-1β) but up-regulated M2 macrophage marker levels (Ym1, CD206 and Arg1) in lung tissues. Consistently, the luteolin-pretreated macrophages exhibited reduced phosphorylation of these regulatory proteins, diminished proinflammatory cytokine production, and down-regulated expression of M1 macrophage markers, but up-regulated expression of IL-10 and M2 macrophage markers.</div></div><div><h3>Conclusion</h3><div>luteolin effectively suppressed the inflammatory responses and M1 macrophage polarization through inhibiting EGFR/PI3K/AKT/NF-κB and EGFR/ERK/AP-1 signaling pathways in the treatment of acute <em>P. aeruginosa</em> pneumonia. This study suggests that luteolin could be a promising candidate for development as a therapeutic agent for acute bacterial pneumo","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"141 ","pages":"Article 156663"},"PeriodicalIF":6.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143683113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-03-19DOI: 10.1016/j.phymed.2025.156646
Ting Yu , Zijie Wei , Jing Wang , Chenghuan Song , Wanying Huang , Pingao Zhang , Jiyun Shi , Rui Zhang , Meifang Jiang , Dandan Wang , Yongfang Zhang , Hongzhuan Chen , Hao Wang
{"title":"Ginkgo biloba Extract GBE50 ameliorates cerebrovascular dysfunction and cognitive impairment in a mouse model of Alzheimer's disease","authors":"Ting Yu , Zijie Wei , Jing Wang , Chenghuan Song , Wanying Huang , Pingao Zhang , Jiyun Shi , Rui Zhang , Meifang Jiang , Dandan Wang , Yongfang Zhang , Hongzhuan Chen , Hao Wang","doi":"10.1016/j.phymed.2025.156646","DOIUrl":"10.1016/j.phymed.2025.156646","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer's disease (AD) is a complex neurodegenerative disorder in which neurovascular unit (NVU) dysfunction plays a critical role. GBE50, a refined extract of <em>Ginkgo biloba</em> containing over 50 % total flavonoids and terpene lactones, is widely used in the clinical prevention and treatment of cardiovascular and cerebrovascular diseases due to its anti-platelet aggregation, anti-inflammatory, and antioxidant properties. However, its specific effects on NVU integrity and cerebrovascular function in AD remain unclear.</div></div><div><h3>Purpose</h3><div>This study aims to investigate the therapeutic effects of GBE50 on NVU integrity and cognitive impairment in an AD mouse model.</div></div><div><h3>Methods</h3><div>APP/PS1 transgenic mice were treated with GBE50 <em>via</em> intragastric administration for 10 weeks. Cognitive performance was assessed through behavioral tests, while the structural and functional integrity of the NVU was evaluated using immunofluorescence, laser speckle imaging, and <em>in vivo</em> multi-photon imaging. Furthermore, target prediction and transcriptomic analyses were conducted to uncover potential molecular mechanisms and identify specific targets of GBE50.</div></div><div><h3>Results</h3><div>GBE50 treatment significantly alleviated cognitive deficits in APP/PS1 mice. It enhanced cerebrovascular structure and function by increasing vessel density, diameter, and branching, leading to improved cerebral blood flow (CBF). GBE50 also restored NVU components such as endothelial cells, astrocytes, and pericytes, promoted parenchyma and perivascular Aβ clearance, and reduced neuroinflammation. Bioinformatics and transcriptomic analyses revealed that GBE50 exerted its effects by regulating pathways related to vascular repair, neuroprotection, and Aβ clearance.</div></div><div><h3>Conclusion</h3><div>The findings demonstrate that GBE50 improves cognitive dysfunction in AD by restoring NVU integrity and cerebrovascular function through multi-target mechanisms. This study highlights the potential of GBE50 as a promising therapeutic approach for AD and other neurodegenerative diseases involved in cerebrovascular dysfunction.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"141 ","pages":"Article 156646"},"PeriodicalIF":6.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-03-19DOI: 10.1016/j.phymed.2025.156617
Xu Dong , Jianyin Miao , Ling Wu , Ziyu Kong , Zenghui Liu , Diyi Jia , Qingqing Zhai , Dan Zhang , Yan Xu
{"title":"Diabetic wound healing breakthrough: theaflavin-3, 3’-digallate nanoparticles@hydrogel activates the TGF-β1/SMAD3 pathway","authors":"Xu Dong , Jianyin Miao , Ling Wu , Ziyu Kong , Zenghui Liu , Diyi Jia , Qingqing Zhai , Dan Zhang , Yan Xu","doi":"10.1016/j.phymed.2025.156617","DOIUrl":"10.1016/j.phymed.2025.156617","url":null,"abstract":"<div><h3>Background</h3><div>Diabetes patients face an elevated wound infection susceptibility and delayed healing processes. Currently, no existing literature has reported on the effect and mechanism of theaflavin-3, 3’-digallate nanoparticles (TFDG NPS) and TFDG NPS@hydrogels on diabetic wounds.</div></div><div><h3>Purpose</h3><div>Given that the treatment options for diabetic wound are limited, the aim of this study is to develop an innovative therapeutic approach to address diabetic wounds.</div></div><div><h3>Methods</h3><div>The TFDG NPS were prepared using ionic cross-linking, and they were then characterized. The biocompatibility of the TFDG NPS and TFDG NPS@hydrogel was assessed using a Cell Counting Kit-8 (CCK-8) assay and live/dead staining on HK-2 cells <em>in vitro</em>. Diabetic ICR mice were induced through intraperitoneal injection of streptozocin (STZ). They were then subjected to the creation of two full-thickness wounds on their dorsal areas. The effect and mechanism of the TFDG NPS and TFDG NPS@hydrogel on wound healing in diabetic mice were evaluated using a histological analysis, a western blot analysis, and molecular docking.</div></div><div><h3>Results</h3><div>The optimal TFDG NPS proportion was found to be TFDG:Gelatin (Gel):Chitosan (CS) = 2:1:1. Images photographed using a transmission electron microscope (TEM) revealed that the TFDG NPS appeared spherical, with a diameter of approximately 140 ± 20 nm. The favorable bio-compatibility of the TFDG NPS and TFDG NPS@hydrogel was confirmed using cell experiments. Animal studies demonstrated that both the TFDG NPS and TFDG NPS@hydrogel enhanced collagen fiber accumulation and new blood vessel density, reduced F4/80 infiltration, and upregulated the expression levels of TGF-β1, SMAD3, Collagen I, and α-SMA. The potential mechanism may involve activation of the TGF-β1/SMAD3 pathway, stimulating the secretion of Collagen I and α-SMA, and thereby facilitating wound closure in diabetic mice. The molecular docking results confirmed a high affinity between TFDG and TGF-β1/SMAD3.</div></div><div><h3>Conclusion</h3><div>TFDG NPS and TFDG NPS@hydrogel promoted wound closure in diabetic mice through the TFG-β1/SMAD3 pathway, thus exhibiting promising therapeutic potential for diabetic wound treatment.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"141 ","pages":"Article 156617"},"PeriodicalIF":6.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}