Phytomedicine最新文献

{"title":"The chemosensitizing activity of betulinic acid in suppressing macrophage polarization through GSK-3β/β-catenin/CXCL1 signaling in breast cancer.","authors":"Zheng Xu, Jianchao Si, Aining Liang, Yu Zhang, Jiaqian Gong, Guanzhi Li, Yue Zhong, Miao Yu, Riyang Feng, Xuezhen Li, Jinrong Chang, Neng Wang","doi":"10.1016/j.phymed.2025.157304","DOIUrl":"https://doi.org/10.1016/j.phymed.2025.157304","url":null,"abstract":"<p><strong>Background: </strong>Autophagy-induced chemoresistance constitutes a principal mechanism underlying therapeutic inefficacy and adverse prognoses in breast cancer. It has been demonstrated that the resistance to chemotherapy in breast cancer is modulated by tumor-associated macrophages (TAMs), with the C-X-C motif chemokine ligand 1 (CXCL1) being identified as the predominant cytokine secreted by these cells. Betulinic acid (BA), a pentacyclic triterpenoid naturally present in plant resources such as birch bark and jujube seeds, and also derived from the Traditional Chinese Medicinal herb Scleromitrion diffusum (Willd.) R.J. Wang has proven notable efficacy in combating breast cancer. However, the effect and mechanism of BA on the chemosensitization of breast cancer are yet to be determined.</p><p><strong>Purpose: </strong>This study aimed to provide evidence indicating that BA could reduce the expression of TAMs/CXCL1 through the GSK-3β/β-catenin signaling pathway, consequently augmenting the chemosensitivity of breast cancer cells.</p><p><strong>Methods: </strong>This study investigated the role of BA in enhancing the chemosensitivity of breast cancer by modulating TAM-induced autophagy, employing both in vitro and in vivo models. The underlying mechanisms were explored through the application of gene recombination technology, antibody microarray analysis and detection of the proteasome degradation pathway.</p><p><strong>Results: </strong>BA was found to markedly impede the polarization of M2-TAMs and the secretion of CXCL1, resulting in diminished chemoresistance in breast cancer cells. Further mechanistic studies revealed that BA targeted the GSK-3β/β-catenin signaling to downregulate CXCL1 expression, thereby suppressing the AMPK/mTOR/Beclin 1 autophagy pathway. Through the ex vivo zebrafish and in vivo murine models, we demonstrated the chemosensitizing properties of BA and its ability to counteract TAM-induced chemoresistance.</p><p><strong>Conclusion: </strong>This study identifies BA as a novel chemosensitizer that targets TAM-mediated autophagy through the GSK-3β/β-catenin/CXCL1 axis, offering a new therapeutic strategy to overcome chemoresistance in breast cancer.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"157304"},"PeriodicalIF":8.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245059","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":"Astragaloside VI attenuates mechanical stress-induced cardiac remodeling through piezo1-VDAC1 dependent endoplasmic reticulum unfolded protein response","authors":"Shiyu Zhang ,&nbsp;Wanyun Gao ,&nbsp;Xiongyi Gao ,&nbsp;Wenshi Xu ,&nbsp;Yan Liu ,&nbsp;Zhongxiu Guo ,&nbsp;Guobin Liu ,&nbsp;Pu Zhang ,&nbsp;Hongshuo Shi ,&nbsp;Xing Chang","doi":"10.1016/j.phymed.2025.157288","DOIUrl":"10.1016/j.phymed.2025.157288","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;The dysregulation of protein homeostasis is a condition associated with mechanical stress-induced cardiac remodeling (CR) due to endoplasmic reticulum (ER) dysfunction and stress.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This research explores the effect of Piezo1 on the ER unfolded protein response (UPR) in cardiomyocytes following hypoxic stress, specifically through its interaction with VDAC1. In addition, the study evaluates the therapeutic potential that this mechanism holds for treating CR and cardiomyocyte hypertrophy.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Study Design&lt;/h3&gt;&lt;div&gt;Considering the relative limitation of potential therapeutic drugs for CR, our goal is to utilize a multi-omics approach to confirm the process by which Astragaloside IV (AS) alleviates CR through the Piezo1-VDAC1 dependent UPR.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We utilized multiple omics studies, such as single-cell sequencing, network pharmacology, and metagenomics, for the validation of AS's targets and phenotypic mechanisms. Following this, we created Piezo1/VDAC1 transgenic mice (Piezo1&lt;sup&gt;TG&lt;/sup&gt;/VDAC1&lt;sup&gt;TG&lt;/sup&gt;) and wild-type mice, which were then subjected to transverse aortic constriction (TAC) to induce myocardial damage. We performed assessments of cardiac function, myocardial injury staining, and cardiomyocyte hypertrophy on these animal models both before and after the drug intervention. The analysis into the interaction between Piezo1-VDAC1 and the structural integrity of cytoskeletal proteins and the ER was conducted utilizing laser confocal microscopy, immunofluorescence, and molecular biology experiments.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The regulation of mechanical stress-induced cardiac remodeling crucially involves Piezo1-VDAC1. Data from single-cell sequencing and network pharmacology suggest that ER damage, mitochondrial energy metabolism dysfunction, and the dysregulation of subcellular organelles are important phenotypes that mediate this process. Our animal experiments demonstrated that AS is capable of improving cardiac function after TAC, inhibiting myocardial injury and the associated inflammatory reaction, and suppressing excessive UPR stress. The therapeutic effect of the drug was eliminated by the transgenic treatment of Piezo1. In &lt;em&gt;vitro&lt;/em&gt; experiments also offered confirmation that AS can ameliorate cardiomyocyte damage through the ER pathway. This is achieved by regulating the Piezo1-VDAC1 interaction mechanism, which restores ER structural collapse after hypoxic injury, enhances energy metabolism levels, and inhibits excessive UPR stress.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;The abnormal activation of the UPR, which is mediated by Piezo1-VDAC1, constitutes the pathological mechanism behind mechanical stress-induced cardiac remodeling. By regulating the Piezo1-VDAC1 interaction, AS inhibits excessive UPR stress and improves the breakdown of ER structure and functional abnormalities. These actions further n","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157288"},"PeriodicalIF":8.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200677","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":"Acetylshikonin regulates the gut microbiota and inhibits the horizontal transmission of colistin-resistant plasmids","authors":"Wei Liu ,&nbsp;Fanrui Gong ,&nbsp;Yanhu Huang ,&nbsp;Yu Shao ,&nbsp;Zhiqiang Wang ,&nbsp;Xia Xiao","doi":"10.1016/j.phymed.2025.157287","DOIUrl":"10.1016/j.phymed.2025.157287","url":null,"abstract":"<div><h3>Background</h3><div>The gut microbiota serves as a major reservoir for antibiotic resistance genes (ARGs), driving the spread of antimicrobial resistance (AMR) <em>via</em> horizontal gene transfer (HGT). Acetylshikonin (ASK), a naphthoquinone derived from the medicinal plant <em>Lithospermum erythrorhizon</em>, was proved to inhibit plasmid conjugation <em>in vitro</em> and <em>in vivo</em>. However, its impact on gut microbiota composition and precise HGT inhibition process within complex gut microbiota community remains unexplored.</div></div><div><h3>Purpose</h3><div>This study aims to clarify the precise inhibition effect of ASK on the transfer process of colistin-resistant plasmid in gut microbiota and its mechanisms.</div></div><div><h3>Methods</h3><div>High-throughput cell sorting and 16S rRNA gene amplicon sequencing were employed to assess the precise gut microbiota species that ASK inhibited the resistant plasmid transfer to. The plasmid stability and re-transferability of transconjugants was evaluated by passaging culture and <em>in vitro</em> conjugative assay. The biochemical impact of ASK on donor cell and gut microbiota were tested by fluorescence assay and ELISA.</div></div><div><h3>Results</h3><div>ASK changed the gut microbiota composition by enriching probiotics and reducing Gram-positive bacteria. In addition, ASK effectively inhibited the conjugative transfer of colistin-resistant plasmids to Proteobacteria (<em>Escherichia</em> and <em>Ligilactobacillus</em>) within the gut community. Furthermore, ASK weakened the stability and re-transferability of transconjugants, thereby limiting ARG further dissemination in gut. Moreover, ASK inhibited the electronic transport chain (ETC) and suppressed the ATP supply for both donor cells and the gut microbiota. Thus the plasmid conjugation processing in gut microbiota was inhibited by ASK.</div></div><div><h3>Conclusion</h3><div>This study demonstrated that ASK restructured gut microbiota and disarmed plasmid-mediated resistance spreading, offering a dual-targeted strategy against antimicrobial resistance.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157287"},"PeriodicalIF":8.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145159301","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":"Recent advances of potential antitumor agents from natural sesquiterpenoids","authors":"Xingrui He ,&nbsp;Rui Fan ,&nbsp;Mengting Liu ,&nbsp;Huixian Wang ,&nbsp;Yingqian Zhang ,&nbsp;Tian Xie","doi":"10.1016/j.phymed.2025.157290","DOIUrl":"10.1016/j.phymed.2025.157290","url":null,"abstract":"<div><h3>Background</h3><div>Sesquiterpenoids, a major class of plant-derived secondary metabolites known for their structural diversity and biological activities, have gained significant attention for their cytotoxic effects against cancer cells, suggesting their potential as promising anticancer agents. Given the rapid advancements and increasing volume of research, there is a crucial need to compile and summarize the latest developments to fully understand their mechanisms and therapeutic potential.</div></div><div><h3>Purpose</h3><div>This review aims to elucidate the diverse antitumor effects of sesquiterpenoids and their potential therapeutic applications. It seeks to provide a comprehensive framework for understanding the key signaling pathways and proteins involved in their antitumor mechanisms, highlight the extensive research conducted from January 2020 to September 2024, and to guide future research directions for translating these findings into clinical applications.</div></div><div><h3>Methods</h3><div>We performed extensive searches in electronic databases, including Web of Science and PubMed, from 2020 onward, using keywords such as ‘antitumor’, ‘sesquiterpenes’, ‘mechanism’, ‘signaling pathways’, and various combinations of these terms.</div></div><div><h3>Results</h3><div>A total of 112 natural sesquiterpenoids were systematically characterized. Their antitumor effects primarily involved: (1) ROS overproduction, (2) inhibition of key signaling pathways (PI3K/Akt, NF-κB, and STAT3), and (3) modulation of apoptosis-related proteins—upregulating executioner caspase-3 and pro-apoptotic BAX while downregulating anti-apoptotic Bcl-2. These collective actions synergistically enhanced programmed cell death in malignant cells.</div></div><div><h3>Conclusion</h3><div>Recently discovered sesquiterpenoids, whether isolated or derived from extracts, have demonstrated antitumor activities. Although these compounds display lower toxicity, fewer adverse effects, and the ability to act on multiple biological targets to combat drug resistance, their effectiveness remains weaker than first-line antitumor agents, limiting their primary use to adjuvant therapeutic roles. The clinical translation of sesquiterpenoids is hindered by inherent pharmacokinetic limitations, particularly poor aqueous solubility and low bioavailability. To overcome these issues, two complementary approaches appear effective: (1) structural modification to develop hydrophilic derivatives through rational drug design, and (2) advanced delivery systems utilizing tumor-targeting nanoparticles to enhance biodistribution and treatment efficacy.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157290"},"PeriodicalIF":8.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145227075","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":"Momordica charantia small extracellular vesicles mitigate neuronal ferroptosis by inhibition of GPX4 ubiquitination in ischemic stroke","authors":"Lin-Yan Huang ,&nbsp;Yi-Ning Liu ,&nbsp;Li-Li Li ,&nbsp;Meng-Nan Zhang ,&nbsp;Xiao-Yue Miao ,&nbsp;Zhi-Yan Liang ,&nbsp;Bin Sun ,&nbsp;Rui-Qi Su ,&nbsp;Zi-Lu Qin ,&nbsp;Zhen-Fu Wen ,&nbsp;Wan Wang ,&nbsp;Jian-Gang Shen ,&nbsp;Su-Hua Qi","doi":"10.1016/j.phymed.2025.157298","DOIUrl":"10.1016/j.phymed.2025.157298","url":null,"abstract":"<div><h3>Background</h3><div>Ischemic stroke (IS) is a prevalent cerebrovascular disorder associated with high rates of mortality and long-term disability. Neuronal ferroptosis, characterized by lipid peroxidation, plays a pivotal role in the pathogenesis of IS-related neurological dysfunction.</div></div><div><h3>Purpose</h3><div>This study aimed to elucidate the neuroprotective role and mechanisms of small extracellular vesicles (sEVs) derived from <em>Momordica charantia</em> (MC-sEVs) in alleviating neuronal ferroptosis after IS.</div></div><div><h3>Methods</h3><div>MC-sEVs were isolated using gradient centrifugation and ultracentrifugation and characterized by particle size analysis, morphology observation, and exosomal marker proteins. Small RNA sequencing and lipidomic analysis were also performed to analyze the components of MC-sEVs. Using behavioral tests and a rat model of middle cerebral artery occlusion, the neuroprotective and anti-ferroptosis role of MC-sEVs was assessed. The oxygen-glucose deprivation/reoxygenation (OGD/R) induced HT22 cell model was used to evaluate the anti-ferroptosis effect of MC-sEVs <em>in vitro</em>. Utilizing bioinformatics analysis and molecular docking prediction, <em>Momordica charantia-</em>derived miR-5813b and its downstream target gene, TRIM62, were identified, which was further confirmed using a dual-luciferase reporter gene assay. TRIM62-mediated GPX4 ubiquitination was detected by co-immunoprecipitation. The miR5813b mimic and AAV-hsyn-EGFP-miR5813b were both constructed, and their neuroprotective roles were observed <em>in vitro</em> and <em>in vivo</em>. The biosafety of intravenous injection of MC-sEVs was also evaluated.</div></div><div><h3>Results</h3><div>we characterized MC-sEVs which resemble mammalian EVs and are enriched in small non-coding RNAs and lipids. Systemic administration of MC-sEVs significantly attenuated neuronal ferroptosis and promoted neurological recovery in the rat model of transient middle cerebral artery occlusion. Mechanistically, we identified miR-5813b, a plant-specific microRNA encapsulated within MC-sEVs, as a direct regulator of TRIM62, an E3 ubiquitin ligase that predominantly facilitates K48-linked ubiquitination of GPX4. Knockdown of TRIM62 or transfection with miR-5813b mimics markedly inhibited neuronal ferroptosis <em>in vitro</em>, while inhibition of miR-5813b abrogated the anti-ferroptotic effects of MC-sEVs. Furthermore, overexpression of AAV-hsyn-miR-5813b enhanced post-stroke neurological function <em>in vivo</em>. Importantly, intravenous administration of MC-sEVs demonstrated excellent biosafety.</div></div><div><h3>Conclusions</h3><div>These findings reveal that MC-sEVs derived miR-5813b effectively modulated GPX4 ubiquitination to counteract neuronal ferroptosis after IS. This study highlights MC-sEVs as a promising and biocompatible therapeutic platform for the treatment of IS.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157298"},"PeriodicalIF":8.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207151","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":"Mangiferin reverses high glucose-induced osteoblast damage and ameliorates osteoporosis by targeting SOX9","authors":"Zebin Chen ,&nbsp;Suzhen Chao ,&nbsp;Yunying Fu ,&nbsp;Ruitong Zhao ,&nbsp;Xinyi Shi ,&nbsp;Shengyuan Li ,&nbsp;Yang Li ,&nbsp;Liping Huang ,&nbsp;Meijuan Shao ,&nbsp;Min Shi ,&nbsp;Xunli Xia ,&nbsp;Bo Liu","doi":"10.1016/j.phymed.2025.157295","DOIUrl":"10.1016/j.phymed.2025.157295","url":null,"abstract":"<div><h3>Background</h3><div>Osteoporosis (OP), a systemic metabolic bone disease, severely threatens middle-aged and elderly populations. Diabetic osteoporosis (DOP) presents exacerbated challenges due to high-glucose (HG)-induced osteoblast dysfunction.</div></div><div><h3>Purpose</h3><div>To investigate protective effects of mangiferin on HG-induced osteoblast damage and elucidate its anti-OP mechanisms via SOX9 targeting.</div></div><div><h3>Methods</h3><div><em>In vitro</em>: HG-damaged MC3T3-E1 osteoblasts treated with mangiferin (5–80 μM) were assessed for proliferation (CCK-8), oxidative stress (ROS/SOD/MDA), osteogenic differentiation (ALP/ARS), and signaling via network pharmacology/proteomics. <em>Mechanistic validation:</em> SOX9 siRNA knockdown and PI3K inhibition (LY294002). <em>In vivo:</em> Dexamethasone-induced OP mice administered mangiferin (100 mg/kg) were evaluated via Micro-CT, histology (HE), serum biomarkers (CTX-1/PINP), and molecular profiling (WB/RT-qPCR).</div></div><div><h3>Results</h3><div>Mangiferin significantly increases bone density and improves bone morphology in OP mice. Specifically, it enhances the expression of p-AKT, p-FOXO1, and SOX9 in osteoblasts. This effect is attenuated by the PI3K inhibitor LY294002 but potentiated by the AKT agonist SC79. SOX9 knockdown suppressed osteogenic genes, and mangiferin rescued this suppression, revealing SOX9 as a key downstream target of the PI3K/AKT/FOXO1 pathway in osteoblasts.</div></div><div><h3>Conclusion</h3><div>This study is the first to demonstrate that mangiferin activates the PI3K/AKT/FOXO1/SOX9 axis to reverse HG-induced osteoblast damage, providing a novel multi-target treatment strategy for DOP.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157295"},"PeriodicalIF":8.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200757","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":"Luteolin attenuates experimental dry eye disease via dual modulation of macrophage JAK-STAT signaling and corneal epithelial MAPK pathways","authors":"Zhirui Du ,&nbsp;Xueqiao Yan ,&nbsp;Lin Cheng ,&nbsp;Haiyu Shen ,&nbsp;Guoguo Zhi ,&nbsp;Baojie Li ,&nbsp;Qian Yu","doi":"10.1016/j.phymed.2025.157300","DOIUrl":"10.1016/j.phymed.2025.157300","url":null,"abstract":"<div><h3>Background</h3><div>Dry eye disease (DED) is a multifactorial ocular condition marked by tear film instability, inflammation, and oxidative stress. Current therapies, including artificial tears and immunosuppressants, offer limited long-term benefit and potential side effects. Natural flavonoids such as luteolin possess anti-inflammatory and antioxidant properties, yet their therapeutic potential in DED remains underexplored.</div></div><div><h3>Purpose</h3><div>This study aimed to evaluate the therapeutic efficacy and mechanisms of luteolin in experimental DED.</div></div><div><h3>Methods</h3><div>Flavonoids were initially screened using lipopolysaccharide-stimulated RAW264.7 macrophages. A benzalkonium chloride-induced DED mouse model was treated with topical luteolin or cyclosporine A. Ocular surface evaluations included tear secretion, corneal fluorescein staining, and goblet cell density. Inflammatory and oxidative markers were examined via histology, immunofluorescence, and qPCR. RNA sequencing and network pharmacology were used to identify target pathways. In vitro studies with RAW264.7 cells and hyperosmolarity-stressed human corneal epithelial cells further validated mechanism-specific effects. Target engagement was further validated using pathway-specific pharmacological inhibitors. Ocular safety and pharmacokinetics were also assessed.</div></div><div><h3>Results</h3><div>Luteolin showed superior anti-inflammatory activity among tested flavonoids. It improved tear production, reduced epithelial damage, and preserved goblet cells. Mechanistically, it modulated macrophage-driven inflammation through JAK-STAT signaling and mitigated oxidative epithelial damage by suppressing the MAPK pathway. Transcriptomic and pharmacological analyses confirmed its dual immunomodulatory and cytoprotective roles. Combined STAT1/3 and MAPK inhibition mimicked its therapeutic effects. Topical luteolin was well-tolerated and achieved corneal bioavailability.</div></div><div><h3>Conclusions</h3><div>Luteolin provides a dual protective effect in DED by targeting inflammation and oxidative stress, supporting its development as a safe and effective disease-modifying therapy.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157300"},"PeriodicalIF":8.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145159293","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":"Gut microbiota metabolite Urolithin B inhibits chondrocyte ferroptosis by rewriting iron homeostasis via FGFR3/NCOA4/FTH1 axis, alleviating osteoarthritis","authors":"Yanlin Li ,&nbsp;Hanwen Gu ,&nbsp;Xiaotian Jiang ,&nbsp;Jiale Li ,&nbsp;Qi Li ,&nbsp;Kangle Song ,&nbsp;Xiangzhen Kong ,&nbsp;Qunbo Meng ,&nbsp;Anhao Shi ,&nbsp;Junhao Lin ,&nbsp;Bin Chen ,&nbsp;Gang Wang ,&nbsp;Hong Zhang ,&nbsp;Qingjia Xu","doi":"10.1016/j.phymed.2025.157292","DOIUrl":"10.1016/j.phymed.2025.157292","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is a prevalent chronic disease characterized by articular cartilage degeneration. The lack of safe and effective therapies has made OA a leading global cause of disability, severely impacting patient quality of life. Urolithin B (UB), a bioactive metabolite derived from gut microbiota processing of ellagic acid, exhibits potent antioxidant and anti-inflammatory properties, positioning it as a promising therapeutic candidate for OA. However, the precise mechanisms by which UB inhibits OA progression remain unknown.</div></div><div><h3>Purpose</h3><div>This study aimed to evaluate the therapeutic potential of UB for OA and elucidate its underlying mechanisms of action.</div></div><div><h3>Methods</h3><div>The therapeutic effects of UB on OA were assessed using interleukin-1β (IL-1β)-induced chondrocyte models and rats subjected to anterior cruciate ligament transection (ACLT). Integrated transcriptome analysis was employed to comprehensively investigate the relevant mechanisms. Fibroblast growth factor receptor 3 (FGFR3)-specific small interfering RNA (siRNA) and overexpression plasmids were utilized <em>in vitro</em> to validate the role of FGFR3 as a specific downstream target of UB and its functional significance in osteoarthritis progression. Furthermore, FGFR3 gene knockdown was performed in UB-treated ACLT rats to confirm the critical role of both UB and its downstream target, FGFR3.</div></div><div><h3>Results</h3><div>This study reports the novel discovery that UB significantly mitigates IL-1β-induced extracellular matrix degradation and alleviates OA progression through a previously unrecognized mechanism involving iron homeostasis regulation. Mechanistically, we demonstrate that UB inhibits chondrocyte ferroptosis by upregulating FGFR3 expression, which suppresses ferritinophagy by disrupting the interaction between nuclear receptor coactivator 4 (NCOA4) and ferritin heavy chain 1 (FTH1). Our findings establish the novel protective role of the FGFR3/NCOA4/FTH1 signaling axis in chondrocytes under inflammatory conditions by restoring iron homeostasis.</div></div><div><h3>Conclusions</h3><div>We identified FGFR3 as a novel therapeutic target for the prevention and alleviation of OA. The validation of UB as a functional agonist of FGFR3, revealing its potential as a new therapeutic candidate and providing a new perspective for combating OA.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157292"},"PeriodicalIF":8.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145159294","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":"Neuroimmunological basis of sympathetic-sensory coupling modulation via capsaicin to restore cardiac function in an acute myocardial ischemia rat model","authors":"Ziwei Yu,&nbsp;Ting Zhang,&nbsp;Xiao Sun,&nbsp;Xiangyu Li,&nbsp;Zhi Yu,&nbsp;Tiancheng Xu,&nbsp;Yaling Wang,&nbsp;Xingyu Yang,&nbsp;Linglong Zhang,&nbsp;Xiao Li,&nbsp;Yue Wu,&nbsp;Jinhong Yuan,&nbsp;Mengjiang Lu,&nbsp;Bin Xu","doi":"10.1016/j.phymed.2025.157294","DOIUrl":"10.1016/j.phymed.2025.157294","url":null,"abstract":"<div><h3>Background</h3><div>Acute myocardial ischemia (AMI) carries a high risk of heart failure and subsequent mortality. However, current therapies remain limited by suboptimal drug efficacy and high costs, prompting exploration of alternative strategies, such as remote therapy. Capsaicin is a natural extract from red chili peppers. Remote therapy using it as the primary component has demonstrated efficacy in AMI treatment. However, this specific mechanism requires further exploration.</div></div><div><h3>Purpose</h3><div>Here, we investigate the therapeutic effects of remote capsaicin application therapy on AMI and elucidate the underlying neuro-immune interactions responsible.</div></div><div><h3>Methods and results</h3><div>We applied capsaicin cream to the ventral forelimb of rats, finding that it enhanced the sympathetic-sensory coupling (SSC) state in the skin and dorsal root ganglia (DRGs) (C8–T6), improving cardiac function over 28 days. Localized yohimbine (YOB) injections in skin /DRGs confirmed the critical role of the SSC structure. Mechanistically, capsaicin-enhanced SSC increased neuropeptide Y-positive (NPY⁺) nerve fiber density in peri‑infarct myocardium, concurrently shifting cardiac NPY receptor expression toward predominant NPY2R. Inhibiting cardiac NPY2R expression eliminated the functional benefits of capsaicin. <em>In vitro</em> co-culture of H9C2 cardiomyocytes and RAW264.7 cells showed functional NPY2R localization in cardiomyocytes. Activation of cardiomyocyte NPY2R promoted macrophages to secrete the anti-inflammatory factor IL-10, reducing hypoxia-induced cardiomyocyte apoptosis. Adeno-associated virus (AAV)-mediated overexpression of NPY2R in cardiomyocytes mimicked the cardioprotective effects of capsaicin. RNA sequencing revealed that NPY2R overexpression inhibited the IL-1β-induced NF-κB pathway in the heart. Flow cytometry confirmed these changes were due to reduced M1 macrophages and neutrophil infiltration in the infarct area.</div></div><div><h3>Conclusion</h3><div>Capsaicin enhances the segmental SSC structure to protect cardiac function in AMI rats, primarily associated with the improvement of the immune microenvironment induced by NPY⁺ nerve and NPY2R activation in the heart.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157294"},"PeriodicalIF":8.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145159298","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":"Integrating metagenomics, lipidomics and proteomics to explore the effect and mechanism of ginsenoside Rb1 on atherosclerosis co-depression disease","authors":"Yulong Zhao ,&nbsp;Tao Song ,&nbsp;Peng Ren ,&nbsp;Xiaoyun Wu ,&nbsp;Qiang Luo ,&nbsp;Jing Xie ,&nbsp;Houmin Lai ,&nbsp;Xue Li ,&nbsp;Youliang Wen ,&nbsp;Xingxing Liao ,&nbsp;Junjie Zhou","doi":"10.1016/j.phymed.2025.157301","DOIUrl":"10.1016/j.phymed.2025.157301","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;The comorbidity of atherosclerosis (AS) and depression presents a significant clinical challenge. Its pathogenesis entails complex abnormalities in inflammatory responses, lipid metabolism, and gut microbiota homeostasis. Ginsenoside Rb1 (GRb1)—a bioactive compound derived from the dried roots of Panax ginseng (Araliaceae)—demonstrates anti-inflammatory, antioxidant, lipid-lowering, and neuroprotective properties. However, GRb1′s therapeutic potential and underlying mechanisms in AS co-depression remain inadequately characterized.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This study aims to elucidate the mechanism of GRb1 in AS co-depression disease, identify potential therapeutic targets, and thereby develop novel therapeutic strategies for this condition.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;An AS co-depression comorbidity model was established using ApoE&lt;sup&gt;⁻/⁻&lt;/sup&gt; mice fed a high-fat diet and subjected to chronic restraint stress. To evaluate GRb1′s therapeutic efficacy, we assessed serum lipid profiles, performed aortic Oil Red O staining, and conducted behavioral tests for depressive-like phenotypes. Furthermore, we employed an integrated multi-omics approach—combining metagenomics, targeted lipid metabolomics, and proteomics—to identify key alterations in gut microbiota, lipid metabolites, and proteins, with subsequent correlation analysis. Key differential proteins and associated pathways identified through multi-omics were validated using both in vivo (AS co-depression mouse model) and in vitro (HT22 cells) experiments. Finally, GRb1′s effects on ferroptosis and specific signaling pathways (CD44/Gls2, ACSL4/LPCAT3/ALOX15, SLC7A11/GPX4) were examined via Western blotting, immunofluorescence, and transmission electron microscopy in both mouse tissues and HT22 cells.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Proteobacteria, Helicobacter, and Helicobacter_typhlonius represent significant intestinal microbiota components. Their primary differential lipids include phosphatidylethanolamine (PE), phosphatidylcholine (PC), and lysophosphatidylcholine (LPC), while key differential proteins encompass CD44, Gls2, and Snrpf. Notably, a strong correlation exists among Helicobacter_typhlonius, PE, and CD44. GRb1 modulates PE metabolic dysregulation by reducing the relative abundance of Helicobacter_typhlonius, thereby inhibiting lipid peroxidation and ameliorating oxidative stress. Furthermore, GRb1 suppresses the CD44/Gls2 axis, ACSL4/LPCAT3/ALOX15 pathway, and activates the SLC7A11/GPX4-mediated ferroptosis pathway, thereby exerting its anti-AS co-depression effects through these multi-target mechanisms.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;GRb1 regulates the intestinal microbiota, abnormal lipid metabolism, modulates protein function, inhibits lipid peroxidation, improves oxidative stress, inhibits ferroptosis, regulates the CD44/Gls2, ACSL4/LPCAT3/ALOX15, SLC7A11/ GPX4 signaling pathways, and prevents the progression of AS ","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157301"},"PeriodicalIF":8.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145159295","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}