Phytomedicine最新文献

{"title":"Mult-omics analysis reveals the lipid-lowering effects of sea buckthorn and milk thistle solid beverage in hyperlipidemic rats","authors":"Yuwei Bai ,&nbsp;Jianglong Li ,&nbsp;Xueqian Wu ,&nbsp;Mei Zhang ,&nbsp;Yaping Zhang ,&nbsp;Ping Chen ,&nbsp;Jiajing Ma ,&nbsp;Suzhen Zhang ,&nbsp;Haicheng Zhang ,&nbsp;Xiangjun Li ,&nbsp;Zhigang Yang","doi":"10.1016/j.phymed.2025.156920","DOIUrl":"10.1016/j.phymed.2025.156920","url":null,"abstract":"<div><h3>Background</h3><div>Hyperlipidemia is a common metabolic disorder and a risk factor for cardiovascular disease. The traditional medicine herb, <em>Hippophae rhamnoides</em> L., known as sea buckthorn<em>,</em> has anti-obesity and lipid-lowering effects, while <em>Silybum marianum</em> (L.) Gaertn, known as milk thistle, has hepatoprotective properties and exhibits antioxidant effects.</div></div><div><h3>Purpose</h3><div>To evaluate the effect of sea buckthorn and milk thistle solid beverage (H-S solid beverage) in alleviating hyperlipidemia in rats and explore the underlying mechanisms by analyzing plasma and liver metabolomics, lipidomics, and liver transcriptomics.</div></div><div><h3>Methods</h3><div>A hyperlipidemic rat model was established after 2 weeks of high-fat diet (HFD) feeding in Sprague Dawley rats. The administered doses of H-S solid beverage were 0.30 g/kg/d, 0.15 g/kg/d and 0.075 g/kg/d. Serum biochemical parameter detection, histopathological section analysis, untargeted plasma and liver metabolomics, lipidomics, and liver transcriptomics were performed to determine the therapeutic effects of H-S solid beverage and predict the related pathways in rats with hyperlipidemia. Changes in genes and proteins related to lipid metabolism were detected using real-time quantitative polymerase chain reaction and western blotting.</div></div><div><h3>Results</h3><div>Eighty-nine components were identified in H-S solid beverage using ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry, with flavonoids being the major constituents. The H-S solid beverage significantly reduced body weight, liver index, body fat percentage, lipid accumulation, and liver injury in HFD-fed rats. Fatty acids (FA), bile acid, phosphatidyl ethanolamine, phosphatidylcholine, triglyceride, cholesterol ester, diglyceride and phosphatidylinositol levels were significantly altered in the liver and plasma. Moreover, the transcriptomic analysis suggested that H-S solid beverage significantly altered the hepatic gene expression of cholesterol synthesis (<em>Pdk4, Hmgcs1</em>, and <em>Dhcr24</em>), lipogenesis (<em>Scd, Angptl4</em>, and <em>Angptl8</em>), and FA β-oxidation (<em>Cpt1α, Pparδ, Acsl, Pgc-1α</em>, and <em>Pla2g2d</em>).</div></div><div><h3>Conclusion</h3><div>The solid beverage of sea buckthorn and milk thistle was firstly demonstrated to ameliorate HFD-induced hyperlipidemia. The lipid-lowering and hepatoprotective effects of H-S solid beverage significantly regulated cholesterol synthesis and de novo lipogenesis, as well as FA β-oxidation. In summary, this study highlights the potential of H-S solid beverages for the treatment of hyperlipidemia.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"144 ","pages":"Article 156920"},"PeriodicalIF":6.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212847","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":"Synergistic effects of heterophyllin B with nintedanib against experimental pulmonary fibrosis in mice","authors":"Ce Chen ,&nbsp;Zeyu Han ,&nbsp;Jiawen Luo ,&nbsp;Jialin Wang ,&nbsp;Tingting Liu ,&nbsp;Jie Zhang ,&nbsp;Chaofeng Zhang","doi":"10.1016/j.phymed.2025.156922","DOIUrl":"10.1016/j.phymed.2025.156922","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary fibrosis (PF) is a chronic, lethal lung disease marked by permanent alterations to the lung tissue architecture. Although nintedanib (NDN) has been approved for clinical use, its therapeutic potential is substantially hampered by severe gastrointestinal side effects, notably diarrhea, which compromise patient adherence and quality of life.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate whether heterophyllin B (HB) could augment the antifibrotic efficacy of NDN while mitigating its gastrointestinal toxicity.</div></div><div><h3>Methods</h3><div>The therapeutic potential of HB was evaluated in a bleomycin (BLM)-induced murine model of PF. Alterations in gut microbiota and serum metabolic profiles were determined via 16S rRNA gene sequencing and untargeted metabolomics, respectively. Mechanistic insights were performed in NCM460 colonic epithelial cells through IDO1 silencing, ferroptosis inhibition, CETSA and molecular dynamics experiments. Furthermore, the synergistic and protective effects of HB on NDN were investigated in BLM-induced mice, along with analysis of intestinal microbiota composition. The active constituents of the EtOAc extract of Radix Pseudostellariae were identified using UPLC-Q-TOF-MS/MS, GNPS, and NMR spectroscopy.</div></div><div><h3>Results</h3><div>Administration of HB (40 mg/kg/day for approximately 14 days) significantly attenuated lung fibrosis progression and substantially alleviated diarrhea in BLM-induced PF mice. HB reshaped the intestinal microecology and reprogrammed serum metabolism, notably by reducing the abundance of <em>Escherichia-Shigella</em>, as revealed by 16S rRNA sequencing and untargeted metabolomics analyses. Furthermore, the co-treatment of HB and NDN demonstrated enhanced efficacy and reduced gastrointestinal toxicity both in vivo and in vitro. Mechanistic investigations indicated that HB-enriched 3-hydroxybutyric acid (3-HA) restored intestinal mucosal barrier integrity by inhibiting IDO1-mediated ferroptosis. Additionally, extracts of Radix Pseudostellariae containing HB-like cyclopeptides significantly improved PF symptoms and intestinal epithelial injury in BLM-induced mice. Nine cyclopeptide compounds (Herterophyllin A-B, D and Psedostellarin A-E, G) were identified in the extract via UPLC-Q-TOF-MS/MS analysis.</div></div><div><h3>Conclusion</h3><div>HB offers dual protection against pulmonary fibrosis and intestinal damage through its regulatory impact on the gut–lung axis and suppression of ferroptosis mechanisms. Collectively, HB offers a promising adjuvant to optimize NDN-based antifibrotic therapy, offering a novel strategy for integrated pulmonary and gastrointestinal protection in PF management.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"144 ","pages":"Article 156922"},"PeriodicalIF":6.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263066","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":"Gene signature-guided isolation identifies cucurbitacins as STAT3 inhibitors from Picria fel-terrae Lour","authors":"Shengrong Li ,&nbsp;Qianyu Wang ,&nbsp;Lei Xiang ,&nbsp;Xiankuo Yu ,&nbsp;Xiaofang Ma ,&nbsp;He Duan ,&nbsp;Chao Hu ,&nbsp;Qingzhou Li ,&nbsp;Jun An ,&nbsp;Yan Luo ,&nbsp;Lijun Huang ,&nbsp;Chen Zhang ,&nbsp;Yumei Wang ,&nbsp;Yuhui Chen ,&nbsp;Dale Guo ,&nbsp;Kaifeng Hu ,&nbsp;Pan Hu ,&nbsp;Dong Wang","doi":"10.1016/j.phymed.2025.156898","DOIUrl":"10.1016/j.phymed.2025.156898","url":null,"abstract":"<div><h3>Background</h3><div>The transcription activator factor signal transducer and activator of transcription 3 (STAT3) diseases, such as triple-negative breast cancer (TNBC), making the need to identify new inhibitors crucial for effective treatment. In this regard, plants used in traditional Chinese medicine, including <em>Picria fel-terrae</em> Lour. (PFL), represent a rich source of bioactive compounds for identifying STAT3 inhibitors.</div></div><div><h3>Aim</h3><div>To identify novel STAT3 inhibitors in PFL based on a gene signature-guided isolation approach</div></div><div><h3>Methods</h3><div>Based on transcriptome analysis, we identified PFL as a potential source of STAT3 inhibitors. We used STAT3 downstream genes C-X-C motif chemokine ligand 10 and 11 (<em>CXCL10</em> and <em>CXCL11</em>) to define the gene signature, and using qPCR, chemical isolation, and other selected methods, we validated STAT3 inhibitors, which were further assessed using TNBC animal models.</div></div><div><h3>Results</h3><div>By performing gene signature-guided isolation, we identified a number of candidate STAT3 inhibitors, namely, Cucurbitacin D (CuD), Cucurbitacin F (CuF), Cucurbitacin I (CuI), along with the novel compound, FN135422. Analyses of these compounds revealed that they inhibited phosphorylation of the Tyr705 residue of the STAT3 protein, and thus the transcriptional function of STAT3. Biochemical assays revealed that CuD, CuF, and CuI can bind directly to STAT3, and we identified one α,β-unsaturated carbonyl group as the important functional group of cucurbitacins associated with the inhibition of STAT3 function. Moreover, we demonstrated that these cucurbitacins can inhibit STAT3 function and TNBC growth <em>in vivo</em>.</div></div><div><h3>Conclusion</h3><div>With this study, we establish a novel approach for the isolation of function-specific bioactive compounds from the medicinal plant PFL, and identified cucurbitacins as potential STAT3-targeting antitumour agents.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"144 ","pages":"Article 156898"},"PeriodicalIF":6.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144253937","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":"Ponicidin triggered ferroptosis in esophageal squamous cell carcinoma by suppressing the SLC7A11/Glutathione/GPX4 signalling axis","authors":"Wenhu Liu ,&nbsp;Jinhua Zhang ,&nbsp;Min Wu ,&nbsp;Dan Ren ,&nbsp;Chuan Chen ,&nbsp;Zuo Du ,&nbsp;Qianhui Li ,&nbsp;Jinxia Chang ,&nbsp;Qi Pu ,&nbsp;Zhenzhong Liu","doi":"10.1016/j.phymed.2025.156925","DOIUrl":"10.1016/j.phymed.2025.156925","url":null,"abstract":"<div><h3>Background</h3><div>Ponicidin, a diterpenoid derived from <em>Rabdosia rubescens</em>, exhibits potent antitumor activity. However, its mechanisms against esophageal squamous cell carcinoma (ESCC) remain obscure. This study aims to explore the effects of ponicidin against ESCC and reveal its molecular mechanisms.</div></div><div><h3>Methods</h3><div>The anti-ESCC effects of ponicidin were evaluated using CCK-8 assay, colony formation and transwell invasion assays. Cell cycle progression and mitochondrial membrane potential were analyzed using flow cytometry. Proteomics was applied to explore ponicidin’s mechanisms. Ferroptosis induction was evaluated by quantifying reactive oxygen species, Fe²⁺, malondialdehyde, glutathione, and lipid peroxidation levels. Docking and molecular dynamics simulations were conducted to identify the targets. siRNA was employed to validate target. The efficacy of ponicidin on tumorigenicity was explored in tumor xenograft mouse models, and its biosafety was evaluated via hemolysis assays, plasma ALT, AST, BUN, and CRE levels, as well as histopathological examinations. Western blot was used to analyze protein expression levels.</div></div><div><h3>Results</h3><div>Ponicidin inhibited ESCC cell proliferation, arrested cells in the G₂/M phase, reduced mitochondrial membrane potential, and suppressed tumor growth without evident toxicity. Proteomics identified that ponicidin-induced ferroptosis is the predominant mechanism against ESCC. Ponicidin increased reactive oxygen species, malondialdehyde, Fe²⁺, lipid peroxidation and glutathione depletion. Ferrostatin-1 pretreatment reduced lipid peroxidation, rescued PON induced inhibition of cell viability, and reversed the decreased expression of SLC7A11, GPX4 and GSR. Molecular docking revealed strong binding affinity of PON to GPX4 (-7.31±0.55 kcal/mol) and SLC7A11 (-8.19±0.37 kcal/mol). Molecular dynamics simulations confirmed stabilized complexes with total interaction energies of -23.43 ± 2.13 kcal/mol (GPX4-PON) and -31.42 ± 0.84 kcal/mol (SLC7A11-PON). siRNA-mediated knockdown of GPX4 and SLC7A11 reduced ESCC sensitivity to ponicidin-induced ferroptosis.</div></div><div><h3>Conclusion</h3><div>This study provides the first evidence that ponicidin triggers ferroptosis in ESCC cells via suppression of the SLC7A11/glutathione/GPX4 signalling axis, offering actionable targets for ferroptosis-enhancing combination therapies.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156925"},"PeriodicalIF":6.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144185590","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":"Protocatechuic acid suppresses ferroptosis to protect against hypoxic-ischemic encephalopathy by targeting the HIF-1α/VEGFA axis","authors":"Xiaoling Zhang ,&nbsp;Jingjing Luo ,&nbsp;Laxman Bharati ,&nbsp;Ziyu Hua ,&nbsp;Sha Chen ,&nbsp;Zhi Dong","doi":"10.1016/j.phymed.2025.156900","DOIUrl":"10.1016/j.phymed.2025.156900","url":null,"abstract":"<div><h3>Background</h3><div>Patients with Hypoxic–ischemic encephalopathy (HIE) face substantial risks of poor neurological outcomes and fatal complications, imposing a substantial clinical burden. Protocatechuic acid (PCA), a safe, water-soluble antioxidant with demonstrated neuroprotective properties, has emerged as a promising perinatal therapeutic candidate. However, its mechanisms of action in HIE remain poorly understood. Notably, previous research on HIE has primarily focused on neuronal cells, with limited attention paid to its effects on endothelial cells. Our study emphasizes the role of PCA in cerebral endothelial cells and the subsequent impact of the altered microenvironment on neuronal cells, which may provide a novel therapeutic strategy for HIE.</div></div><div><h3>Purpose</h3><div>Our subject discuss the role and mechanisms of PCA in HIE.</div></div><div><h3>Study design</h3><div>This study observed that PCA exhibits a mitigating effect on HIE, prompting further investigation. Utilizing network pharmacology and RNA sequencing analysis, we elucidated the pathways through which PCA exerts its effects on HIE. Subsequently, we conducted verification using animal and cellular models.</div></div><div><h3>Methods</h3><div>The Rice-Vannucci technique was used to generate neonatal HIE, and Bend. 3 cells were used to create an oxygen–glucose deprivation/reoxygenation (OGD/R) model. To clarify the neuroprotective mechanisms of PCA, a thorough multidisciplinary approach was used, including network pharmacology, RNA sequencing, TTC staining, behavioral evaluations, western blotting, and immunofluorescence.</div></div><div><h3>Results</h3><div>The results showed that PCA helps prevent ferroptosis and reduces damage caused by HIE, suggesting it could be a useful treatment in medicine. In vivo, PCA improved neurological outcomes, reduced the infarct volume, and alleviated HIE-related pathological changes by enhancing VEGFA nuclear translocation and activating the hypoxia-inducible factor 1-alpha (HIF-1α)/VEGFA signaling pathway in cerebrovascular endothelial cells. In vitro, PCA suppressed oxidative stress and ferroptosis marker levels, effects that were reversed by the HIF-1α inhibitor PX-478, and co-culture with neuronal cells alleviated OGD/R-induced neuronal confirming the critical role of this pathway in PCA-mediated neuroprotection.</div></div><div><h3>Conclusion</h3><div>In conclusion, PCA confers robust protection against ferroptosis-mediated damage in HIE, with its neuroprotective effects mechanistically linked to the regulation of ferroptosis through the HIF-1α/VEGFA axis in brain microvascular endothelial cells. Moreover, PCA-modified endothelial cell microenvironment ameliorates neuronal damage following injury. These results highlight PCA's therapeutic potential and lay the groundwork for additional translational studies.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156900"},"PeriodicalIF":6.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144147801","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":"Lian Qiao Wen Dan Decoction attenuates gastric carcinogenesis by alleviating oxidative phosphorylation dysfunction","authors":"Xiuping Chi ,&nbsp;Yanru Song ,&nbsp;Sisi Wei ,&nbsp;Guangjun Wang ,&nbsp;Yang Wen ,&nbsp;Zhe Zhang ,&nbsp;Cong Zhang ,&nbsp;Hongtao Zhang ,&nbsp;Zhongdong Hu ,&nbsp;Haiyang Yu ,&nbsp;Bingjie Huo ,&nbsp;Baoen Shan ,&nbsp;Lianmei Zhao","doi":"10.1016/j.phymed.2025.156924","DOIUrl":"10.1016/j.phymed.2025.156924","url":null,"abstract":"<div><h3>Background</h3><div>Wen Dan Decoction (WDD) is primarily utilized as an “expectorant” in clinical practice. The combination of WDD and Lian Qiao (LQWDD) exhibits synergistic effects on phlegm resolution, qi regulation, and detoxification. In preliminary clinical practice, we observed that LQWDD effectively alleviates the severity of gastric precancerous lesions. Nevertheless, the underlying mechanism remains elusive.</div></div><div><h3>Purpose</h3><div>This study was designed to explore the efficacy and potential mechanisms of LQWDD against gastric carcinogenesis.</div></div><div><h3>Methods</h3><div>Retrospective analyses of patients with gastric precancerous lesions and an N-methyl-N9-nitro-N-nitrosoguanidine (MNNG)-induced rat gastric cancer model were conducted to evaluate the efficacy of LQWDD against gastric carcinogenesis. Proteomic analyses were employed to investigate the underlying mechanisms of LQWDD. Moreover, energy metabolites were quantified using metabolomics. Network pharmacology and high-performance liquid chromatography-mass spectrometry were integrated to elucidate the potential active components of LQWDD. Additionally, seahorse analysis and RNA sequencing were used to explore the effects and underlying mechanisms of compound quercetin on oxidative phosphorylation.</div></div><div><h3>Results</h3><div>LQWDD effectively impeded gastric carcinogenesis in an MNNG-induced rat gastric cancer model and patients. Proteomic analyses revealed that LQWDD protected the integrity of the oxidative phosphorylation pathway during gastric carcinogenesis, which was significantly suppressed in human gastric intraepithelial neoplasia and MNNG-induced gastric carcinoma. Moreover, LQWDD administration significantly reversed MNNG-induced reductions in the expression of mitochondrial complex I-related proteins (ALDH3A1 and NDUFS4), as well as in ATP, NAD⁺, and metabolite levels, indicating its protective role against oxidative phosphorylation dysfunction through the modulation of mitochondrial complex I-associated proteins. Furthermore, quercetin and kaempferol were identified as potential active components of LQWDD. These components suppressed the growth of gastric cancer cells and patient-derived organoids while simultaneously increasing intracellular ATP and NAD⁺ levels. Notably, quercetin exerted its preferential regulatory role in mitochondrial oxidative respiration by activating the AMPK signaling pathway.</div></div><div><h3>Conclusions</h3><div>Our study provides the first systematic evidence that mitochondrial OXPHOS dysfunction plays a pivotal role in gastric carcinogenesis. LQWDD and its potential active ingredient quercetin inhibit gastric carcinogenesis by mitigating oxidative phosphorylation impairment, highlighting on a promising therapeutic prescription for treating with gastric precancerous lesions.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"144 ","pages":"Article 156924"},"PeriodicalIF":6.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241483","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":"CBX5 loss drives Pl3Kδ inhibitor resistance in mantle cell lymphoma and propolis restores sensitivity by inducing CBX5-mediated ferroptosis","authors":"Jun Lu ,&nbsp;Ya-Qin Yang ,&nbsp;Jia-Yi Tang ,&nbsp;Si-Yue Lou ,&nbsp;Chen Wang ,&nbsp;Hong-Tao Hu ,&nbsp;Ya-Nan Zheng ,&nbsp;Hai An ,&nbsp;Mao-Wei Ni ,&nbsp;Hua-Jun Zhao","doi":"10.1016/j.phymed.2025.156911","DOIUrl":"10.1016/j.phymed.2025.156911","url":null,"abstract":"<div><h3>Background</h3><div>The generation of drug-resistance limits chemotherapy application such as phosphoinositide 3-kinase δ (PI3Kδ) inhibitors in mantle cell lymphoma (MCL). Propolis has been regarded as a resistance reversal agent for many tumors, but its role in the sensitivity of MCL to PI3Kδ inhibitors remains unclear.</div></div><div><h3>Purpose</h3><div>The study investigated the synergistic effect, material basis and underlying mechanism of propolis in PI3Kδ inhibitor-resistant MCL cells.</div></div><div><h3>Methods</h3><div>A PI3Kδ inhibitor resistance-acquired model was established and proteomics was utilized to identify differentially expressed proteins. The ethanol extract of propolis (EEP) was obtained and its components were detected by using UPLC-Q-TOF-MS/MS analysis. Active ingredients with potential resistance-reversal effect were obtained by reverse pharmacology. The sensitizing effect of caffeic acid phenethyl ester (CAPE) on idelalisib was demonstrated by cell viability assay <em>in vitro</em> and tumor-growth study <em>in vivo</em>. RNA-sequencing was applied to obtain CAPE-regulated genes. The occurrence of ferroptosis was confirmed by relevant detections such as lipid ROS detection. The regulation of chromobox homolog 5 (CBX5) was achieved by molecular inhibitors, transfection of recombinant plasmid or siRNA.</div></div><div><h3>Results</h3><div>EEP combined with idelalisib synergistically reduced the viability of resistant MCL cells, with CAPE playing a major role. The combination of CAPE and idelalisib combated the growth of idelalisib-resistant MCL cells <em>in vivo and in vitro</em> by inducing ferroptosis. The CBX5 level influences the sensitivity to PI3Kδ inhibitors, and CAPE reversed resistance in MCL-R by inducing CBX5-mediated ferroptosis.</div></div><div><h3>Conclusions</h3><div>CBX5 loss drives Pl3Kδ inhibitor resistance in MCL and CAPE in propolis restores sensitivity by inducing CBX5-mediated ferroptosis. This is the first study to demonstrate the reversal of PI3Kδ inhibitor resistance through CAPE-induced ferroptosis via CBX5 modulation.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156911"},"PeriodicalIF":6.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144194838","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":"Efficacy and safety of Shuxuening injection in patients with unstable angina: a multicenter, randomized, placebo-controlled trial","authors":"Lintong Yu ,&nbsp;Shiyi Tao ,&nbsp;Qian Lin ,&nbsp;Sheng Gao ,&nbsp;Xitian Hu ,&nbsp;Xiaoping Li ,&nbsp;Xiaofeng Wang ,&nbsp;Huijun Chen ,&nbsp;Xianyou Ji ,&nbsp;Qiufang Lian ,&nbsp;Daoqun Jin ,&nbsp;Jingyu Xu ,&nbsp;Jun Feng ,&nbsp;Yanling Qu ,&nbsp;Deying An ,&nbsp;Chunmei Qi ,&nbsp;Ling Chen ,&nbsp;Mingqi Zheng ,&nbsp;Guiqiu Cao ,&nbsp;Jing Liu ,&nbsp;Helin Li","doi":"10.1016/j.phymed.2025.156916","DOIUrl":"10.1016/j.phymed.2025.156916","url":null,"abstract":"<div><h3>Objective</h3><div>To determine the efficacy and safety of adjunct Shuxuening Injection (SXN) on conventional therapy in patients with unstable angina (UA) which provides a complementary choice and its evidence for clinical medication for treating UA.</div></div><div><h3>Methods</h3><div>In this multicenter, randomized, double-blind, placebo-controlled trial, 469 patients with UA from 25 hospitals in China who had an episode of angina within 48 hours were randomly assigned 3:1 to SXN and placebo group for 10 days in addition to conventional treatment. The primary outcome is the frequency of angina pectoris attacks after 10 days of intervention. The secondary outcomes are the frequency of angina pectoris attacks on day 30, the duration of angina pectoris symptoms, the visual analogue scale (VAS) score, total score of angina pectoris symptoms, the Global Registry of Acute Coronary Events (GRACE) score, total ischemia burden (TIB), and the level of high-sensitivity C-reactive protein (hs-CRP).</div></div><div><h3>Results</h3><div>A total of 469 participants from 25 hospitals in China were enrolled in this trial. After 10 days of treatment, the frequency and duration of angina pectoris attacks, VAS score, and total score of angina pectoris symptoms exhibited a significant improvement in the SXN group compared to the placebo group both on days 10 and 30 (all <em>P</em>&lt;0.05). The GRACE risk score classification, TIB, and hs-CRP levels in the SXN group showed no statistically significant decrease compared to the control group on day 10 (all <em>P</em>&gt;0.05). The medication compliance, concomitant medication, and rates of adverse events were similar between the two groups (<em>P</em>&gt;0.05).</div></div><div><h3>Conclusion</h3><div>In patients with UA, SXN added on conventional treatment reduced the frequency and duration of angina pectoris attacks, even after discontinuation of the intervention for 20 days.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"144 ","pages":"Article 156916"},"PeriodicalIF":6.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144229715","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":"Unveiling XinJia-LuHuang Granules' protective mechanism against atherosclerosis: Integrating network pharmacology, metabolomics, and experimental validation","authors":"Xueqian Liu ,&nbsp;Lele Liu ,&nbsp;Xiang Ren ,&nbsp;Yunhu Chen ,&nbsp;Moqing Yin ,&nbsp;Haitao Xie ,&nbsp;Tong Sun ,&nbsp;Yali Tan ,&nbsp;Shi Wang ,&nbsp;Dan Xu ,&nbsp;Shuhua Tang","doi":"10.1016/j.phymed.2025.156919","DOIUrl":"10.1016/j.phymed.2025.156919","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Atherosclerosis (AS) is a primary contributor to cardiovascular disease. XinJia-LuHuang Granules (XLG), a formula used in traditional Chinese medicine (TCM), has been employed to treat AS. However, the underlying mechanism through which XLG exerts its effects remains unclear and warrants further investigation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;The purposes of this research are to assess the therapeutic effect of XLG on AS and to investigate its potential underlying procedures.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Materials and Methods&lt;/h3&gt;&lt;div&gt;Network pharmacology was implemented to recognize XLG's active ingredients, along with their associated targets and pathways involved in the treatment of AS. Metabolomics was employed to detect changes in metabolites following XLG administration. Furthermore, a combined analysis of metabolomics and network pharmacology elucidated the key targets and pathways underlying the therapeutic effects of XLG in AS. The interactions between XLG's active ingredients and their specific targets were evaluated using molecular docking. In addition, an apolipoprotein E knockout (ApoE&lt;sup&gt;-/-&lt;/sup&gt;) mouse model was used to simulate AS. Hematoxylin-Eosin (HE) staining and Oil Red O staining were utilized to assess the extent of pathological changes. An enzyme-linked immunosorbent assay (ELISA) was employed to measure inflammatory responses. The biochemical analyzer was applied to evaluate serum lipid levels in the mice. Immunofluorescence (IF) staining was conducted to measure the expression levels of key proteins in the sphingosine-1-phosphate receptor 1 (S1PR1)-activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) signaling pathway. In cell experiments, the viability of human umbilical vein endothelial cells (HUVECs) was detected using Cell Counting Kit-8 (CCK-8). Western blot (WB) analysis and ELISA were executed to measure the expression levels of proteins in the S1PR1-activated PI3K/Akt/eNOS signaling pathway both before and after the administration of specific inhibitors.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;XLG contains 143 active ingredients and 309 potential targets, of which 193 are associated with AS. Metabolomic analysis revealed alterations in lipid substance levels. Combined with molecular docking analysis, it was observed that the principal active ingredients of XLG interact directly with these targets, potentially exerting anti-AS effects through the PI3K/Akt/eNOS signaling pathway. Animal experiments found that XLG reduced blood lipid levels and inflammatory cytokine content in AS mice. Additionally, the expression levels of PI3K, AKT, eNOS, and S1PR1 were significantly upregulated following XLG administration. Furthermore, XLG promoted the proliferation of HUVECs in response to lipopolysaccharide stimulation and improved vascular function through the S1PR1-activated PI3K/Akt/eNOS signaling pathway. Conversely, the therapeutic efficacy o","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156919"},"PeriodicalIF":6.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144194837","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":"Hickory nut polyphenols enhance oxidative stress resilience and improve the longevity of Caenorhabditis elegans through modulating DAF-16/DAF-2 insulin/IGF-1 signaling","authors":"Song Wang ,&nbsp;Chenyu Jiang ,&nbsp;Shitong Yu ,&nbsp;Qianru Fan ,&nbsp;Kai Yang ,&nbsp;Jianqin Huang ,&nbsp;Yan Li","doi":"10.1016/j.phymed.2025.156918","DOIUrl":"10.1016/j.phymed.2025.156918","url":null,"abstract":"<div><h3>Background</h3><div>Hickory (<em>Carya cathayensis</em>) nuts, renowned for their health benefits and delightful taste, contain abundant bioactive compounds, particularly polyphenols. However, the specific mechanisms underlying their antioxidant properties and anti-aging effects remain elusive.</div></div><div><h3>Purpose</h3><div>This study aims to investigate the effects of hickory nut polyphenols (HNP) on oxidative stress mitigation and aging modulation.</div></div><div><h3>Methods</h3><div>The innovative integration of medium-pressure liquid chromatography (MPLC) with in <em>vitro</em> bioactive screening was employed to discover an optimized HNP fraction (HNP3–2). Anti-aging effects of HNP3–2 on <em>Caenorhabditis elegans</em> (<em>C. elegans</em>) were determined through lifespan analysis, lipofuscin accumulation quantification, and motility assessments. Oxidative stress resistance was further evaluated by detecting the reactive oxygen species (ROS) contents, lipid peroxidation, and antioxidase activities. Integrative approaches combining transcriptomic, qRT-PCR, GFP reporter strains, and gene knockout mutants were utilized to explore the potential regulatory mechanisms. Non-targeted metabolomics was employed to conduct a comprehensive profiling analysis of HNP and their bioactive fractions.</div></div><div><h3>Results</h3><div>HNP3–2 significantly decreased ROS production, lipofuscin accumulation, and lipid peroxidation, while enhanced the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). It also conferred robust protection against oxidative stress induced by H₂O₂ and juglone. HNP3–2 regulated lifespan extension mainly via the DAF-16/-2 insulin/IGF-1 signaling (IIS), which was further validated using loss- and gain-of-function mutants including <em>age-1, akt-1/2, daf-2</em>, and <em>daf-16</em>, as well as worms overexpressing SOD-3, GST-4, and DAF-16. Metabolomic analysis identified 31 kinds of polyphenol compounds displaying abundance patterns congruent with the overall antioxidant potency in vitro.</div></div><div><h3>Conclusion</h3><div>This study first reveals the efficacy of HNP as a promising antioxidant and anti-aging intervention. Notably, the screened bioactive fraction HNP3–2 acts primarily by modulating the DAF-16/DAF-2 insulin/IGF-1 signaling cascade, operating through a mechanism independent of dietary restriction. Collectively, these findings position HNP as a breakthrough candidate for next-generation gerotherapeutics, with translational potential for advancing human aging research.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156918"},"PeriodicalIF":6.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144194743","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}