Pub Date : 2026-01-01Epub Date: 2025-12-30DOI: 10.1016/j.phymed.2025.157747
Huiling Zhang, Yuna Shao, Di Lu, Chenkang Ma, Liying Zhang, Yang Yang, Jianjun Li, Yuanyuan Zeng, Jianjie Zhu, Jian-An Huang, Zhe Lei, Zeyi Liu
Focal adhesion kinase (FAK) is an attractive therapeutic target overexpressed in numerous cancers. Despite extensive efforts, no FAK inhibitor has reached the market. Here, we identified poliumoside (Pol), a compound from Chinese herbs, as a novel FAK inhibitor through high-throughput virtual screening. Pol exhibited potent anti-proliferative and anti-metastatic activities both in vitro and in vivo. Mechanistically, Pol directly binds to His89 of FAK, thereby inhibiting its autophosphorylation at Y397. This inhibition led to the downregulation of the ERK-c-Myc axis, reduced transcription of IL-6, and consequent suppression of the JAK3-STAT3 signaling pathway. Our findings establish Pol as a promising FAK-targeting agent, exerting its anti-tumor effects in a FAK-dependent manner.
{"title":"Unveiling poliumoside: A herbal-derived FAK kinase inhibitor with anti-proliferative and anti-metastatic efficacy.","authors":"Huiling Zhang, Yuna Shao, Di Lu, Chenkang Ma, Liying Zhang, Yang Yang, Jianjun Li, Yuanyuan Zeng, Jianjie Zhu, Jian-An Huang, Zhe Lei, Zeyi Liu","doi":"10.1016/j.phymed.2025.157747","DOIUrl":"10.1016/j.phymed.2025.157747","url":null,"abstract":"<p><p>Focal adhesion kinase (FAK) is an attractive therapeutic target overexpressed in numerous cancers. Despite extensive efforts, no FAK inhibitor has reached the market. Here, we identified poliumoside (Pol), a compound from Chinese herbs, as a novel FAK inhibitor through high-throughput virtual screening. Pol exhibited potent anti-proliferative and anti-metastatic activities both in vitro and in vivo. Mechanistically, Pol directly binds to His89 of FAK, thereby inhibiting its autophosphorylation at Y397. This inhibition led to the downregulation of the ERK-c-Myc axis, reduced transcription of IL-6, and consequent suppression of the JAK3-STAT3 signaling pathway. Our findings establish Pol as a promising FAK-targeting agent, exerting its anti-tumor effects in a FAK-dependent manner.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"157747"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900206","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}
Pub Date : 2026-01-01DOI: 10.1016/j.phymed.2025.157751
Fuqiang Ma , Lele Zhang , Yitao Fan , Ziyi Xu , Yuhua He , Jiachun Sun , Juan Lu , Xinyu Gu
Background
Hepatocellular carcinoma (HCC) represents the predominant type of primary malignant liver cancer, characterized by high morbidity and mortality rates. The steroidal alkaloid cyclovirobuxine D (CVB-D), which is extracted from Buxus microphylla, has garnered increasing attention for its potential in anti-tumor research. Despite this, the immunoregulatory effects of CVB-D in HCC remain insufficiently explored.
Purpose
This study investigated the role and underlying mechanisms of CVB-D in inhibiting HCC progression, aiming to identify potential therapeutic targets and provide new scientific evidence for HCC treatment.
Study design
CVB-D was administrated to orthotopic HCC mouse models. The effects of CVB-D on the tumor immune microenvironment were systematically assessed via integrated cytometry by time of flight (CyTOF) and single-cell RNA sequencing (scRNA-seq).
Methods
An orthotopic HCC model was generated in C57BL/6 mice via Hepa1–6 cell implantation, followed by intraperitoneal administration of different doses of CVB-D. Following a 14-day treatment period, fresh tumor tissues were collected for CyTOF and scRNA-seq analyses. Multiplexed immunofluorescence staining was performed on liver tissue sections to validate the in suit localization of key biomarkers. Serum cytokine levels were evaluated utilizing the Quantibody® Mouse Inflammation Array Kit.
Results
This research demonstrated that administration of CVB-D in orthotopic HCC mouse models notably inhibited tumor progression. Comprehensive analyses combining CyTOF and scRNA-seq demonstrated that CVB-D remodeled the hepatic immune microenvironment by enhancing CD8+T cell functionality, modulating macrophage polarization, and reducing the abundance of malignant epithelial cells.
Conclusion
These findings highlight the therapeutic promise of CVB-D as a novel candidate for HCC treatment, offering new insights into the development of innovative anti-cancer therapies.
背景：肝细胞癌（HCC）是原发性恶性肝癌的主要类型，具有高发病率和高死亡率的特点。从小叶黄杨中提取的甾体生物碱环virobuxine D （CVB-D）因其在抗肿瘤研究中的潜力而受到越来越多的关注。尽管如此，CVB-D在HCC中的免疫调节作用仍未得到充分探讨。目的探讨CVB-D在抑制HCC进展中的作用及其机制，旨在发现潜在的治疗靶点，为HCC的治疗提供新的科学依据。研究设计cvb - d给予原位肝癌小鼠模型。通过飞行时间（CyTOF）和单细胞RNA测序（scRNA-seq）集成细胞术系统评估CVB-D对肿瘤免疫微环境的影响。方法在C57BL/6小鼠原位肝癌模型中植入Hepa1-6细胞，然后腹腔注射不同剂量的CVB-D。在14天的治疗期后，收集新鲜肿瘤组织进行CyTOF和scRNA-seq分析。对肝组织切片进行多重免疫荧光染色，以验证关键生物标志物的匹配定位。使用Quantibody®小鼠炎症阵列试剂盒评估血清细胞因子水平。结果本研究表明，CVB-D在原位肝癌小鼠模型中显著抑制肿瘤进展。结合CyTOF和scRNA-seq的综合分析表明，CVB-D通过增强CD8+ T细胞功能、调节巨噬细胞极化和降低恶性上皮细胞丰度来重塑肝脏免疫微环境。结论这些发现突出了CVB-D作为HCC治疗的新候选药物的治疗前景，为创新抗癌疗法的发展提供了新的见解。
{"title":"Integrating CyTOF with scRNA-seq reveals that Cyclovirobuxine D inhibits HCC progression through hepatic immune microenvironment remodeling","authors":"Fuqiang Ma , Lele Zhang , Yitao Fan , Ziyi Xu , Yuhua He , Jiachun Sun , Juan Lu , Xinyu Gu","doi":"10.1016/j.phymed.2025.157751","DOIUrl":"10.1016/j.phymed.2025.157751","url":null,"abstract":"<div><h3>Background</h3><div>Hepatocellular carcinoma (HCC) represents the predominant type of primary malignant liver cancer, characterized by high morbidity and mortality rates. The steroidal alkaloid cyclovirobuxine D (CVB-D), which is extracted from <em>Buxus microphylla</em>, has garnered increasing attention for its potential in anti-tumor research. Despite this, the immunoregulatory effects of CVB-D in HCC remain insufficiently explored.</div></div><div><h3>Purpose</h3><div>This study investigated the role and underlying mechanisms of CVB-D in inhibiting HCC progression, aiming to identify potential therapeutic targets and provide new scientific evidence for HCC treatment.</div></div><div><h3>Study design</h3><div>CVB-D was administrated to orthotopic HCC mouse models. The effects of CVB-D on the tumor immune microenvironment were systematically assessed <em>via</em> integrated cytometry by time of flight (CyTOF) and single-cell RNA sequencing (scRNA-seq).</div></div><div><h3>Methods</h3><div>An orthotopic HCC model was generated in C57BL/6 mice <em>via</em> Hepa1–6 cell implantation, followed by intraperitoneal administration of different doses of CVB-D. Following a 14-day treatment period, fresh tumor tissues were collected for CyTOF and scRNA-seq analyses. Multiplexed immunofluorescence staining was performed on liver tissue sections to validate the in suit localization of key biomarkers. Serum cytokine levels were evaluated utilizing the Quantibody® Mouse Inflammation Array Kit.</div></div><div><h3>Results</h3><div>This research demonstrated that administration of CVB-D in orthotopic HCC mouse models notably inhibited tumor progression. Comprehensive analyses combining CyTOF and scRNA-seq demonstrated that CVB-D remodeled the hepatic immune microenvironment by enhancing CD8<sup>+</sup> <em>T</em> cell functionality, modulating macrophage polarization, and reducing the abundance of malignant epithelial cells.</div></div><div><h3>Conclusion</h3><div>These findings highlight the therapeutic promise of CVB-D as a novel candidate for HCC treatment, offering new insights into the development of innovative anti-cancer therapies.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"Article 157751"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884117","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}
Pub Date : 2026-01-01DOI: 10.1016/j.phymed.2025.157692
Yuxin Jiang , Danfeng Wang , Xiaoran Lin , Zihao Yuan , Xinyu Xing , Qingzhuo Gao , Tianshuo Zhang , Shu Jing , He Li
Background
Skin photoaging (SP) is a major contributor to skin aging. Anwulignan (AN) has been confirmed to possess diverse biological activities. This study investigated the protective effect of AN against SP and explored its underlying mechanisms.
Methods
A UVB-induced SP model in mice was established to evaluate skin erythema index (EI), transepidermal water loss (TEWL), and skin hydration. Histopathological assessments were performed using hematoxylin and eosin (HE), Masson, and Sirius red staining. Transmission electron microscopy examined the morphology and quantity of mitochondria in epidermal cells. ELISA measured levels of hydroxyproline (HYP), hyaluronic acid (HA), oxidative stress markers, and inflammation indicators. Molecular docking predicted the potential targets of AN on UVB-induced SP. Western blot and immunofluorescence staining assessed the expression of proteins related to oxidation, inflammation, aging, ferroptosis, and autophagy. Zebrafish experiments further validated the effects.
Results
AN significantly alleviated SP, evidenced by increased levels of HA and HYP, suppressed pro-inflammatory cytokine expression, reduced reactive oxygen species (ROS), 8-hydroxy-2′-deoxyguanosine (8-OHdG), and malondialdehyde (MDA), while enhancing activities of total superoxide dismutase (T-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). It also regulated the expression of proteins involved in the Nrf2/PINK1/Parkin mitophagy axis and the Nrf2/SLC7A11/GPX4 ferroptosis regulatory axis. Significant differences were observed among groups in tail fin area, β-galactosidase staining fluorescence intensity, yolk sac fluorescence, and mitochondrial fluorescence in muscle.
Conclusion
AN may exert protective effects against SP by targeting Nrf2 and subsequently activating both the Nrf2/PINK1/Parkin mitophagy axis and the Nrf2/SLC7A11/GPX4 ferroptosis regulatory axis.
{"title":"Anwulignan mitigates UVB-induced skin photodamage by dual activation of the Nrf2/PINK1/Parkin and Nrf2/SLC7A11/GPX4 signaling pathways","authors":"Yuxin Jiang , Danfeng Wang , Xiaoran Lin , Zihao Yuan , Xinyu Xing , Qingzhuo Gao , Tianshuo Zhang , Shu Jing , He Li","doi":"10.1016/j.phymed.2025.157692","DOIUrl":"10.1016/j.phymed.2025.157692","url":null,"abstract":"<div><h3>Background</h3><div>Skin photoaging (SP) is a major contributor to skin aging. Anwulignan (AN) has been confirmed to possess diverse biological activities. This study investigated the protective effect of AN against SP and explored its underlying mechanisms.</div></div><div><h3>Methods</h3><div>A UVB-induced SP model in mice was established to evaluate skin erythema index (EI), transepidermal water loss (TEWL), and skin hydration. Histopathological assessments were performed using hematoxylin and eosin (HE), Masson, and Sirius red staining. Transmission electron microscopy examined the morphology and quantity of mitochondria in epidermal cells. ELISA measured levels of hydroxyproline (HYP), hyaluronic acid (HA), oxidative stress markers, and inflammation indicators. Molecular docking predicted the potential targets of AN on UVB-induced SP. Western blot and immunofluorescence staining assessed the expression of proteins related to oxidation, inflammation, aging, ferroptosis, and autophagy. Zebrafish experiments further validated the effects.</div></div><div><h3>Results</h3><div>AN significantly alleviated SP, evidenced by increased levels of HA and HYP, suppressed pro-inflammatory cytokine expression, reduced reactive oxygen species (ROS), 8-hydroxy-2′-deoxyguanosine (8-OHdG), and malondialdehyde (MDA), while enhancing activities of total superoxide dismutase (T-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). It also regulated the expression of proteins involved in the Nrf2/PINK1/Parkin mitophagy axis and the Nrf2/SLC7A11/GPX4 ferroptosis regulatory axis. Significant differences were observed among groups in tail fin area, β-galactosidase staining fluorescence intensity, yolk sac fluorescence, and mitochondrial fluorescence in muscle.</div></div><div><h3>Conclusion</h3><div>AN may exert protective effects against SP by targeting Nrf2 and subsequently activating both the Nrf2/PINK1/Parkin mitophagy axis and the Nrf2/SLC7A11/GPX4 ferroptosis regulatory axis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"Article 157692"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917468","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}
Pub Date : 2026-01-01Epub Date: 2025-12-20DOI: 10.1016/j.phymed.2025.157733
Qing Wang, Yali Wu, Yan Wang, Xin Pang, Mingliang Zhang, Ya Zhao, Xi Qin, Bowen Zheng, Mingyue Li, Xuyang Li, Weixia Li, Xiaoyan Wang, Liuqing Yang, Xiaofei Chen, Jinfa Tang
Background: Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to global public health due to its multidrug resistance, highlighting the need for the development of novel antimicrobial strategies. Computational repurposing has predicted that Shuganning injection (SGN), a clinically used hepatoprotective traditional Chinese medicine, exhibits synergistic activity with antibiotics against MRSA. However, the antimicrobial properties of SGN remain insufficiently characterized.
Purpose: To evaluate the anti-MRSA activity of SGN and to elucidate the mechanism underlying its synergy with linezolid (LZD).
Methods: The components of SGN were identified using UPLC-Q/TOF-MS/MS. Antimicrobial potential was predicted through computational repurposing and validated through bactericidal and synergy assays. Biofilm inhibition, morphological changes, and cell wall integrity were assessed. Integrated metabolomics and transcriptomics were employed to investigate SGN-LZD synergy. Key findings were subsequently validated by RT-qPCR and confirmed through targeted pharmacological inhibition. Finally, in vivo efficacy was assessed in Galleria mellonella and murine skin infection models.
Results: Fifty-two components were identified in SGN. Computational repurposing analysis indicated that SGN reversed sepsis-associated gene dysregulation and inhibited the growth of clinically isolated MRSA417, with corresponding MIC and MBC values of 42.5 and 170 mg/mL (crude drug equivalent), respectively. SGN demonstrated partial synergy with LZD (FICI = 0.75). The combination markedly inhibited MRSA biofilm formation by 94.25%, compared to 40.40% for SGN alone. Sub-MIC combinations caused structural damage, evidenced by increased extracellular alkaline phosphatase levels and disrupted bacterial morphology. Multi-omics analysis indicated co-downregulation of two-component system (TCS)-related metabolites (e.g., L-malic acid) and genes (saeRS, vraSR), indicating TCS suppression as the key mechanism underlying SGN-LZD synergy. The combination downregulated key TCS mRNAs. Furthermore, TCS inhibitors did not enhance its anti-biofilm and antibacterial effects. Notably, the SGN-LZD combination improved survival in G. mellonella and promoted wound healing in a murine skin infection model.
Conclusion: This study provides evidence supporting the repositioning of SGN for MRSA treatment. SGN impairs TCS-mediated virulence regulation, cell envelope integrity, and essential metabolic pathways, thereby enhancing the efficacy of LZD. These findings offer a translational framework for drug repurposing and highlight the clinical potential of SGN-LZD combination therapy for drug-resistant infections.
{"title":"Unveiling TCM-antibiotic synergy through multi-omics: Shuganning injection potentiates the effect of linezolid against methicillin-resistant Staphylococcus aureus.","authors":"Qing Wang, Yali Wu, Yan Wang, Xin Pang, Mingliang Zhang, Ya Zhao, Xi Qin, Bowen Zheng, Mingyue Li, Xuyang Li, Weixia Li, Xiaoyan Wang, Liuqing Yang, Xiaofei Chen, Jinfa Tang","doi":"10.1016/j.phymed.2025.157733","DOIUrl":"10.1016/j.phymed.2025.157733","url":null,"abstract":"<p><strong>Background: </strong>Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to global public health due to its multidrug resistance, highlighting the need for the development of novel antimicrobial strategies. Computational repurposing has predicted that Shuganning injection (SGN), a clinically used hepatoprotective traditional Chinese medicine, exhibits synergistic activity with antibiotics against MRSA. However, the antimicrobial properties of SGN remain insufficiently characterized.</p><p><strong>Purpose: </strong>To evaluate the anti-MRSA activity of SGN and to elucidate the mechanism underlying its synergy with linezolid (LZD).</p><p><strong>Methods: </strong>The components of SGN were identified using UPLC-Q/TOF-MS/MS. Antimicrobial potential was predicted through computational repurposing and validated through bactericidal and synergy assays. Biofilm inhibition, morphological changes, and cell wall integrity were assessed. Integrated metabolomics and transcriptomics were employed to investigate SGN-LZD synergy. Key findings were subsequently validated by RT-qPCR and confirmed through targeted pharmacological inhibition. Finally, in vivo efficacy was assessed in Galleria mellonella and murine skin infection models.</p><p><strong>Results: </strong>Fifty-two components were identified in SGN. Computational repurposing analysis indicated that SGN reversed sepsis-associated gene dysregulation and inhibited the growth of clinically isolated MRSA417, with corresponding MIC and MBC values of 42.5 and 170 mg/mL (crude drug equivalent), respectively. SGN demonstrated partial synergy with LZD (FICI = 0.75). The combination markedly inhibited MRSA biofilm formation by 94.25%, compared to 40.40% for SGN alone. Sub-MIC combinations caused structural damage, evidenced by increased extracellular alkaline phosphatase levels and disrupted bacterial morphology. Multi-omics analysis indicated co-downregulation of two-component system (TCS)-related metabolites (e.g., L-malic acid) and genes (saeRS, vraSR), indicating TCS suppression as the key mechanism underlying SGN-LZD synergy. The combination downregulated key TCS mRNAs. Furthermore, TCS inhibitors did not enhance its anti-biofilm and antibacterial effects. Notably, the SGN-LZD combination improved survival in G. mellonella and promoted wound healing in a murine skin infection model.</p><p><strong>Conclusion: </strong>This study provides evidence supporting the repositioning of SGN for MRSA treatment. SGN impairs TCS-mediated virulence regulation, cell envelope integrity, and essential metabolic pathways, thereby enhancing the efficacy of LZD. These findings offer a translational framework for drug repurposing and highlight the clinical potential of SGN-LZD combination therapy for drug-resistant infections.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"157733"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878854","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}
Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer and is associated with a poor prognosis. Current treatment options for advanced HCC remain limited, highlighting the need for more effective and safer therapies.
Purpose
This study aimed to elucidate the anti-cancer efficacy and explore the molecular mechanism of Bruceantin (BCT) against HCC.
Methods
We screened natural compounds using an extensive literature review and CCK-8 assays to identify novel therapeutic candidates. Using in vitro (HepG2.2.15 and Hep3B) and in vivo models, we assessed the BCT’s effects through CCK-8, colony formation, wound-healing, flow cytometry, Hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), qPCR, Western blot (WB), Luciferase reporter assay, and CETSA.
Results
Bruceantin (BCT) significantly inhibited HCC cell proliferation and migration and induced apoptosis. In mouse xenograft models, it markedly suppressed tumor growth without observable toxicity. Transcriptomic profiling revealed that BCT broadly downregulated ribosomal protein genes, with RPL27A showing the most notable reduction. Further investigations demonstrated that RPL27A plays a crucial role in supporting HCC cell survival and inhibiting apoptosis, and its high expression is clinically associated with poor prognosis. Mechanistically, BCT decreased RPL27A expression by inhibiting c-Myc's transcriptional activity, thus preventing its capacity to activate RPL27A transcription. This disruption of the c-Myc/RPL27A axis contributes to BCT's antitumor effects.
Conclusion
This study reveals a new molecular mechanism underlying BCT’s antitumor activity and supports its potential as a therapeutic agent for HCC.
背景：肝细胞癌（HCC）是最常见的肝癌，且预后较差。目前晚期HCC的治疗选择仍然有限，这表明需要更有效和更安全的治疗方法。目的研究Bruceantin （BCT）对肝癌的抗癌作用，探讨其分子机制。方法通过广泛的文献回顾和CCK-8测定来筛选天然化合物，以确定新的候选治疗药物。采用体外（HepG2.2.15和Hep3B）和体内模型，通过CCK-8、菌落形成、伤口愈合、流式细胞术、苏木精和伊红（H&；E）染色、免疫组织化学（IHC）、qPCR、Western blot （WB）、荧光素酶报告基因检测和CETSA等方法评估BCT的作用。结果bruceantin （BCT）能明显抑制肝癌细胞的增殖和迁移，诱导细胞凋亡。在小鼠异种移植模型中，它明显抑制肿瘤生长，无明显毒性。转录组学分析显示，BCT广泛下调核糖体蛋白基因，其中RPL27A的下调最为显著。进一步研究表明，RPL27A在支持HCC细胞存活和抑制细胞凋亡中起着至关重要的作用，其高表达在临床上与不良预后相关。从机制上讲，BCT通过抑制c-Myc的转录活性来降低RPL27A的表达，从而阻止其激活RPL27A转录的能力。这种c-Myc/RPL27A轴的破坏有助于BCT的抗肿瘤作用。结论本研究揭示了BCT抗肿瘤活性的新分子机制，支持其作为HCC治疗药物的潜力。
{"title":"Bruceantin inhibits the c-Myc/RL27A axis to suppress tumor progression in hepatocellular carcinoma","authors":"Baitul Islam , Saro Adonira , Weiye Xu , Ceshi Chen , Haiyang Yu , Jufang Huang","doi":"10.1016/j.phymed.2025.157740","DOIUrl":"10.1016/j.phymed.2025.157740","url":null,"abstract":"<div><h3>Background</h3><div>Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer and is associated with a poor prognosis. Current treatment options for advanced HCC remain limited, highlighting the need for more effective and safer therapies.</div></div><div><h3>Purpose</h3><div>This study aimed to elucidate the anti-cancer efficacy and explore the molecular mechanism of Bruceantin (BCT) against HCC<em>.</em></div></div><div><h3>Methods</h3><div>We screened natural compounds using an extensive literature review and CCK-8 assays to identify novel therapeutic candidates. Using <em>in vitro</em> (HepG2.2.15 and Hep3B) and <em>in vivo</em> models, we assessed the BCT’s effects through CCK-8, colony formation, wound-healing, flow cytometry, Hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), qPCR, Western blot (WB), Luciferase reporter assay, and CETSA.</div></div><div><h3>Results</h3><div>Bruceantin (BCT) significantly inhibited HCC cell proliferation and migration and induced apoptosis. In mouse xenograft models, it markedly suppressed tumor growth without observable toxicity. Transcriptomic profiling revealed that BCT broadly downregulated ribosomal protein genes, with RPL27A showing the most notable reduction. Further investigations demonstrated that RPL27A plays a crucial role in supporting HCC cell survival and inhibiting apoptosis, and its high expression is clinically associated with poor prognosis. Mechanistically, BCT decreased RPL27A expression by inhibiting c-Myc's transcriptional activity, thus preventing its capacity to activate RPL27A transcription. This disruption of the c-Myc/RPL27A axis contributes to BCT's antitumor effects.</div></div><div><h3>Conclusion</h3><div>This study reveals a new molecular mechanism underlying BCT’s antitumor activity and supports its potential as a therapeutic agent for HCC.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"Article 157740"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884162","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}
Pub Date : 2026-01-01DOI: 10.1016/j.phymed.2025.157742
Honglin Li , Guanru Wang , Yuchen Fan , Zhixuan Li , Hongxuan Wei , Suning Mao , Cheng Miao , Liu Liu , Junsheng Chen , Chunjie Li , Zhangfan Ding , Yubin Cao
Background
Radiation-induced salivary gland injury is a common complication of radiotherapy for head and neck tumors. The traditional Chinese herbal compound Shengmai San (SMS) can regulate Qi-Yin deficiency, promote fluid secretion, and alleviate thirst. However, its therapeutic effects on radiation-induced salivary gland damage remain unexplored.
Purpose
This study aimed to investigate the therapeutic efficacy of Shengmai San in irradiation-induced salivary gland injury, identify its active pharmaceutical components, and elucidate the underlying molecular mechanisms of radioprotection.
Material and methods
The natural drug components of Shengmai San were analyzed, and a murine model of irradiation-induced salivary gland injury was established. SMS extract was administered to irradiated mice, and the functional restoration of salivary glands was evaluated. Network pharmacology was employed to identify the active constituents of SMS, while molecular docking and protein-protein interaction analysis were used to screen key signaling pathways associated with glandular functional preservation. In vitro and in vivo experiments were conducted to validate these findings.
Results
Shengmai San significantly alleviated irradiation-induced salivary gland injury by promoting M2 macrophage polarization and reducing the levels of Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) in serum and salivary gland tissues. It also ameliorated glandular fibrosis and inflammation. Network pharmacology analysis revealed that ophiopogonanone E was one of the primary active components, and molecular docking demonstrated its strong interaction with sphingosine kinase 1 (SPHK1) protein. In vivo experiments showed that SMS suppressed SPHK1 activity and sphingosine-1-phosphate (S1P) production in irradiated salivary glands. Additionally, SMS effectively inhibited the downstream receptor S1PR1. In vitro studies confirmed that SMS attenuated mitochondrial damage in acinar cells by inhibiting the SPHK1-S1P-S1PR1 axis and reduced glandular inflammation and oxidative stress by suppressing Nucleotide-binding Oligomerization Domain-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation, thereby preserving salivary gland function.
Conclusion
Shengmai San effectively attenuates irradiation-induced salivary gland hypofunction and fibrosis, mainly through inhibition of the SPHK1-S1P-S1PR1 signaling pathway.
{"title":"Shengmai San attenuates irradiation-induced salivary gland injury and fibrosis by inhibiting the SPHK1-S1P-S1PR1 axis","authors":"Honglin Li , Guanru Wang , Yuchen Fan , Zhixuan Li , Hongxuan Wei , Suning Mao , Cheng Miao , Liu Liu , Junsheng Chen , Chunjie Li , Zhangfan Ding , Yubin Cao","doi":"10.1016/j.phymed.2025.157742","DOIUrl":"10.1016/j.phymed.2025.157742","url":null,"abstract":"<div><h3>Background</h3><div>Radiation-induced salivary gland injury is a common complication of radiotherapy for head and neck tumors. The traditional Chinese herbal compound Shengmai San (SMS) can regulate Qi-Yin deficiency, promote fluid secretion, and alleviate thirst. However, its therapeutic effects on radiation-induced salivary gland damage remain unexplored.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate the therapeutic efficacy of Shengmai San in irradiation-induced salivary gland injury, identify its active pharmaceutical components, and elucidate the underlying molecular mechanisms of radioprotection.</div></div><div><h3>Material and methods</h3><div>The natural drug components of Shengmai San were analyzed, and a murine model of irradiation-induced salivary gland injury was established. SMS extract was administered to irradiated mice, and the functional restoration of salivary glands was evaluated. Network pharmacology was employed to identify the active constituents of SMS, while molecular docking and protein-protein interaction analysis were used to screen key signaling pathways associated with glandular functional preservation. <em>In vitro</em> and <em>in vivo</em> experiments were conducted to validate these findings.</div></div><div><h3>Results</h3><div>Shengmai San significantly alleviated irradiation-induced salivary gland injury by promoting M2 macrophage polarization and reducing the levels of Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) in serum and salivary gland tissues. It also ameliorated glandular fibrosis and inflammation. Network pharmacology analysis revealed that ophiopogonanone E was one of the primary active components, and molecular docking demonstrated its strong interaction with sphingosine kinase 1 (SPHK1) protein. <em>In vivo</em> experiments showed that SMS suppressed SPHK1 activity and sphingosine-1-phosphate (S1P) production in irradiated salivary glands. Additionally, SMS effectively inhibited the downstream receptor S1PR1. <em>In vitro</em> studies confirmed that SMS attenuated mitochondrial damage in acinar cells by inhibiting the SPHK1-S1P-S1PR1 axis and reduced glandular inflammation and oxidative stress by suppressing Nucleotide-binding Oligomerization Domain-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation, thereby preserving salivary gland function.</div></div><div><h3>Conclusion</h3><div>Shengmai San effectively attenuates irradiation-induced salivary gland hypofunction and fibrosis, mainly through inhibition of the SPHK1-S1P-S1PR1 signaling pathway.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"Article 157742"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884121","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}
Pub Date : 2026-01-01DOI: 10.1016/j.phymed.2025.157750
Hongyu Qi , Zepeng Zhang , Tong Hou , Lu Ding , Qing Liu , Ying Wang , Siyu Song , Jiaqi Liu , Chang Sun , Yahui Sun , Zeyu Wang , Fengmei Lian , Xiangyan Li
Background
The global prevalence of obesity continues to rise annually. Jiangtang Tiaozhi (JTTZ) formula, a traditional Chinese medicine formula, is clinically utilized for treating obesity and type 2 diabetes due to its therapeutic efficacy. However, the underlying mechanisms of JTTZ formula for improving obesity and insulin resistance (IR) remain unclear.
Purpose
This study aimed to elucidate the mechanistic basis of JTTZ formula's anti-obesity effects, specifically evaluating its role in ameliorating IR and reducing body weight.
Methods
High-fat diet (HFD)- and high-fat and high-sucrose diet (HFHSD)-induced obese (DIO) mice were assessed for determining the effects of JTTZ formula on body weights, IR, serum lipid profiles, and inflammatory markers in the serum and gastrocnemius muscle. Transcriptomic analysis of the gastrocnemius tissues of HFD-fed mice was performed, followed by RT-qPCR analysis and immunofluorescence staining to evaluate the changes of inflammation- and pyroptosis-related genes/proteins. Molecular docking and surface plasmon resonance assays were used to assess the binding affinity of 12 blood components derived from JTTZ formula to the pyroptosis-associated protein, NLRP3. In addition, the influences of JTTZ formula and its bioactive compounds on cell viability, lipid accumulation, inflammatory cytokine release, and pyroptosis were determined in the palmitic acid (PA)-induced C2C12 and L6 myotubes model of IR.
Results
JTTZ formula significantly reduced the body weight, adiposity, and improved IR of HFD- and HFHSD-induced DIO mice while improving gastrocnemius muscle morphology and suppressing systemic and muscular inflammation. Transcriptomics and molecular assays revealed that JTTZ formula could regulate the tumor necrosis factor, NOD-like receptor, and nuclear factor kappa B signaling pathways to inhibit inflammation and pyroptosis for the improvement of IR in muscles. Among the various components of JTTZ formula, cryptotanshinone, diosgenin, and timosaponin A1 exhibited significant NLRP3-binding affinity. The active constituents of JTTZ formula including berberine, cryptotanshinone, neomangiferin, and palmatine attenuated PA-induced IR, lipid deposition, inflammation, and pyroptosis in C2C12 and L6 myotubes.
Conclusion
JTTZ formula could ameliorate obesity-associated metabolic dysfunction and improve IR by enhancing glucose uptake, reducing lipid accumulation in skeletal muscles. Its effects were mediated by attenuating inflammation and pyroptosis in muscle tissues. Berberine, cryptotanshinone, neomangiferin, and palmatine might be the bioactive components of JTTZ formula against obesity-related IR.
{"title":"Jiangtang Tiaozhi formula improves obesity and insulin resistance by inhibiting skeletal muscle inflammation and pyroptosis in diet-induced obese mice","authors":"Hongyu Qi , Zepeng Zhang , Tong Hou , Lu Ding , Qing Liu , Ying Wang , Siyu Song , Jiaqi Liu , Chang Sun , Yahui Sun , Zeyu Wang , Fengmei Lian , Xiangyan Li","doi":"10.1016/j.phymed.2025.157750","DOIUrl":"10.1016/j.phymed.2025.157750","url":null,"abstract":"<div><h3>Background</h3><div>The global prevalence of obesity continues to rise annually. Jiangtang Tiaozhi (JTTZ) formula, a traditional Chinese medicine formula, is clinically utilized for treating obesity and type 2 diabetes due to its therapeutic efficacy. However, the underlying mechanisms of JTTZ formula for improving obesity and insulin resistance (IR) remain unclear.</div></div><div><h3>Purpose</h3><div>This study aimed to elucidate the mechanistic basis of JTTZ formula's anti-obesity effects, specifically evaluating its role in ameliorating IR and reducing body weight.</div></div><div><h3>Methods</h3><div>High-fat diet (HFD)- and high-fat and high-sucrose diet (HFHSD)-induced obese (DIO) mice were assessed for determining the effects of JTTZ formula on body weights, IR, serum lipid profiles, and inflammatory markers in the serum and gastrocnemius muscle. Transcriptomic analysis of the gastrocnemius tissues of HFD-fed mice was performed, followed by RT-qPCR analysis and immunofluorescence staining to evaluate the changes of inflammation- and pyroptosis-related genes/proteins. Molecular docking and surface plasmon resonance assays were used to assess the binding affinity of 12 blood components derived from JTTZ formula to the pyroptosis-associated protein, NLRP3. In addition, the influences of JTTZ formula and its bioactive compounds on cell viability, lipid accumulation, inflammatory cytokine release, and pyroptosis were determined in the palmitic acid (PA)-induced C2C12 and L6 myotubes model of IR.</div></div><div><h3>Results</h3><div>JTTZ formula significantly reduced the body weight, adiposity, and improved IR of HFD- and HFHSD-induced DIO mice while improving gastrocnemius muscle morphology and suppressing systemic and muscular inflammation. Transcriptomics and molecular assays revealed that JTTZ formula could regulate the tumor necrosis factor, NOD-like receptor, and nuclear factor kappa B signaling pathways to inhibit inflammation and pyroptosis for the improvement of IR in muscles. Among the various components of JTTZ formula, cryptotanshinone, diosgenin, and timosaponin A1 exhibited significant NLRP3-binding affinity. The active constituents of JTTZ formula including berberine, cryptotanshinone, neomangiferin, and palmatine attenuated PA-induced IR, lipid deposition, inflammation, and pyroptosis in C2C12 and L6 myotubes.</div></div><div><h3>Conclusion</h3><div>JTTZ formula could ameliorate obesity-associated metabolic dysfunction and improve IR by enhancing glucose uptake, reducing lipid accumulation in skeletal muscles. Its effects were mediated by attenuating inflammation and pyroptosis in muscle tissues. Berberine, cryptotanshinone, neomangiferin, and palmatine might be the bioactive components of JTTZ formula against obesity-related IR.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"Article 157750"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925104","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}
Pub Date : 2026-01-01Epub Date: 2025-12-11DOI: 10.1016/j.phymed.2025.157694
Han Zhang, Ao Lin, Chenguang Zhai, Tianli Lai, Xueling Gong, Mengyuan Wang, Hui Wu, Taochun Ye, Lingjun Wang, Dina Tawulie
<p><strong>Background: </strong>Myocardial ischemia-reperfusion injury (MIRI) drives adverse cardiac remodeling and ventricular dysfunction, posing a major therapeutic challenge and substantially contributing to global mortality. Despite therapeutic advances, effective MIRI treatments remain limited. Ginsenoside Rd (GSRd), a bioactive constituent from traditional Chinese herbs, has been widely recognized to have cardioprotective effects. However, the role of GSRd in MIRI remains unclear.</p><p><strong>Purpose: </strong>To elucidate the therapeutic efficacy and the underlying molecular mechanisms of GSRd against MIRI.</p><p><strong>Methods: </strong>A MIRI model was established in male C57BL/6J mice via left anterior descending coronary artery (LAD) ligation followed by reperfusion. Post-surgery, mice received daily intraperitoneal injections of vehicle, dapagliflozin (1 mg/kg), or GSRd (5, 10, 20 mg/kg) for 28 days. Cardiac function was evaluated by echocardiography. Histopathological changes were assessed using hematoxylin and eosin (H&E), Masson's trichrome, TUNEL, and immunofluorescence staining. In vitro, isolated adult mouse CMs were subjected to H/R injury and GSRd-containing serum treatment to assess proliferation. Cardiomyocyte proliferation was assessed by Ki-67 immunofluorescence and BrdU flow cytometry. Integrated cardiac untargeted metabolomics (UPLC-MS/MS) and transcriptomics (RNA-seq) were conducted to identify differential metabolites and genes following GSRd intervention. Key targets were validated by RT-qPCR and western blotting. Adeno-associated virus9 (AAV9) with cardiac-specific 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) knockdown and overexpression were employed to confirm the therapeutic targets of GSRd against MIRI. In addition, transcription factor prediction was performed by multi-platform database analysis, with subsequent chromatin immunoprecipitation-qPCR (ChIP-qPCR) providing mechanistic validation. Furthermore, molecular docking, dynamics simulation, and surface plasmon resonance (SPR) were implemented to evaluate the binding capacity between GSRd and peroxisome proliferator-activated receptor gamma (PPARG). Additionally, GW9662, a PPARG inhibitor, was used to determine the dependence of GSRd-mediated cardioprotection against MIRI on the PPARG/HMGCS2 signaling pathway.</p><p><strong>Results: </strong>The results revealed that GSRd intervention substantially improved cardiac dysfunction, attenuated ventricular remodeling, ameliorated myocardial pathology, and suppressed inflammatory cytokine and oxidative stress levels in MIRI mice. Mechanistically, multi-omics analysis demonstrated enrichment in ketone body synthesis, carnitine and lipid metabolism, and PPAR signaling after GSRd treatment. Cardiac untargeted metabolomics indicated that GSRd alleviated metabolic dysregulation, concomitant with increased cardiac β-hydroxybutyrate (β-OHB). Transcriptomics identified upregulated ketogenic enzyme gene Hmgcs2 follo
{"title":"Ginsenoside Rd promotes cardiac regeneration through PPARG/HMGCS2-driven ketone body metabolic reprogramming in myocardial ischemia-reperfusion injury.","authors":"Han Zhang, Ao Lin, Chenguang Zhai, Tianli Lai, Xueling Gong, Mengyuan Wang, Hui Wu, Taochun Ye, Lingjun Wang, Dina Tawulie","doi":"10.1016/j.phymed.2025.157694","DOIUrl":"10.1016/j.phymed.2025.157694","url":null,"abstract":"<p><strong>Background: </strong>Myocardial ischemia-reperfusion injury (MIRI) drives adverse cardiac remodeling and ventricular dysfunction, posing a major therapeutic challenge and substantially contributing to global mortality. Despite therapeutic advances, effective MIRI treatments remain limited. Ginsenoside Rd (GSRd), a bioactive constituent from traditional Chinese herbs, has been widely recognized to have cardioprotective effects. However, the role of GSRd in MIRI remains unclear.</p><p><strong>Purpose: </strong>To elucidate the therapeutic efficacy and the underlying molecular mechanisms of GSRd against MIRI.</p><p><strong>Methods: </strong>A MIRI model was established in male C57BL/6J mice via left anterior descending coronary artery (LAD) ligation followed by reperfusion. Post-surgery, mice received daily intraperitoneal injections of vehicle, dapagliflozin (1 mg/kg), or GSRd (5, 10, 20 mg/kg) for 28 days. Cardiac function was evaluated by echocardiography. Histopathological changes were assessed using hematoxylin and eosin (H&E), Masson's trichrome, TUNEL, and immunofluorescence staining. In vitro, isolated adult mouse CMs were subjected to H/R injury and GSRd-containing serum treatment to assess proliferation. Cardiomyocyte proliferation was assessed by Ki-67 immunofluorescence and BrdU flow cytometry. Integrated cardiac untargeted metabolomics (UPLC-MS/MS) and transcriptomics (RNA-seq) were conducted to identify differential metabolites and genes following GSRd intervention. Key targets were validated by RT-qPCR and western blotting. Adeno-associated virus9 (AAV9) with cardiac-specific 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) knockdown and overexpression were employed to confirm the therapeutic targets of GSRd against MIRI. In addition, transcription factor prediction was performed by multi-platform database analysis, with subsequent chromatin immunoprecipitation-qPCR (ChIP-qPCR) providing mechanistic validation. Furthermore, molecular docking, dynamics simulation, and surface plasmon resonance (SPR) were implemented to evaluate the binding capacity between GSRd and peroxisome proliferator-activated receptor gamma (PPARG). Additionally, GW9662, a PPARG inhibitor, was used to determine the dependence of GSRd-mediated cardioprotection against MIRI on the PPARG/HMGCS2 signaling pathway.</p><p><strong>Results: </strong>The results revealed that GSRd intervention substantially improved cardiac dysfunction, attenuated ventricular remodeling, ameliorated myocardial pathology, and suppressed inflammatory cytokine and oxidative stress levels in MIRI mice. Mechanistically, multi-omics analysis demonstrated enrichment in ketone body synthesis, carnitine and lipid metabolism, and PPAR signaling after GSRd treatment. Cardiac untargeted metabolomics indicated that GSRd alleviated metabolic dysregulation, concomitant with increased cardiac β-hydroxybutyrate (β-OHB). Transcriptomics identified upregulated ketogenic enzyme gene Hmgcs2 follo","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"157694"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828000","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}
Pub Date : 2026-01-01Epub Date: 2025-12-30DOI: 10.1016/j.phymed.2025.157752
Junjie Huang, Ruigang Zhou, Weilong Peng, Weimei Wang, Jun Chen, Chenglong Yu, Lianggang Wang, Mingjiang Liu, Ruonan Bo, Jingui Li
Introduction: Artesunate (ARS) has demonstrated therapeutic potential in experimental ulcerative colitis (UC) through immunomodulatory activities. However, the role of macrophages and the underlying mechanisms remain unclear.
Methods: In this study, a DSS-induced UC model was established, along with macrophage depletion, polarized macrophage reinfusion, and Transwell coculture systems. The typical colitis characteristics, including weight change, disease activity index, inflammation, and tissue damage, were systematically assessed. Key proteins in the mTORC1/HIF-1α pathway were analyzed. SPR-MS was employed to identify ARS targets in M1 macrophages.
Results: This study indicated that ARS markedly suppressed DSS-enhanced M1 polarization and macrophage infiltration. In a Caco2-BMDM coculture system, ARS reduced macrophage migration and inflammation. Macrophage depletion significantly attenuated the anti-colitis effect of ARS. Compared with M1 reinfusion, ARS-pretreated M1 cells alleviated UC symptoms. ARS also inhibited LPS- or DSS-induced M1 polarization and proinflammatory cytokine upregulation in vivo and in vitro, linked to mTORC1/HIF-1α signaling, as confirmed by the agonist Leucine (LEU). Moreover, ARS protected intestinal barrier function by preventing tight junction loss and permeability increases via suppression of M1 polarization. SPR-MS and molecular docking revealed that ARS directly activated INSR, inhibiting mTORC1/HIF-1α-driven glycolytic M1 polarization.
Conclusions: Overall, macrophages are essential for ARS-mediated protection in UC. ARS alleviates UC by reprogramming macrophage polarization via the INSR/mTORC1/HIF-1α axis, providing new mechanistic insights and potential clinical applications.
{"title":"Artesunate alleviated DSS induced colitis via inhibiting M1 polarization through directly targeting INSR/mTORC1/HIF-1α pathway.","authors":"Junjie Huang, Ruigang Zhou, Weilong Peng, Weimei Wang, Jun Chen, Chenglong Yu, Lianggang Wang, Mingjiang Liu, Ruonan Bo, Jingui Li","doi":"10.1016/j.phymed.2025.157752","DOIUrl":"10.1016/j.phymed.2025.157752","url":null,"abstract":"<p><strong>Introduction: </strong>Artesunate (ARS) has demonstrated therapeutic potential in experimental ulcerative colitis (UC) through immunomodulatory activities. However, the role of macrophages and the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>In this study, a DSS-induced UC model was established, along with macrophage depletion, polarized macrophage reinfusion, and Transwell coculture systems. The typical colitis characteristics, including weight change, disease activity index, inflammation, and tissue damage, were systematically assessed. Key proteins in the mTORC1/HIF-1α pathway were analyzed. SPR-MS was employed to identify ARS targets in M1 macrophages.</p><p><strong>Results: </strong>This study indicated that ARS markedly suppressed DSS-enhanced M1 polarization and macrophage infiltration. In a Caco2-BMDM coculture system, ARS reduced macrophage migration and inflammation. Macrophage depletion significantly attenuated the anti-colitis effect of ARS. Compared with M1 reinfusion, ARS-pretreated M1 cells alleviated UC symptoms. ARS also inhibited LPS- or DSS-induced M1 polarization and proinflammatory cytokine upregulation in vivo and in vitro, linked to mTORC1/HIF-1α signaling, as confirmed by the agonist Leucine (LEU). Moreover, ARS protected intestinal barrier function by preventing tight junction loss and permeability increases via suppression of M1 polarization. SPR-MS and molecular docking revealed that ARS directly activated INSR, inhibiting mTORC1/HIF-1α-driven glycolytic M1 polarization.</p><p><strong>Conclusions: </strong>Overall, macrophages are essential for ARS-mediated protection in UC. ARS alleviates UC by reprogramming macrophage polarization via the INSR/mTORC1/HIF-1α axis, providing new mechanistic insights and potential clinical applications.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"157752"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900972","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}
Pub Date : 2026-01-01Epub Date: 2026-01-03DOI: 10.1016/j.phymed.2026.157769
Shan Gao, Zhennan Xiao, Hongtao Liu
Background: Cognitive impairment is a major complication of traumatic brain injury (TBI), yet effective therapies remain lacking. As a natural compound extracted from Cannabis sativa, cannabidiol (CBD) possesses antioxidant properties and has shown neuroprotective potential in several neurological disorders. However, its effects in cognitive impairment after TBI remain unclear.
Purpose: This study aimed to investigate the therapeutic effects of CBD on cognitive impairment after TBI and elucidate its underlying molecular mechanisms.
Study design: In vitro H2O2 model and in vivo TBI model were used to evaluate the neuroprotective effects of CBD.
Methods: Neuronal oxidative stress models induced by H2O2 and controlled cortical impact model were used to detect the neuroprotective effects of CBD. Western blotting, histological staining, and biochemical assays were employed to investigate the effects of CBD on oxidative stress and apoptosis in neurons. RNA-Seq analysis, co-immunoprecipitation, molecular dynamics simulations, CETSA, SPR and immunofluorescence were performed to elucidate the molecular mechanisms.
Results: CBD can inhibit neuronal oxidative stress and apoptosis both in vivo and in vitro. Mechanistically, we identify a novel SET/PP2A/Akt signaling axis, in which CBD directly bound to SET, induced conformational changes in its nuclear localization signal and promoted its retention in the cytoplasm. Elevated cytoplasmic SET suppresses PP2A activity, activates Akt signaling pathway, and inhibits oxidative stress and pro-apoptotic cascades, promoting neuronal survival.
Conclusion: CBD exerts its neuroprotective effects by inhibiting neuronal oxidative stress and apoptosis through SET/PP2A/Akt signaling axis. These findings provide a novel potential drug target for the treatment of cognitive impairment after TBI.
{"title":"Cannabidiol improves cognitive impairment after traumatic brain injury by attenuating neuronal oxidative stress and apoptosis via the SET/PP2A/Akt signaling axis.","authors":"Shan Gao, Zhennan Xiao, Hongtao Liu","doi":"10.1016/j.phymed.2026.157769","DOIUrl":"10.1016/j.phymed.2026.157769","url":null,"abstract":"<p><strong>Background: </strong>Cognitive impairment is a major complication of traumatic brain injury (TBI), yet effective therapies remain lacking. As a natural compound extracted from Cannabis sativa, cannabidiol (CBD) possesses antioxidant properties and has shown neuroprotective potential in several neurological disorders. However, its effects in cognitive impairment after TBI remain unclear.</p><p><strong>Purpose: </strong>This study aimed to investigate the therapeutic effects of CBD on cognitive impairment after TBI and elucidate its underlying molecular mechanisms.</p><p><strong>Study design: </strong>In vitro H<sub>2</sub>O<sub>2</sub> model and in vivo TBI model were used to evaluate the neuroprotective effects of CBD.</p><p><strong>Methods: </strong>Neuronal oxidative stress models induced by H<sub>2</sub>O<sub>2</sub> and controlled cortical impact model were used to detect the neuroprotective effects of CBD. Western blotting, histological staining, and biochemical assays were employed to investigate the effects of CBD on oxidative stress and apoptosis in neurons. RNA-Seq analysis, co-immunoprecipitation, molecular dynamics simulations, CETSA, SPR and immunofluorescence were performed to elucidate the molecular mechanisms.</p><p><strong>Results: </strong>CBD can inhibit neuronal oxidative stress and apoptosis both in vivo and in vitro. Mechanistically, we identify a novel SET/PP2A/Akt signaling axis, in which CBD directly bound to SET, induced conformational changes in its nuclear localization signal and promoted its retention in the cytoplasm. Elevated cytoplasmic SET suppresses PP2A activity, activates Akt signaling pathway, and inhibits oxidative stress and pro-apoptotic cascades, promoting neuronal survival.</p><p><strong>Conclusion: </strong>CBD exerts its neuroprotective effects by inhibiting neuronal oxidative stress and apoptosis through SET/PP2A/Akt signaling axis. These findings provide a novel potential drug target for the treatment of cognitive impairment after TBI.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"150 ","pages":"157769"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145945544","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号