Phytomedicine最新文献

{"title":"Ponicidin promotes ferroptosis to enhance treatment sensitivity in Lenvatinib-resistant hepatocellular carcinoma cells through regulation of KEAP1/NRF2","authors":"Lisha Zhang ,&nbsp;Hao Wang ,&nbsp;Beibei Liang ,&nbsp;Lijuan Qin ,&nbsp;Mingzhu Zhang ,&nbsp;Xingxian Lv ,&nbsp;Shi Hu ,&nbsp;Xiaoyu Fan ,&nbsp;Wei Xie ,&nbsp;Hao Yang ,&nbsp;Gang Huang ,&nbsp;Wei Jing ,&nbsp;Jian Zhao","doi":"10.1016/j.phymed.2025.156824","DOIUrl":"10.1016/j.phymed.2025.156824","url":null,"abstract":"<div><h3>Objective</h3><div>This study explores the therapeutic potential of Ponicidin on Lenvatinib-resistant hepatocellular carcinoma (HCC), elucidates its mechanism in reversing Lenvatinib resistance, and provides experimental evidence for its clinical application in overcoming this resistance.</div></div><div><h3>Methods</h3><div>Huh7 and HCC-LM3 cells were used to construct Lenvatinib-resistant cell lines, Huh7-LR and HCC-LM3-LR. Changes in the ferroptosis pathway post-drug resistance were observed by measuring ferroptosis-related markers. The proliferation assay were assessed by CCK-8, while the migration and invasion were measured by scratch and Transwell invasion assays. In mechanistic study, chip analysis and immunoprecipitation with biotin-labeled Ponicidin, were conducted to explore how Ponicidin overcame drug resistance. Xenograft model in nude mice was established to examine Ponicidin’s anti-HCC effects <em>In vivo</em>. Clinical specimens were used to assess the true status of patients in Lenvatinib-resistant HCC patients.</div></div><div><h3>Results</h3><div>Our study reveals for the first time that ferroptosis inhibition drives Lenvatinib resistance in HCC and identifies Ponicidin as a novel KEAP1-targeting agent to reverse this process. In vitro, ferroptosis pathway was suppressed in Lenvatinib-resistant cells. Ponicidin suppressed proliferation, clonogenicity, migration, and invasion in these cells. The combination of Ponicidin and Lenvatinib significantly inhibited proliferation and reversed drug resistance by activating the ferroptosis pathway. Preliminary mechanistic studies showed that Ponicidin binds to KEAP1, stabilizing the KEAP1/NRF2 interaction, inhibiting the nuclear translocation and activation of NRF2, and thereby inducing ferroptosis to overcome Lenvatinib resistance. <em>In vivo</em>, the combination of Ponicidin and Lenvatinib exhibited a synergistic effect, significantly delaying tumor growth. Clinically, p-NRF2 and GPX4 expression was higher in the Lenvatinib-insensitive group, suggesting that the ferroptosis pathway was inhibited in these patients. Thus, this study demonstrated that Ponicidin promotes ferroptosis to enhances treatment sensitivity in Lenvatinib-resistant HCC cells through KEAP1/NRF2.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156824"},"PeriodicalIF":6.7,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144070877","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}

{"title":"Helja lectin inhibits Candida albicans phagocytosis and induces pro-inflammatory responses in dendritic cells","authors":"Maia Chop ,&nbsp;Marianela Del Rio ,&nbsp;Melisa B. Radicioni ,&nbsp;Ágata C. Cevey ,&nbsp;Marco J. Hernández-Chávez ,&nbsp;Héctor M. Mora-Montes ,&nbsp;Mariana Regente ,&nbsp;Christian Rodriguez Rodrigues","doi":"10.1016/j.phymed.2025.156637","DOIUrl":"10.1016/j.phymed.2025.156637","url":null,"abstract":"<div><h3>Background</h3><div>Plant lectins have gained attention for their antimicrobial and immunomodulatory properties and potential therapeutic applications in controlling infectious diseases and inflammatory disorders.</div></div><div><h3>Purpose</h3><div>This study focused on the effect of the sunflower lectin Helja on <em>Candida albicans</em> phagocytosis and its immunomodulatory effects on dendritic cells, to explore alternative immunotherapeutic strategies to control infectious diseases.</div></div><div><h3>Results</h3><div>Here, we showed that Helja lectin opsonizes and inhibits <em>C. albicans</em> phagocytosis by bone marrow-derived dendritic cells, induces dendritic cell maturation by upregulating co-stimulatory molecules, such as CD86 and MHC class II, promotes reactive oxygen species and nitric oxide generation and increases the production of the pro-inflammatory cytokines TNF-α, IL-12, and TGF-β. This cytokine profile was also observed in peripheral blood mononuclear cells, where Helja and <em>C. albicans</em> pre-incubated with the lectin promoted the release of TNF-α and IL-1β.</div></div><div><h3>Conclusion</h3><div>These findings suggest that Helja lectin has the potential to modulate dendritic cells and cytokine responses, indicating its role in immune regulation and underscoring the significance of this plant lectin as a potential therapeutic agent.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156637"},"PeriodicalIF":6.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927808","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}

{"title":"Valtrate alleviates inflammation by targeting USP9X to enhance NLRP3 degradation","authors":"Kaiyue Su ,&nbsp;Neng Ye ,&nbsp;Lei Lin ,&nbsp;Jie Wu ,&nbsp;Min Zhao ,&nbsp;Xueqin Jiang ,&nbsp;Ruijia Zhang ,&nbsp;Xiaoying Cai ,&nbsp;Xinlu Zhang ,&nbsp;Jing Peng ,&nbsp;Minghai Tang ,&nbsp;Na Li ,&nbsp;Lijuan Chen ,&nbsp;Haoyu Ye ,&nbsp;Wenshuang Wu","doi":"10.1016/j.phymed.2025.156835","DOIUrl":"10.1016/j.phymed.2025.156835","url":null,"abstract":"<div><h3>Background</h3><div>The NLRP3 inflammasome is a key regulator of innate immunity and plays a critical role in the pathogenesis of various inflammatory diseases. Regulating NLRP3 has emerged as a promising strategy for the development of anti-inflammatory therapies. Valtrate (Val), a natural compound derived from <em>Valeriana officinalis</em> Jones, has demonstrated significant anti-inflammatory activity. However, its precise mechanism of action remains unclear.</div></div><div><h3>Purpose</h3><div>This study elucidates the molecular mechanisms of Val suppressing NLRP3 inflammasome activation.</div></div><div><h3>Methods</h3><div>We screened 100 natural compounds for anti-pyroptotic in lipopolysaccharide (LPS)/nigericin-stimulated THP-1 cells and bone marrow-derived macrophages (BMDMs) using lactate dehydrogenase (LDH) release assays. Val's effect on NLRP3 were assessed <em>via</em> immunoblotting and ELISA. Target identification employed DARTS, proteomics, thermal shift assay (TSA), microscale thermophoresis (MST), and molecular dynamics (MD) simulations. <em>In vivo</em> efficacy was evaluated in acetaminophen (APAP)- and LPS-induced liver injury models.</div></div><div><h3>Results</h3><div>Val potently inhibited pyroptosis (99.20 % LDH reduction) and selectively degraded NLRP3 <em>via</em> post-translation mechanisms (PTMs) without altering its mRNA. DARTS and CETSA confirmed that Val directly interacts with the C2 fragment of USP9X without inhibiting its enzymatic activity, while RMSD, RMSF, and Gibbs energy landscape analyses supported its stable binding to USP9X, which was further confirmed by MST. Mechanistically, Val downregulated USP9X protein expression and promoted K48- and K63-linked ubiquitination and proteasomal degradation of NLRP3. <em>In vivo</em>, Val exhibited therapeutic potential in murine models of acute liver injury induced by APAP and LPS. Val reduced serum ALT and AST levels, inflammatory cytokines, and liver injury (histopathological analysis (H&amp;E) and TUNEL).</div></div><div><h3>Conclusion</h3><div>This study uncovers an unrecognized mechanism by which Val attenuates NLRP3 inflammasome activation by disrupting the USP9X-NLRP3 axis, thereby promoting NLRP3 ubiquitination and proteasomal degradation. Notably, Val down-regulates USP9X protein levels without impairing its catalytic activity, representing a distinct mechanism from existing USP9X inhibitors. These findings not only deepen our understanding of Val’s anti-inflammatory action but also underscore its promise as a lead compound for the development of novel therapeutics targeting NLRP3-driven inflammatory diseases.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156835"},"PeriodicalIF":6.7,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948048","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}

{"title":"Deciphering the molecular mechanisms of QLQX capsules in heart failure: A multi-omics perspective","authors":"Jiameng Hao ,&nbsp;Mingye Wang ,&nbsp;Qiulan Wu ,&nbsp;Tao Song ,&nbsp;Yuanyuan Hao ,&nbsp;Liping Chang ,&nbsp;Yunlong hou ,&nbsp;Zhenhua Jia","doi":"10.1016/j.phymed.2025.156828","DOIUrl":"10.1016/j.phymed.2025.156828","url":null,"abstract":"<div><h3>Purpose</h3><div>This study investigates the therapeutic mechanisms of Qiliqiangxin (QLQX) capsules in treating Heart Failure with Preserved Ejection Fraction (HFpEF). The study aims to understand how QLQX impacts cardiac function and underlying molecular pathways.</div></div><div><h3>Methods</h3><div>HFpEF was induced in a rat model through unilateral nephrectomy, DOCA pellet implantation, and a high-salt diet. Cardiac function was assessed via M-mode imaging and Doppler flow measurements, focusing on key parameters like ejection fraction and diastolic function. A network pharmacology approach identified active QLQX components and potential targets, followed by comprehensive multi-omics analyses—including transcriptomics, proteomics, and metabolomics—to uncover the molecular mechanisms modulated by QLQX. Quantitative RT-PCR was employed to measure mRNA levels of key cardiac markers, providing further insights into QLQX's impact on cardiac remodeling.</div></div><div><h3>Results</h3><div>QLQX treatment significantly improved cardiac function, with notable enhancements in ejection fraction and left ventricular diastolic function. Network pharmacology revealed 530 potential targets of QLQX, with 38 overlapping HFpEF targets. Key pathways identified include cGMP-PKG, adrenergic signaling, and calcium signaling. Transcriptomic analysis showed significant gene expression changes related to inflammation, energy metabolism, and myocardial remodeling, which were reversed by QLQX. Proteomic analysis identified 401 differentially expressed proteins, enriched in pathways such as cGMP-PKG and NF-κB signaling. Metabolomic profiling highlighted the role of lipid metabolism and adrenergic signaling in HFpEF, which were normalized by QLQX. In vivo validation confirmed the involvement of the cGMP-PKG pathway, with increased serum NO and cGMP levels, improved endothelial function, and reduced pro-fibrotic markers following QLQX treatment.</div></div><div><h3>Conclusion</h3><div>QLQX exerts multifaceted therapeutic effects on HFpEF by modulating gene expression, protein function, and metabolic pathways, particularly through the cGMP-PKG signaling pathway. These findings support QLQX as a promising therapeutic intervention for HFpEF, offering improvements in cardiac function and reversing pathological changes at multiple molecular levels.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156828"},"PeriodicalIF":6.7,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948049","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}

{"title":"Jian-pi Qu-tan Hua-yu Decoction improves oxidative stress-induced inflammation in endothelial cells in atherosclerotic ApoE-/- mice through the NOX1-ROS-ERK1/2 pathway","authors":"De Zhao Kong ,&nbsp;Xue Zhi Zhang ,&nbsp;Yi Lu ,&nbsp;Yuan Yuan Zhou ,&nbsp;Yi Hui Pan ,&nbsp;Xin Qi Zhao ,&nbsp;Xin Yu Wu ,&nbsp;Wei Wei Li ,&nbsp;Hui Ye","doi":"10.1016/j.phymed.2025.156815","DOIUrl":"10.1016/j.phymed.2025.156815","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis (AS) is a key mechanism in cardiovascular diseases and a major target for interventions. Jian-pi Qu-tan Hua-yu Decoction (JPQTHYD), a herbal formula, has been shown to alleviate AS.</div></div><div><h3>Objective</h3><div>This study aimed to evaluate the therapeutic effect of JPQTHYD on AS and explore its molecular mechanisms.</div></div><div><h3>Materials and Methods</h3><div>In vivo, we established a mouse model through a high-fat diet for 16 weeks combined with a 4-week exhaustive swimming experiment. The body weight and food intake of the mice were measured every 4 weeks. At the end of the 16 weeks, the moisture content of the mice's feces was measured, the morphology of the thoracic aorta and myocardium was observed using HE staining, and lipid deposition in the aorta and myocardium was assessed using Oil Red O staining. The ultrastructure of myocardial tissue was observed via transmission electron microscopy. Levels of TC, TG, and LDL-C were measured using an automatic biochemical analyzer. ELISA was used to detect the levels of ROS, IL-6, IL-10, TNF-α, hs-CRP, VCAM-1, and ICAM-1. In vitro, we induced HUVECs injury using 700 nM of Ang II. Cell viability was assessed using the CCK-8 assay, while ROS levels were measured by a ROS detection kit. NOX1 gene suppression was achieved using a NOX1 inhibitor. Protein expression levels of NOX1, ERK1/2, P-ERK1/2, VCAM-1, and ICAM-1 were measured by Western blot both in vivo and in vitro.</div></div><div><h3>Results</h3><div>1. JPQTHYD improved fecal water content and exercise capacity in ApoE-/- mice. 2. JPQTHYD reduced TC, TG, LDL-C levels, decreased arterial intimal thickness, and inhibited atherosclerotic plaque formation. 3. JPQTHYD decreased proinflammatory factors and adhesion molecules by inhibiting the NOX1-ROS-ERK1/2 pathway. 4. In vitro, JPQTHYD suppressed endothelial inflammation by reducing NOX1-ROS-ERK1/2 signaling.</div></div><div><h3>Conclusion</h3><div>JPQTHYD reduced blood lipids, inhibited oxidative stress-induced inflammation, and alleviated AS in ApoE-/- mice, likely through the NOX1-ROS-ERK1/2 pathway. This study offers a novel investigation into the mechanisms and regulatory pathways through which traditional Chinese medicine contributes to the prevention and treatment of atherosclerosis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156815"},"PeriodicalIF":6.7,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090247","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}

{"title":"Plantamajoside alleviates DSS-induced ulcerative colitis by modulating gut microbiota, upregulating CBS, and inhibiting NF-κB","authors":"Yongheng Jia ,&nbsp;Xianjun Liu ,&nbsp;Xinyi Gao ,&nbsp;Siyuan Yin ,&nbsp;Kun Wu ,&nbsp;Xianglong Meng ,&nbsp;Hui Ren ,&nbsp;Jiawei Liu ,&nbsp;Zijing Liu ,&nbsp;Hao Li ,&nbsp;Yang Jiang","doi":"10.1016/j.phymed.2025.156827","DOIUrl":"10.1016/j.phymed.2025.156827","url":null,"abstract":"<div><h3>Background</h3><div>Plantamajoside (PMS) is a natural bioactive compound derived from medicinal, food homologous plants of the genus <em>Plantago</em>.</div></div><div><h3>Purpose and Methods</h3><div>This study aimed to investigate the protective effects of PMS on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and explore the associated mechanisms.</div></div><div><h3>Results</h3><div>We found that PMS treatment significantly alleviated UC symptoms in mice by preventing body weight loss, increasing colon length, and reducing disease activity index scores. Moreover, PMS alleviated colonic lesions, increased the number of goblet cells, upregulated the expression of intestinal barrier proteins (ZO-1, occludin, and claudin-3), and decreased the levels of pro-inflammatory factors. PMS treatment modulated the gut microbiota by increasing the relative abundance of Bacteroidota and Verrucomicrobiota and decreasing that of Firmicutes and Proteobacteria at the phylum level. At the genus level, PMS suppressed the abundance of pathogenic bacteria, such as <em>Turicibacter</em> and upregulated the abundance of <em>[Eubacterium]_xylanophilum_group</em>. Fecal microbiota transplantation experiments further confirmed that PMS treatment alleviated UC by modulating the gut microbiota. Transcriptomic analysis of colon tissues, coupled with reverse transcription-quantitative polymerase chain reaction and western blotting, showed that PMS treatment upregulated cystathionine beta-synthase (CBS) expression and inhibited NF-κB pathway activation. In a lipopolysaccharide-induced inflammation model in RAW264.7 cells, PMS treatment inhibited the secretion of pro-inflammatory cytokines, upregulated CBS expression, and prevented NF-κB pathway activation.</div></div><div><h3>Conclusion</h3><div>PMS protects against UC in mice via multiple mechanisms, including modulating the gut microbiota, increasing the expression levels of CBS, and inhibiting the NF-κB pathway.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156827"},"PeriodicalIF":6.7,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144068031","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}

{"title":"Sophocarpine suppresses MAPK-mediated inflammation by restoring gut microbiota in colorectal cancer","authors":"Xiangjun Liu ,&nbsp;Yu Li ,&nbsp;Chenyue Yuan ,&nbsp;Yong Zhao ,&nbsp;Lin Zhou ,&nbsp;Yuting Yan ,&nbsp;Jianlin Ren ,&nbsp;Qingzhong Liu","doi":"10.1016/j.phymed.2025.156833","DOIUrl":"10.1016/j.phymed.2025.156833","url":null,"abstract":"<div><h3>Background</h3><div>Colorectal cancer (CRC), as one of the most common cancers globally, poses a significant challenge to public health due to its high incidence and mortality rates. This underscores the need for continuous exploration of new therapeutic targets and effective drugs. Sophocarpine (SC), a natural compound derived from traditional Chinese medicine, holds considerable therapeutic potential in the treatment of CRC, however, the relevant mechanisms remains unclear.</div></div><div><h3>Purpose</h3><div>This study aims to explore the anti-tumor effects of SC against CRC by modulating gut microbiota, and uncover potential mechanisms linking SC’s therapeutic effects to gut microbiota regulation by analyzing the impact of SC on microbiota composition and CRC progression.</div></div><div><h3>Material</h3><div>This study explores the impact of SC on the gut microbiota in CRC by constructing subcutaneous xenograft tumors of CRC and integrating 16S rRNA sequencing and RNA transcriptomic sequencing. The fecal microbiota transplantation (FMT) mouse model was used to validate the biological function of SC in correcting gut microbiota dysbiosis to treat CRC. Subsequently, we conducted <em>in vitro</em> studies on the molecular mechanisms by which SC regulates the gut microbiota as an effective hallmark of CRC treatment, using lipopolysaccharide (LPS) to simulate an inflammatory gut microbiota environment and P38 MAPK knockdown cell line.</div></div><div><h3>Results</h3><div>SC significantly inhibited CRC cell proliferation with IC₅₀ values of 2.547±0.256 μM for HCT116 and 2.851±0.332 μM for LoVo cells. <em>In vivo</em> experiments demonstrated that SC effectively suppressed tumor growth in xenograft models. 16S rRNA sequencing revealed that SC modulated gut microbiota composition, particularly affecting <em>Bacteroides</em> and <em>Alistipes</em> populations. SC significantly reduced the levels of inflammatory factors and inhibited the MAPK signaling pathway, as evidenced by decreased p-JNK, p-p38 MAPK, and p-NF-κB p65 expression.</div></div><div><h3>Conclusions</h3><div>Current clinical practice still lacks effective therapeutic agents targeting CRC through gut microbiota modulation. This study presents the first evidence that SC, a natural compound, exhibits dual-action therapeutic efficacy against CRC progression by simultaneously modulating gut microbial composition and suppressing MAPK pathway-mediated inflammatory responses. These findings highlight SC's novel therapeutic potential as a promising microbiota-regulating candidate for CRC intervention, offering an innovative approach that bridges microbial ecology with cancer signaling pathways.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156833"},"PeriodicalIF":6.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090245","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}

{"title":"Lonicerin targets ADRA1D and RSPO3 to ameliorate diabetes-induced vascular injury through Ca2+/Calcineurin/NFAT1-dependent anti-EndMT pathway","authors":"Minghui Wang ,&nbsp;Huiying Cai ,&nbsp;Manman Wang ,&nbsp;Honggang Gao ,&nbsp;Xiaona Zhao ,&nbsp;Ruixue Rong ,&nbsp;Jing Zhang ,&nbsp;Zejin Zhang ,&nbsp;Guoqing Liu ,&nbsp;Tao Yuan ,&nbsp;Fangjie Xia ,&nbsp;Lin Zhu ,&nbsp;Zhenzhen Yan ,&nbsp;Xinxin Kong ,&nbsp;Wei Qin","doi":"10.1016/j.phymed.2025.156832","DOIUrl":"10.1016/j.phymed.2025.156832","url":null,"abstract":"<div><h3>Background</h3><div>Cardiovascular complications are the primary cause of mortality and disability among diabetic patients. Lonicerin, a major bioactive compound in <em>Lonicera japonica</em> Thunb., has unclear effects and mechanisms on diabetic vascular injury.</div></div><div><h3>Purpose</h3><div>The research aims to investigate the therapeutic effects of lonicerin on diabetic vascular injury and elucidate its underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>Streptozotocin (STZ)-induced mice and high glucose-treated human aortic endothelial cells (HAECs) were employed as animal and cellular models of diabetes. Endothelial-to-mesenchymal transition (EndMT) was validated by examining EndMT-related markers and endothelial/mesenchymal functions. RNA sequencing was used to identify potential mechanisms through which lonicerin alleviates EndMT. The relationship between lonicerin and its targets was investigated using RNAi, plasmid overexpression, western blot, qRT-PCR, immunofluorescence, flow cytometry, and calcineurin activity assays.</div></div><div><h3>Results</h3><div>Lonicerin dose-dependently alleviates diabetes-induced vascular injury (intimal damage, inflammation, calcification, and fibrosis) and EndMT. Lonicerin produces anti-EndMT effect by inhibiting cytoplasmic Ca²⁺ levels. Further analysis reveals that adrenoceptor alpha 1D (ADRA1D) and R-spondin 3 (RSPO3) are targets of lonicerin. Lonicerin reduces high glucose-induced upregulation of ADRA1D and RSPO3, leading to decreased cytoplasmic Ca²⁺ levels. This reduction inhibits calcineurin activity, promotes nuclear factor of activated T cells 1 (NFAT1) phosphorylation, and prevents its nuclear translocation, ultimately exerting an anti-EndMT effect. EC-specific overexpression of ADRA1D or RSPO3 negates the inhibitory effects of lonicerin on EndMT and its therapeutic impact on diabetic vascular injury.</div></div><div><h3>Conclusion</h3><div>Lonicerin targets ADRA1D and RSPO3 to ameliorate diabetes-induced vascular injury through the Ca²⁺/Calcineurin/NFAT1-dependent anti-EndMT pathway. Thus, this study provides the first evidence that lonicerin is a potential novel therapeutic agent for diabetic vasculopathy.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156832"},"PeriodicalIF":6.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107495","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}

{"title":"Camellia Japonica Radix modulates gut microbiota and 9(S)-HpODE-mediated ferroptosis to alleviate oxidative stress against MASLD","authors":"Simin Gu ,&nbsp;Chong Chen ,&nbsp;Junmin Wang ,&nbsp;Yanping Wang ,&nbsp;Lina Zhao ,&nbsp;Zhekun Xiong ,&nbsp;Hui Zhang ,&nbsp;Taoying Deng ,&nbsp;Qihui Pan ,&nbsp;Yiyuan Zheng ,&nbsp;Yong Li","doi":"10.1016/j.phymed.2025.156806","DOIUrl":"10.1016/j.phymed.2025.156806","url":null,"abstract":"<div><h3>Background</h3><div><em>Camellia japonica radix</em> (CJR), derived from the root of <em>Camellia japonica</em> L., has the potential to function as an herbal tea substitute for the prevention and intervention of metabolic dysfunction-associated steatotic liver disease (MASLD). It can provide systemic therapeutic benefits, boast a favorable safety profile, facilitate convenient consumption, and support long-term applicability. Despite its potential, research on CJR remains limited.</div></div><div><h3>Purpose</h3><div>The aim of this study aims is to elucidate the therapeutic mechanisms of CJR in MASLD, thereby providing evidence to support its clinical application.</div></div><div><h3>Methods</h3><div>The therapeutic effects of CJR were evaluated using a water-supplementation model in MASLD mice. Integrated microbiome, transcriptome, proteome, and metabolome analyses were employed to comprehensively explore the mechanisms involved. A drug-target pull-down assay was performed to identify specific protein targets of small molecule metabolites in vitro. Fecal microbiota transplantation in antibiotic-treated ABX mice was conducted to confirm the critical role of gut microbiota and its metabolites. Furthermore, customized medicated feed supplemented with linoleic acid was used to explore the intervention effect of its metabolite, 9(S)-HpODE, as well as to evaluate its dietary intervention potential.</div></div><div><h3>Results</h3><div>This present study explicitly elucidates the efficacy of CJR extract in alleviating hepatic inflammation and steatosis in a MASLD model mice, with its pharmacological mechanism associated with gut microbiota, linoleic acid metabolism, and GPX4-mediated ferroptosis. Notably, 9(S)-HpODE was discovered to be a key metabolite of linoleic acid, which could target both KEAP1 and SLC7A11, bidirectionally regulating GPX4-mediated ferroptosis, while acting as a signaling molecule at low doses to induce redox adaptation via oxidative preconditioning, thus ameliorating oxidative stress in MASLD.</div></div><div><h3>Conclusion</h3><div>Our findings indicate that both CJR and linoleic acid exhibit significant potential as dietary interventions for the management of MASLD, offering promising avenues for future research and clinical application.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156806"},"PeriodicalIF":6.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913295","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}

{"title":"Deoxypodophyllotoxin inhibited the growth of malignant pleural mesothelioma by inducing necroptosis and mitotic catastrophe","authors":"Cheng Zhong ,&nbsp;Shenqi Wang ,&nbsp;Jingyuan Zhang ,&nbsp;Qi Zheng ,&nbsp;Yuqiong Lei ,&nbsp;Yongle Xu ,&nbsp;Tao Ren ,&nbsp;Rong Sun","doi":"10.1016/j.phymed.2025.156786","DOIUrl":"10.1016/j.phymed.2025.156786","url":null,"abstract":"<div><h3>Background:</h3><div>Malignant pleural mesothelioma (MPM) is an extremely aggressive cancer with a poor prognosis and limited effective treatment options. However, recent studies have shown that targeting microtubule regulation is a viable approach for treating MPM.</div></div><div><h3>Purpose:</h3><div>This study aimed to assess the antitumor behavior of deoxypodophyllotoxin (DPT) on MPM in vitro and in vivo and to identify its underlying mechanisms.</div></div><div><h3>Study Design:</h3><div>The study employed in vitro and in vivo models to evaluate the efficacy and mechanisms of DPT against MPM. We used cell-culture techniques, molecular-biology assays, and a xenograft mice module to thoroughly study the effects of DPT.</div></div><div><h3>Methods:</h3><div>Three MPM cell lines (H2452, H28, and 211H) and a xenograft mice module were used to assess the antitumor effects of DPT. The cell-cycle and cell-death rates were assessed by flow cytometry to study DPT-induced mitotic cell death. Moreover, the role of necroptosis in the antitumor effect of DPT was determined through transmission electron microscopy and western blot analysis, with further validation being done via RIP1 inhibition by Necrostatin-1 (Nec-1), a RIPK1 inhibitor, and MLKL silencing by siRNAs.</div></div><div><h3>Results:</h3><div>DPT was found to inhibit MPM cell growth in a dose-dependent manner in vitro and in vivo. Specifically, transmission electron microscopy showed plasma-membrane rupture with the preserved nuclear integrity of MPM cells after DPT treatment, indicating necroptosis in DPT-treated MPM cells. Moreover, a western blot revealed further proof of tumor necrosis factor alpha (TNF-<span><math><mi>α</mi></math></span>)-associated necroptosis-pathway activation, as revealed by the phosphorylation of the key proteins receptor-interacting protein kinase 1 (RIP1), receptor-interacting protein kinase 3 (RIP3), and mixed-lineage kinase domain-like pseudokinase (MLKL). Additional experiments with TNF-<span><math><mi>α</mi></math></span> receptor TNFR1 silencing, RIP1 inhibitors and MLKL silencing reinforced the influential role of TNF-<span><math><mi>α</mi></math></span>- RIP1-RIP3-MLKL activation in DPT-induced necroptosis. Also, DPT triggered mitotic catastrophe, observable by a defective spindle assembly, multinucleation, and micronucleation. Pretreatment with the S-phase arrest inducer thymidine was reduced both DPT-induced cell death and RIP1 phosphorylation, suggesting an interplay between necroptosis and mitotic arrest.</div></div><div><h3>Conclusion:</h3><div>DPT may offer a novel therapeutic option for MPM, with drug-induced necroptosis and mitotic catastrophe being key underlying mechanisms.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156786"},"PeriodicalIF":6.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948047","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}