Phytomedicine最新文献

{"title":"Molecular mechanisms of natural polysaccharides in female-prevalent cancers.","authors":"Hao Li, Meiqi Jiang, Yaqing Fan, Yian Shen, Yuelong Han, Huijuan Xu, Biao Cai, Maowen Chen","doi":"10.1016/j.phymed.2025.157340","DOIUrl":"https://doi.org/10.1016/j.phymed.2025.157340","url":null,"abstract":"<p><strong>Background: </strong>Cancer remains a critical global health threat, significantly compromising women's health and survival rates worldwide. However, most current chemotherapy drugs are often limited in clinical application due to their substantial side effects. Therefore, there is a pressing demand for the discovery and development of novel drugs. Given their low toxicity and multifaceted bioactivities, natural polysaccharides have emerged as promising anticancer candidates, attracting considerable research attention for their therapeutic potential.</p><p><strong>Purpose: </strong>This comprehensive review synthesized the anti-tumor effects and underlying mechanisms of various polysaccharides. This review aims to consolidate fragmented evidence and bridge existing knowledge gaps, while providing a scientific basis for the clinical utility of bioactive polysaccharides in treating common female-specific tumors.</p><p><strong>Methods: </strong>A systematic literature search was conducted in Web of Science, PubMed, ScienceDirect, and ProQuest, as well as publisher databases (Elsevier, ACS, RSC, Springer) up to April 2025 using predefined keywords.</p><p><strong>Results: </strong>This study reviewed 179 articles published between 2010 and 2025, covering 81 polysaccharides obtained from 75 natural products. Among these publications, 48 were based on in vivo studies and 99 on in vitro studies. The molecular weight of the polysaccharides was reported in 25 articles, while monosaccharide composition was analyzed in 36 articles. Systematic analysis revealed that these polysaccharides exert therapeutic effects on common female cancers through multiple mechanisms, including inhibiting tumor cell proliferation and metastasis, inducing apoptosis, arresting cell cycle progression, enhancing immune surveillance, and modulating gut microbiota. Key signaling pathways involved include PI3K/AKT/mTOR, NF-κB, TNF-α, and MAPK, among others.</p><p><strong>Conclusion: </strong>The review highlights the potential of natural polysaccharides as anticancer resources, because they can modulate key cellular signaling pathways, which are critical for advancing targeted therapies against common tumors in women. Elucidating these antitumor mechanisms not only reveals therapeutic potentials but also facilitates innovative treatment strategies.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"157340"},"PeriodicalIF":8.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245015","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":"Ethyl acetate extract of Sargentodoxa cuneata and Patrinia villosa alleviates pelvic inflammation by shifting macrophages polarization.","authors":"Qiulu Yu, Puwei Shao, Xiaoqin Liu, Ying Wang, Liu Luo, Xinru Li, Si Zhao, Yanqun An, Bohan Li, Jiahe Pei, Shiyi Liu, Changshui Yang, Junsong Wang, Shuna Cui","doi":"10.1016/j.phymed.2025.157345","DOIUrl":"https://doi.org/10.1016/j.phymed.2025.157345","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Pelvic inflammatory disease (PID) is a prevalent gynecological infection, that poses significant therapeutic challenges. Sargentodoxa cuneata and Patrinia villosa (S&P) demonstrate empirical efficacy in PID treatment within traditional Chinese medicine practice. However, their active components and precise anti-inflammatory mechanisms should be systematically elucidated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;This study aimed to investigate the pharmacologically active components of S&P and decipher their anti-inflammatory mechanism through integrated multi-omics approaches.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Materials and methods: &lt;/strong&gt;CCK-8 and NO inhibition assays were used to screen the optimal extract from three solvent partitions (ethyl acetate [EtOAc], n-butanol [n-BuOH], and water). The chemical components of different extracts and S&P were detected by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). The effects of EtOAc extract on PID were studied in an lipopolysaccharide (LPS) -induced PID murine model to evaluate uterine histopathology and macrophage phenotype. RNA sequencing was utilized to analyze the differentially expressed genes after EtOAc extract treatment. Cytokines and macrophage phenotype markers were detected by flow cytometry. LC-MS/MS-based metabolic analysis and western blotting were used to study the potential mechanism.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Bioactivity screening identified EtOAc extract as the most potent fraction, suppressing iNOS-mediated NO production without cytotoxicity. EtOAc extract inhibited the release of IL-6 and upregulated the M2 phenotypic marker CD206 in LPS induced RAW264.7 and THP-1 cells. In the murine PID model, EtOAc extract treatment alleviated LPS-induced pelvic inflammation, reduced uterine F4/80&lt;sup&gt;+&lt;/sup&gt; and CD86&lt;sup&gt;+&lt;/sup&gt; (M1) macrophages, and upregulated CD206&lt;sup&gt;+&lt;/sup&gt; (M2) subset. Transcriptomics of uterine tissue demonstrated that EtOAc extract upregulated genes related to M2 macrophages polarization, tissue repair and vascular remodeling, and endometrial receptivity and lactic acid metabolism, and downregulated genes involved in M1 macrophages, inflammation, and glycolysis and lactic acid synthesis. Metabolomics analysis showed that EtOAc extract ameliorated LPS-induced metabolic disorder. The differentially expressed metabolites were involved in the tricarboxylic acid (TCA) cycle, arginine and proline metabolism, pyruvate metabolism, and glycolysis or gluconeogenesis pathways. EtOAc extract inhibited the expression of glucose metabolism key proteins HKI, HKII, PKM2 and PD, and NF-κB and IκB-ɑ phosphorylation, and synergized with HK-II inhibitor (2-deoxy-D-glucose).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;EtOAc extract alleviates LPS-induced PID via a novel immunometabolic axis, namely, by suppressing HK-II-mediated glycolysis through the NF-κB axis and balancing macrophages polarization. The mechanistic elucidation of macrophage immunometabolic rep","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"157345"},"PeriodicalIF":8.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252326","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":"Euchrenone A10 attenuates septic lung injury though S100A8/A9-dependent TLR4/MyD88/NF-κB signaling","authors":"Lvzhou Zhou ,&nbsp;Yao Xiao ,&nbsp;Jinlian He ,&nbsp;Hong Ren ,&nbsp;Caiping Zhao ,&nbsp;Chuanhai Zhang ,&nbsp;Xiao Shu ,&nbsp;Ying Chen ,&nbsp;Danli Chen ,&nbsp;Yulian Chen ,&nbsp;Xizi He ,&nbsp;Lirong Lian ,&nbsp;Jie Shao ,&nbsp;Juan Wang ,&nbsp;Yi Wang ,&nbsp;Canzhe Li ,&nbsp;Jianjie OuYang ,&nbsp;Runze Li ,&nbsp;Zhongde Zhang ,&nbsp;Liang Liu ,&nbsp;Hudan Pan","doi":"10.1016/j.phymed.2025.157336","DOIUrl":"10.1016/j.phymed.2025.157336","url":null,"abstract":"<div><h3>Background</h3><div>Euchrenone A10 (A10), an isoprenylated flavanone isolated from <em>Glycyrrhiza</em> (licorice), exhibits significant bioactivities, including anti-inflammatory and antioxidant effects. However, the effects and mechanisms underlying A10′s protective role in sepsis-associated acute lung injury (SALI) remain incompletely understood.</div></div><div><h3>Objective</h3><div>This study aims to elucidate the pharmacological effects of A10 and the underlying mechanisms by which it protects against SALI, using both <em>in vitro</em> and <em>in vivo</em> experiments.</div></div><div><h3>Methods</h3><div>To evaluate the effects of A10 against SALI, mice were pretreated with A10 (12.5, 25, or 50 mg/kg) or dexamethasone (<strong>Dex</strong>, 50 μg/kg) prior to sepsis induction <em>via</em> intraperitoneal administration of lipopolysaccharide (<strong>LPS</strong>, 10 mg/kg) or cecal ligation and puncture (<strong>CLP</strong>). Survival rates, pulmwasy function, bronchoalveolar lavage fluid inflammatory cell infiltration, protein exudation, and lung histopathology were systematically assessed. Molecular docking and biolayer interferometry (<strong>BLI</strong>) were employed to characterize the interactions between S100A8/A9 and A10 or paquinimod (<strong>paq</strong>). Complementary <em>in vitro</em> studies using LPS (150 ng/ml)-stimulated Raw264.7 macrophages were conducted to examine A10′s effects on inflammatory gene expression.</div></div><div><h3>Results</h3><div>To evaluate the therapeutic effects of A10, we employed LPS-induced SALI and CLP-induced ALI models. A10 dose-dependently alleviated pulmonary injury and improved survival rates in septic mice. Notably, A10 inhibited the expression of <strong>S100A8/A9</strong> and suppressed the TLR4/MyD88/NF-κB signaling pathway in both <em>in vivo and in vitro</em> models. Mechanistic studies using molecular docking and BLI indicated that A10 directly binds to S100A8/A9, thereby blocking its interaction with the TLR4 receptor. Furthermore, <em>in vivo</em> and <em>in vitro</em> experiments confirmed that A10 shares the same binding site on S100A8/A9 as the S100A9-specific inhibitor paq, competitively displacing paq and inhibiting downstream TLR4/MyD88/NF-κB signaling.</div></div><div><h3>Conclusion</h3><div>A10 exerts its anti-inflammatory effects by binding to the S100A8/A9 protein, thereby inhibiting the TLR4–NF-κB inflammatory cascade. These properties highlight its therapeutic potential as monotherapy for SALI.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157336"},"PeriodicalIF":8.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213316","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":"Zhenqi Fuzheng Granule targets the SCFAs-GPR109A axis to enhance PD-1 antibody efficacy via immunometabolic remodeling in colorectal cancer","authors":"Luxuan Guo ,&nbsp;Jia Yi ,&nbsp;Ao Zhang ,&nbsp;Xiaoqing Zheng ,&nbsp;Miao Wang ,&nbsp;Fan Yang ,&nbsp;Xianbin Kong ,&nbsp;Jingyan Meng","doi":"10.1016/j.phymed.2025.157312","DOIUrl":"10.1016/j.phymed.2025.157312","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Immune checkpoint inhibitors (ICIs), particularly PD-1 antibodies, represent a breakthrough in colorectal cancer (CRC) treatment. However, their clinical efficacy remains limited by tumour-induced immunosuppression. Traditional Chinese medicine (TCM) has attracted growing interest as a potential adjuvant to immunotherapy. Zhenqi Fuzheng Granule (ZQFZ) is a clinically approved herbal prescription widely used as an adjuvant therapy for CRC, yet its mechanistic underpinnings remain elusive.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;To investigate how ZQFZ improves the efficacy in CRC, with emphasis on gut microbiota modulation, SCFAs production, and downstream immunometabolic pathways involving GPR109A, and confirms that butyrate plays an important role in colorectal cancer inhibition.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Phytochemical analysis of ZQFZ was conducted using LC-MS/MS and UPLC-MS/MS, identifying and quantifying seven major compounds. &lt;em&gt;In vivo&lt;/em&gt; experiments, AOM/DSS-induced CRC mouse models were treated with ZQFZ, PD-1 antibody, or their combination. Tumour progression, body weight, and survival were monitored. Gut microbial composition and colonic SCFAs levels were assessed via 16S rRNA sequencing and gas chromatography. RT-qPCR was employed to validate the expression of key genes associated with the GPR109A/AKT/mTOR/HIF-1α signaling pathway. Molecular changes in the GPR109A/AKT/mTOR/HIF-1α pathway were evaluated through Western blotting, transcriptomic, and proteomic analyses. Immune cell infiltration and phenotypes were analyzed by flow cytometry. Molecular docking and molecular dynamics simulations were conducted to predict the binding affinity and structural stability between GPR109A and AKT1. The interactions between GPR109A and AKT1, as well as between butyrate and GPR109A, were further validated &lt;em&gt;in vitro&lt;/em&gt; using microscale thermophoresis (MST) assays. To evaluate the microbial basis of ZQFZ activity, antibiotic-pretreated mice received ZQFZ-derived fecal microbiota transplantation (FMT). &lt;em&gt;In vitro&lt;/em&gt; experiments, to investigate the mechanism by which sodium butyrate (NaB), the major gut microbial metabolite of ZQFZ, inhibits glycolysis in colorectal cancer under hypoxic conditions, CCK-8 assays, flow cytometry, lactate measurements, and Western blotting were performed to assess cell viability, apoptosis, lactate production, and the expression of AKT/mTOR/HIF-1α and glycolysis-related proteins.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;LC-MS/MS profiling identified multiple bioactive constituents in ZQFZ. Targeted UPLC-MS/MS quantification revealed that the formulation contained Adenosine (0.87mg/g), Salidroside (0.11 mg/g), Astragaloside IV (0.07 mg/g), Calycosin (0.03 mg/g), Formononetin (6.7 μg /g), Chlorogenic acid (1.4 μg/g), Apigenin (0.5 μg/g). &lt;em&gt;In vivo&lt;/em&gt; studies, both ZQFZ and PD-1 antibody inhibited tumour growth, with the combination treatment exerting the most pronounced anti","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157312"},"PeriodicalIF":8.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213300","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":"FoxO1/PINK1/Parkin-dependent mitophagy mediates the chondroprotective effect of Guzhi Zengsheng Zhitong decoction in osteoarthritis","authors":"Lu Bocheng ,&nbsp;Chen Yongfu ,&nbsp;Cai Junjie ,&nbsp;Li Ziqi ,&nbsp;Guo Lina ,&nbsp;Qu Tingli ,&nbsp;Tang Li ,&nbsp;Zheng Qian","doi":"10.1016/j.phymed.2025.157322","DOIUrl":"10.1016/j.phymed.2025.157322","url":null,"abstract":"<div><h3>Objective</h3><div>Guzhi Zengsheng Zhitong Decoction (GZZD) is a classic traditional Chinese medicine (TCM) prescription for treating knee osteoarthritis (OA), and has been widely used in clinical practice in China. Given that Forkhead box protein O 1 (FoxO1) has been identified as a potential therapeutic target for OA treatment, this study investigates the chondroprotective effects of GZZD through FoxO1-mediated mitochondrial regulation, bridging traditional medicine with contemporary molecular insights.</div></div><div><h3>Methods</h3><div>The therapeutic effects of GZZD on OA and its chondroprotective mechanisms were evaluated both <em>in vivo</em> and <em>in vitro</em>. A rat model of knee OA was established by intra-articular injection of monosodium iodoacetate (MIA), while an <em>in vitro</em> OA model was induced by IL-1β stimulation in chondrocytes. Histological staining, immunohistochemistry, and Western blot analyses were performed to assess cartilage protection. Serum ingredients of GZZD were identified using LC-MS/MS, and the core pathways involved in GZZD-mediated chondroprotection were explored through transcriptomics and network pharmacology. Key protein expression was examined, and molecular biology techniques were applied to validate the role of FoxO1 and its downstream pathways in regulating chondrocyte autophagy, apoptosis, and mitochondrial dysfunction. Additionally, molecular docking and molecular dynamics simulations were conducted to analyze interactions between bioactive compounds and FoxO1.</div></div><div><h3>Results</h3><div>GZZD significantly ameliorated MIA-induced knee joint damage, reduced cartilage degradation and subchondral bone destruction, and decreased OARSI scores. Treatment with GZZD markedly decreased serum levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) while enhancing protective autophagy in chondrocytes. Furthermore, GZZD inhibited chondrocyte apoptosis and mitochondrial dysfunction, accompanied by the upregulation of the cartilage matrix protein COL2A1 and the anti-apoptotic protein BCL2, along with downregulation of catabolic factors (MMP13, IL-1β). Mechanistically, GZZD activated the FoxO1/PINK1/Parkin pathway, restoring mitochondrial homeostasis and mitigating mitochondrial-dependent apoptosis, ultimately protecting chondrocytes from OA-related damage.</div></div><div><h3>Conclusion</h3><div>For the first time, this study demonstrates that the traditional Chinese medicine formula GZZD alleviates osteoarthritis by activating the FoxO1/PINK1/Parkin pathway, thereby restoring mitochondrial function and protecting chondrocytes from injury. These findings not only establish GZZD as a promising complementary therapy for OA but also provide a scientific foundation for developing FoxO1-targeted therapeutics.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157322"},"PeriodicalIF":8.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213279","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":"Urolithin B promotes the functional recovery of spinal cord injury by alleviating neuroinflammation via the inhibition of NLRP3 signaling pathway.","authors":"Yujing Su, Hao Wang, Wenzhi Yang, Shenhong Zhang, Feifan Liu, Kang Han, Fangxia Guan, Shanshan Ma, Yuanbo Cui","doi":"10.1016/j.phymed.2025.157331","DOIUrl":"https://doi.org/10.1016/j.phymed.2025.157331","url":null,"abstract":"<p><strong>Background: </strong>Spinal cord injury (SCI) leads to motor, sensory and autonomic dysfunction with no effective therapy till now. The malignant microenvironment and glial scars at the injury site impede neural circuit remodeling and functional recovery of SCI. Urolithin B (UB), an intestinal metabolite of ellagitannin, possesses anti-inflammatory, antioxidant, antitumor and neuropharmacological activities.</p><p><strong>Purpose: </strong>To investigate the effects and mechanism of UB in SCI recovery both in vitro and in vivo.</p><p><strong>Methods: </strong>At the cellular level, the study focused on the effects of UB on H₂O₂-induced PC12 cells damage and LPS-induced HMC3 cells polarization. At the in vivo level, the repair effect of UB gavage on SCI mice was performed by behavioral analysis, immunofluorescence, histopathology, and ELISA. Finally, network pharmacology, transcriptome sequencing, molecular docking, DARTS, and reverse validation were conducted to explore the molecular mechanism by which UB promotes SCI repair.</p><p><strong>Results: </strong>UB protected PC12 cells against H₂O₂-induced injury and decreased LPS-induced M1-type polarization of HMC3 cells. In addition, UB promoted nerve regeneration, regulated M1/M2 polarization of microglia, and reduced the formation of glial scars, thereby facilitating the motor function recovery of SCI mice. Further studies indicated that UB inhibited the NLRP3/Caspase-1/IL-1β pathway both in vivo and in vitro to reduce neuroinflammation. In contrast, BMS-986,299 (an agonist of NLRP3 inflammasome) attenuated the restorative effects of UB in SCI mice.</p><p><strong>Conclusion: </strong>UB inhibits the NLRP3/Caspase-1/IL-1β signaling pathway and M1 polarization of microglia to attenuate neuroinflammation and promote the functional recovery of SCI mice. Therefore, UB may be a potential therapeutic agent for the treatment of SCI.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"157331"},"PeriodicalIF":8.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252299","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":"Glycyrrhetinic acid orchestrates ERS-pyroptosis crosstalk to elicit immunogenic cell death in hepatocellular carcinoma","authors":"Mianli Bian ,&nbsp;Junyang Ji ,&nbsp;Naqi Lian ,&nbsp;Yongjie Li ,&nbsp;Weijie Zhu ,&nbsp;Peng Cao ,&nbsp;Feng Zhang","doi":"10.1016/j.phymed.2025.157309","DOIUrl":"10.1016/j.phymed.2025.157309","url":null,"abstract":"<div><h3>Background</h3><div>Hepatocellular carcinoma (HCC) remains a magnitude global public health challenges since its aggressive biological behavior and persistently high morbidity and mortality rates. Glycyrrhetinic acid (GA), a bioactive triterpenoid extracted from Glycyrrhiza glabra, has been reported in certain contexts to suppress HCC cell migration and proliferation. In addition, the markedly immunosuppressive tumor microenvironment of HCC represents a major obstacle to achieving durable responses with immunotherapy.</div></div><div><h3>Purpose</h3><div>This study focused on elucidating the anti-hepatoma activity of GA, uncover the underlying molecular pathways, and assess its ability to trigger immunogenic cell death (ICD) as a potential therapeutic strategy for HCC.</div></div><div><h3>Methods</h3><div>Tumor-suppressive effects of GA were evaluated through histopathological analysis in multiple murine models, including cell line-derived xenografts (CDX), orthotopic liver implantation, and lung metastasis models. Transmission electron microscopy (TEM), intracellular calcium (Ca²⁺) assays, ROS staining, and immunofluorescence were used to investigate GA-induced endoplasmic reticulum stress (ERS) and pyroptosis in HCC cells. Proteomics and transcriptomics were applied to profile changes in protein and transcript expression. CETSA, DARTS, pull-down and molecular docking were employed to identify the direct molecular target of GA.</div></div><div><h3>Results</h3><div>The studies suggested that GA exhibited considerably similar anticancer efficacy (IRT = 46.62 %) compared with DOX (IRT = 48.87 %) in a CDX mouse model. Additionally, GA robustly activated ERS via PERK signaling and induced GSDME-mediated pyroptosis, increasing the cytoplasmic Ca²⁺ concentration, driving the translocation of calreticulin (83.32 %) to the tumor cell surface, resulting in the strong release of proinflammatory cytokines and immunogenic signals. This coordinated interaction enhanced DC maturation and T-cell dependent adaptive immune responses, amplifying antitumor immunity.</div></div><div><h3>Conclusion</h3><div>Our findings highlight a novel mechanism whereby GA exploits the ERS-pyroptosis axis to potentiate ICD and amplify antitumor immunity in HCC, providing mechanistic insight and potential therapeutic implications.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157309"},"PeriodicalIF":8.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213347","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":"Ginsenoside compound K ameliorates depressive-like behaviors by targeting kynurenine 3-monooxygenase","authors":"Wen Li ,&nbsp;Ziyang Kong ,&nbsp;Lili Yang ,&nbsp;Feiyan Chen ,&nbsp;Yao Chen ,&nbsp;Jie Han ,&nbsp;Chenmin Sheng ,&nbsp;Li Zeng ,&nbsp;Yiwen Hu ,&nbsp;Yunan Zhao ,&nbsp;Hongsheng Wang ,&nbsp;Yaoyao Bian","doi":"10.1016/j.phymed.2025.157335","DOIUrl":"10.1016/j.phymed.2025.157335","url":null,"abstract":"<div><h3>Background</h3><div>With its high prevalence, frequent recurrence, and significant disability rates, depression has emerged as a major global health burden. Ginsenosides, the primary components of the herbal medicine ginseng, demonstrate antidepressant effects.</div></div><div><h3>Methods</h3><div>Drug affinity-responsive target stability (DARTS) and lipid chromatography-mass spectrometry were employed to identify the potential targets of ginsenosides. Active components were characterized through biolayer interferometry (BLI), molecular docking, and site-directed mutagenesis assays to assess binding affinity and interaction sites. RNAscope in situ hybridization and tissue clearing were used to visualize the expression pattern of kynurenine 3-monooxygenase (KMO) and the distribution of ginsenoside metabolite compound K (CK) in brain. In corticosterone-induced depressive mouse models, behavioral phenotyping, viral-mediated gene manipulations, and bulk RNA sequencing with Mfuzz clustering were performed to explore the roles of KMO and ginsenosides in vivo.</div></div><div><h3>Results</h3><div>DARTS-based screening identified KMO as a critical binding target of ginsenosides. Among the components, CK showed the strongest direct binding to KMO, as confirmed by BLI. Molecular docking and mutations of candidate residues (I309 and G316) validated the specificity of the KMO-CK interaction. Spatial visualization via tissue clearing revealed colocalization of KMO and CK in the brain, with notable enrichment of KMO in thalamic neurons. Importantly, CK exerts antidepressant effects in a KMO-dependent pattern: it alleviated corticosterone-induced depressive-like behaviors and counteracted the associated upregulation of KMO expression. Furthermore, CK restored the neuroactive kynurenine pathway balance by modulating the quinolinic acid/kynurenic acid ratio.</div></div><div><h3>Conclusions</h3><div>KMO serves as a direct target of ginsenosides in the brain. CK acts as a novel brain-penetrant KMO inhibitor that confers antidepressant activity. The enrichment of KMO in thalamic neurons—as opposed to cortical microglia—offers new insights into the neuroanatomical basis of KMO function and the mechanism of antidepressant interventions.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157335"},"PeriodicalIF":8.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226984","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":"Crocin inhibits neutrophil migration and activation to treat hypoxic pulmonary hypertension through targeting HCK","authors":"Yanling Sheng ,&nbsp;Feitian Min ,&nbsp;Yuming Wang ,&nbsp;Xuan Zhang ,&nbsp;Tao Tian ,&nbsp;Meixing Zhao ,&nbsp;Huan Pei ,&nbsp;Jing Zhao ,&nbsp;Xin Liu ,&nbsp;Jing Zhang ,&nbsp;Zhijuan Li ,&nbsp;Huantian Cui ,&nbsp;Ning Wang ,&nbsp;Yuhong Bian ,&nbsp;Weibo Wen","doi":"10.1016/j.phymed.2025.157334","DOIUrl":"10.1016/j.phymed.2025.157334","url":null,"abstract":"<div><h3>Background</h3><div>Crocin (CRO) holds promise as a treatment for hypoxic pulmonary hypertension (HPH); however, its pharmacological mechanism remains poorly understood.</div></div><div><h3>Objectives</h3><div>We investigated how CRO improves HPH by acting on multiple cell types and pathological pathways, using single-cell RNA sequencing (scRNA-seq).</div></div><div><h3>Materials and methods</h3><div>We first established a hypoxia-induced HPH rat model to evaluate the therapeutic effects of CRO. We then performed scRNA-seq to analyze how CRO alters cell populations and gene expression. Then, the effects of CRO on neutrophil migration and activation were investigated. Furthermore, molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) were used to validate the direct target of CRO. Finally, a co-culture system of neutrophils and pulmonary arterial smooth muscle cells (PASMCs) was used to confirm the link between CRO-mediated inhibition of PASMCs proliferation and neutrophil migration and activation.</div></div><div><h3>Results</h3><div>In HPH rat model, CRO treatment significantly improved hemodynamic parameters and alleviated pathological changes in lung. scRNA-seq analysis revealed a marked reduction in the proportions of neutrophils and PASMCs. KEGG analysis of differentially expressed genes (DEGs) in neutrophils showed significant enrichment in cell migration and activation-related pathways. <em>In vitro</em>, CRO inhibited fMLP-induced neutrophils migration and PMA-induced neutrophil extracellular traps (NETs) formation. Molecular docking, CETSA, and DARTS analyses identified HCK as a primary binding target of CRO. Subsequent experiments using an HCK inhibitor confirmed that CRO inhibited neutrophils migration and activation through HCK. Furthermore, neutrophil–PASMCs co-culture experimental system confirmed that the inhibitory effects of CRO on PASMCs were associated with the inhibition of neutrophils activation.</div></div><div><h3>Conclusion</h3><div>CRO targets HCK to inhibit neutrophils migration and activation, and subsequently preventing neutrophil-induced PASMCs proliferation. These results highlight a novel therapeutic target for HPH and provide a scientific basis for the potential clinical application of CRO.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"Article 157334"},"PeriodicalIF":8.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225929","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":"Piperine targets SOAT1 to inhibit the progression of esophageal squamous cell carcinoma via ferroptosis.","authors":"Chengming Wei, Meina Shi, Liujiao Wei, Caituan Wei","doi":"10.1016/j.phymed.2025.157332","DOIUrl":"https://doi.org/10.1016/j.phymed.2025.157332","url":null,"abstract":"<p><strong>Background: </strong>Esophageal squamous cell carcinoma (ESCC) is a major contributor to cancer-associated mortality worldwide. Therefore, there is an urgent need to identify novel therapeutic targets and treatment modalities for this disease. Piperine, a natural alkaloid, has been shown to possess notable anticancer properties. However, the anticancer efficacy of piperine in ESCC and its underlying molecular mechanisms remain unclear.</p><p><strong>Purpose: </strong>This study aimed to investigate the anticancer effect and molecular mechanism of piperine in ESCC.</p><p><strong>Methods: </strong>To evaluate the anticancer potential of piperine against ESCC, a series of experiments was conducted. These included key gene knockdown, CCK-8 assays, colony formation tests, molecular docking studies, bioinformatics analyses, Western blotting, and real-time PCR arrays.</p><p><strong>Results: </strong>Piperine inhibited cell proliferation, migration, and invasion. Importantly, piperine was identified as a potential Sterol O-acyltransferase 1 (SOAT1) inhibitor. Interestingly, piperine targets SOAT1 to enhance ferroptosis and inhibit cell viability. Furthermore, piperine targets SOAT1 to synergistically enhance the anticancer effects of cisplatin in ESCC. Further data analysis showed that inhibiting SOAT1 increased KLF4-induced ALOX12B expression by decreasing the PI3K-AKT pathway. Finally, in vivo studies demonstrated that the SOAT1 inhibitor piperine hindered tumor growth in mice without altering body weight.</p><p><strong>Conclusion: </strong>This study is the first to demonstrate that piperine targets SOAT1 to enhance ferroptosis by inhibiting the PI3K-AKT axis and upregulating the expression of KLF4/ALOX12B. This study strongly emphasizes the potential of piperine as a promising clinical therapeutic candidate for ESCC.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"148 ","pages":"157332"},"PeriodicalIF":8.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252302","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}