Pub Date : 2026-01-06DOI: 10.1016/j.phymed.2026.157776
Liang Cao , Zi-yin Wu , Yan Gao , Xin-yi Geng , Wan-ting Yang , Qian-ru Yin , Qiu Liu , Chao Wang , Chun-yan Ji , Ying Chen , Xin Liu , Lei Wang , Jun Shao , Jia-yu Dong , Chen-xu Zhang , Zhi-hong Guo , Tuan-jie Wang , Zhen-zhong Wang , Xin-zhuang Zhang , Jing-hui Wang , Wei Xiao
<div><h3>Background</h3><div>Sepsis-induced systemic inflammation, characterized by immune dysregulation and cytokine storms, presents significant therapeutic challenges. Reduning injection (RDN), a Traditional Chinese Medicine formulation, demonstrates clinical efficacy in sepsis management, yet its molecular mechanisms remain elusive.</div></div><div><h3>Purpose</h3><div>This study aimed to unravel RDN’s immunomodulatory mechanisms and identify its core effective components targeting key inflammatory signaling networks in sepsis.</div></div><div><h3>Methods</h3><div>Initially, six complementary <em>in vitro</em> hyperinflammation models (macrophages, endothelial, epithelial, and intestinal barrier cells) were established, with their transcriptomes integrated with patient-derived septic data to prioritize canonical pathways. Transcriptome profiling of RDN, its 14 phytochemicals, and dexamethasone (DEX) was then performed to analyze pathway enrichment and identify key components. In vitro mechanistic validation included enzyme-linked immunosorbent assay (ELISA) for IL-6 inhibition screening; ADP-Glo™ Kinase Assay for IKKβ/TBK1 inhibition; Western blot to assess phosphorylation dynamics of tank-binding kinase 1 (TBK1), inhibitor of nuclear factor-kappa B kinase subunit beta (IKKβ), and nuclear factor-kappa B (NF-κB); quantitative real-time polymerase chain reaction (qRT-PCR) to confirm downregulation of canonical NF-κB targets; and molecular dynamics (MD) simulations to explore binding mechanisms. For <em>in vivo</em> studies, an LPS-rat sepsis model was used, with preliminary studies defining optimal LPS dose, induction timepoint, and RDN dose. Assessments on septic rats included histopathology (hematoxylin-eosin staining), cytokine profiling (ELISA), complete blood counts, transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) to uncover NF-κB pathway modulation, and qRT-PCR validation of transcriptomic changes.</div></div><div><h3>Results</h3><div>The clinically anchored approach effectively prioritized canonical pathways (NF-κB, TNF, and cytokine-cytokine receptor interactions) with strong translational relevance. Transcriptome profiling revealed RDN’s broad pathway enrichment and identified cynaroside (CYN) as the principal effective component exerting multi-pathway anti-inflammatory effects. Mechanistically, CYN dual-inhibited TBK1 (IC₅₀: 8.9 μM) and IKKβ (IC₅₀: 23.3 μM), suppressing NF-κB signaling and cytokine production in macrophages. MD simulations showed stable IKKβ-CYN and TBK1-CYN complexes, with CYN occupying catalytic pockets via hydrogen bonds with key residues and minimal binding site fluctuations. In LPS-induced septic rats, RDN and CYN mitigated multi-organ injury, reduced systemic inflammation (decreased IL-6 and TNF-α), restored complete blood counts, and inhibited NF-κB activation.</div></div><div><h3>Conclusion</h3><div>This study advances understanding of TCM’s multi-target immunomodulation in sepsis via a f
{"title":"A novel mechanism of Reduning injection in sepsis treatment: Targeting inflammatory kinases TBK1 and IKKβ","authors":"Liang Cao , Zi-yin Wu , Yan Gao , Xin-yi Geng , Wan-ting Yang , Qian-ru Yin , Qiu Liu , Chao Wang , Chun-yan Ji , Ying Chen , Xin Liu , Lei Wang , Jun Shao , Jia-yu Dong , Chen-xu Zhang , Zhi-hong Guo , Tuan-jie Wang , Zhen-zhong Wang , Xin-zhuang Zhang , Jing-hui Wang , Wei Xiao","doi":"10.1016/j.phymed.2026.157776","DOIUrl":"10.1016/j.phymed.2026.157776","url":null,"abstract":"<div><h3>Background</h3><div>Sepsis-induced systemic inflammation, characterized by immune dysregulation and cytokine storms, presents significant therapeutic challenges. Reduning injection (RDN), a Traditional Chinese Medicine formulation, demonstrates clinical efficacy in sepsis management, yet its molecular mechanisms remain elusive.</div></div><div><h3>Purpose</h3><div>This study aimed to unravel RDN’s immunomodulatory mechanisms and identify its core effective components targeting key inflammatory signaling networks in sepsis.</div></div><div><h3>Methods</h3><div>Initially, six complementary <em>in vitro</em> hyperinflammation models (macrophages, endothelial, epithelial, and intestinal barrier cells) were established, with their transcriptomes integrated with patient-derived septic data to prioritize canonical pathways. Transcriptome profiling of RDN, its 14 phytochemicals, and dexamethasone (DEX) was then performed to analyze pathway enrichment and identify key components. In vitro mechanistic validation included enzyme-linked immunosorbent assay (ELISA) for IL-6 inhibition screening; ADP-Glo™ Kinase Assay for IKKβ/TBK1 inhibition; Western blot to assess phosphorylation dynamics of tank-binding kinase 1 (TBK1), inhibitor of nuclear factor-kappa B kinase subunit beta (IKKβ), and nuclear factor-kappa B (NF-κB); quantitative real-time polymerase chain reaction (qRT-PCR) to confirm downregulation of canonical NF-κB targets; and molecular dynamics (MD) simulations to explore binding mechanisms. For <em>in vivo</em> studies, an LPS-rat sepsis model was used, with preliminary studies defining optimal LPS dose, induction timepoint, and RDN dose. Assessments on septic rats included histopathology (hematoxylin-eosin staining), cytokine profiling (ELISA), complete blood counts, transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) to uncover NF-κB pathway modulation, and qRT-PCR validation of transcriptomic changes.</div></div><div><h3>Results</h3><div>The clinically anchored approach effectively prioritized canonical pathways (NF-κB, TNF, and cytokine-cytokine receptor interactions) with strong translational relevance. Transcriptome profiling revealed RDN’s broad pathway enrichment and identified cynaroside (CYN) as the principal effective component exerting multi-pathway anti-inflammatory effects. Mechanistically, CYN dual-inhibited TBK1 (IC₅₀: 8.9 μM) and IKKβ (IC₅₀: 23.3 μM), suppressing NF-κB signaling and cytokine production in macrophages. MD simulations showed stable IKKβ-CYN and TBK1-CYN complexes, with CYN occupying catalytic pockets via hydrogen bonds with key residues and minimal binding site fluctuations. In LPS-induced septic rats, RDN and CYN mitigated multi-organ injury, reduced systemic inflammation (decreased IL-6 and TNF-α), restored complete blood counts, and inhibited NF-κB activation.</div></div><div><h3>Conclusion</h3><div>This study advances understanding of TCM’s multi-target immunomodulation in sepsis via a f","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157776"},"PeriodicalIF":8.3,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941423","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 : 2026-01-06DOI: 10.1016/j.phymed.2026.157783
Wenjing Huang , Xuemei Wang , Xin Yan , Si Wang , Lan Lin , Lingyu Li , Linling Liu , Yingling Wang , Xinyue Li , Yan Mao , Xiao Liu , YiXin Chen , Jiayi Kong , Lin Shen , Qiying Jiang , Ruli Li , He Li , Junyan Zhang , Ran Zhang , Fan Wang , Wei Jiang
Background
Myocardial fibrosis (MF), a hallmark of cardiovascular diseases (CVDs) such as myocardial infarction (MI), drives progressive cardiac dysfunction and adverse remodeling. Histone acetylation is a critical epigenetic regulator in cardiovascular pathology. Anacardic acid (AA), a histone acetyltransferase inhibitor (HATi) with pleiotropic bioactivities, has been studied in various disease contexts; however, its antifibrotic efficacy and mechanisms in MF remain unclear.
Methods
In vivo, a mouse model of post-infarction MF was established by permanent left anterior descending (LAD) ligation. Using pirfenidone (PFD, an antifibrotic by inhibiting TGF-β) as a positive control, AA’s effects were assessed by cardiac function, histopathology, and quantification of fibrotic burden. In vitro, primary cardiac fibroblasts (CFs) stimulated with TGF-β1 were used to delineate mechanisms, focusing on proliferation, migration, myofibroblast differentiation, and transcription of fibrosis-related genes.
Results
In vivo, AA and PFD comparably attenuated cardiac fibrosis and collagen deposition, downregulated fibrosis-related gene expression, and improved heart failure biomarkers in MI mice. Transcriptomic profiling indicated that MAPK pathway and GATA3 expression were reduced in AA-treated MI mouse hearts but increased in CFs in human MI single-cell RNA-sequencing datasets. In vitro, AA inhibited TGF-β1-induced CF proliferation, migration, and myofibroblast differentiation by suppressing p38/JNK phosphorylation, limiting GATA3 nuclear translocation, and reducing H3K9ac levels, thereby decreasing transcription of α-SMA, Col1a1, and Col3a1.
Conclusions
AA protects against post-infarction MF by suppressing the p38/JNK–GATA3 pathway and downregulating H3K9ac-dependent epigenetic activation, supporting AA as a potential antifibrotic strategy and therapeutic candidate for cardiac fibrosis.
{"title":"Anacardic acid mitigates post‑MI cardiac fibrosis via suppressing p38/JNK–GATA3 pathway and H3K9ac‑dependent epigenetic regulation","authors":"Wenjing Huang , Xuemei Wang , Xin Yan , Si Wang , Lan Lin , Lingyu Li , Linling Liu , Yingling Wang , Xinyue Li , Yan Mao , Xiao Liu , YiXin Chen , Jiayi Kong , Lin Shen , Qiying Jiang , Ruli Li , He Li , Junyan Zhang , Ran Zhang , Fan Wang , Wei Jiang","doi":"10.1016/j.phymed.2026.157783","DOIUrl":"10.1016/j.phymed.2026.157783","url":null,"abstract":"<div><h3>Background</h3><div>Myocardial fibrosis (MF), a hallmark of cardiovascular diseases (CVDs) such as myocardial infarction (MI), drives progressive cardiac dysfunction and adverse remodeling. Histone acetylation is a critical epigenetic regulator in cardiovascular pathology. Anacardic acid (AA), a histone acetyltransferase inhibitor (HATi) with pleiotropic bioactivities, has been studied in various disease contexts; however, its antifibrotic efficacy and mechanisms in MF remain unclear.</div></div><div><h3>Methods</h3><div>In vivo, a mouse model of post-infarction MF was established by permanent left anterior descending (LAD) ligation. Using pirfenidone (PFD, an antifibrotic by inhibiting TGF-β) as a positive control, AA’s effects were assessed by cardiac function, histopathology, and quantification of fibrotic burden. In vitro, primary cardiac fibroblasts (CFs) stimulated with TGF-β1 were used to delineate mechanisms, focusing on proliferation, migration, myofibroblast differentiation, and transcription of fibrosis-related genes.</div></div><div><h3>Results</h3><div>In vivo, AA and PFD comparably attenuated cardiac fibrosis and collagen deposition, downregulated fibrosis-related gene expression, and improved heart failure biomarkers in MI mice. Transcriptomic profiling indicated that MAPK pathway and GATA3 expression were reduced in AA-treated MI mouse hearts but increased in CFs in human MI single-cell RNA-sequencing datasets. In vitro, AA inhibited TGF-β1-induced CF proliferation, migration, and myofibroblast differentiation by suppressing p38/JNK phosphorylation, limiting GATA3 nuclear translocation, and reducing H3K9ac levels, thereby decreasing transcription of α-SMA, Col1a1, and Col3a1.</div></div><div><h3>Conclusions</h3><div>AA protects against post-infarction MF by suppressing the p38/JNK–GATA3 pathway and downregulating H3K9ac-dependent epigenetic activation, supporting AA as a potential antifibrotic strategy and therapeutic candidate for cardiac fibrosis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157783"},"PeriodicalIF":8.3,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941424","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 : 2026-01-06DOI: 10.1016/j.phymed.2026.157803
Zhu Li , Guanghui Jin , Xuanxuan Li , Zhanyu Cui , Yongjie Su , Sulan Ye , Kexin Wang , Qinhai Ma , Zifeng Yang
Background
Phillyrin (KD-1), the principal bioactive component of Forsythia suspensa (Thunb.) Vahl, exhibits well-documented multifaceted anti-inflammatory and broad-spectrum antiviral activities. Notably, its specific antiviral efficacy against respiratory syncytial virus (RSV) and the underlying epigenetic regulatory mechanisms remain unexplored.
Purpose
To delineate phillyrin’s dual-targeting mechanism against RSV pathogenesis, focusing on m6A methylome reprogramming and host-virus interactome modulation.Methods: Employing comprehensive models spanning cellular systems, multi-age respiratory organoids, and animal models, this study evaluated the anti-RSV activity of phillyrin.
Results
Integrated multi-model analyses demonstrate that phillyrin exhibits potent anti-RSV activity and dose-dependently suppresses virus-induced inflammation. Crucially, phillyrin significantly restored RSV-mediated global N6-methyladenosine (m6A) hypomethylation and downregulated the demethylase fat mass and obesity-associated protein (FTO). Mechanistically, FTO knockdown suppressed NF-κB/STAT3 pathway activation, with phillyrin synergistically enhancing this suppression. Conversely, FTO overexpression abolished phillyrin's inhibitory effects on these pathways. Molecular studies revealed dual targeting: phillyrin formed stable complexes with RSV-N protein, while FTO directly bound RSV-N, evidenced by co-localization in cytoplasmic compartments via laser scanning confocal microscopy.
Conclusion
These results revealed that phillyrin combats RSV infection through a dual mechanism: Direct engagement with the viral N protein to disrupt viral function, and resolution of inflammation via FTO/m6A-mediated silencing of the NF-κB/STAT3 signaling axis.
{"title":"Targeting FTO/m6A epigenetics: Phillyrin dual-blocks respiratory syncytial virus replication and inflammation via NF-κB/STAT3 silencing","authors":"Zhu Li , Guanghui Jin , Xuanxuan Li , Zhanyu Cui , Yongjie Su , Sulan Ye , Kexin Wang , Qinhai Ma , Zifeng Yang","doi":"10.1016/j.phymed.2026.157803","DOIUrl":"10.1016/j.phymed.2026.157803","url":null,"abstract":"<div><h3>Background</h3><div>Phillyrin (KD-1), the principal bioactive component of <em>Forsythia suspensa</em> (Thunb.) Vahl, exhibits well-documented multifaceted anti-inflammatory and broad-spectrum antiviral activities. Notably, its specific antiviral efficacy against respiratory syncytial virus (RSV) and the underlying epigenetic regulatory mechanisms remain unexplored.</div></div><div><h3>Purpose</h3><div>To delineate phillyrin’s dual-targeting mechanism against RSV pathogenesis, focusing on m<sup>6</sup>A methylome reprogramming and host-virus interactome modulation.<em><strong>Methods:</strong></em> Employing comprehensive models spanning cellular systems, multi-age respiratory organoids, and animal models, this study evaluated the anti-RSV activity of phillyrin.</div></div><div><h3>Results</h3><div>Integrated multi-model analyses demonstrate that phillyrin exhibits potent anti-RSV activity and dose-dependently suppresses virus-induced inflammation. Crucially, phillyrin significantly restored RSV-mediated global N6-methyladenosine (m<sup>6</sup>A) hypomethylation and downregulated the demethylase fat mass and obesity-associated protein (FTO). Mechanistically, FTO knockdown suppressed NF-κB/STAT3 pathway activation, with phillyrin synergistically enhancing this suppression. Conversely, FTO overexpression abolished phillyrin's inhibitory effects on these pathways. Molecular studies revealed dual targeting: phillyrin formed stable complexes with RSV-N protein, while FTO directly bound RSV-N, evidenced by co-localization in cytoplasmic compartments via laser scanning confocal microscopy.</div></div><div><h3>Conclusion</h3><div>These results revealed that phillyrin combats RSV infection through a dual mechanism: Direct engagement with the viral N protein to disrupt viral function, and resolution of inflammation via FTO/m<sup>6</sup>A-mediated silencing of the NF-κB/STAT3 signaling axis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157803"},"PeriodicalIF":8.3,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980976","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 : 2026-01-06DOI: 10.1016/j.phymed.2026.157787
Mengmeng Chen , Huijie Zhang , Congcong Li , Jiaqi Liu , Huahe Zhu , Weifeng Tang , Xueyi Zhu , Jiemin He , Yuting Shi , Yalikun Maimaititusun , Na Wang , Jingcheng Dong
<div><h3>Background</h3><div>Chronic asthma features persistent airway inflammation, airway hyper-responsiveness, and structural remodeling. Macrophages, especially alternatively activated M2 cells, are key drivers of type-2 immunity and fibrosis. Icariside II (ICAII), a flavonoid from <em>Epimedium</em>, exhibits known anti-inflammatory properties, but its precise immunomodulatory effects on M2 macrophages in asthma remain elusive.</div></div><div><h3>Objective</h3><div>This work sought to evaluate the potential therapeutic role of ICAII using a mouse model that mimics chronic asthma and define the underlying mechanisms, with emphasis on macrophage polarization and immune-mediated tissue remodeling.</div></div><div><h3>Methods</h3><div>Chronic asthma was established in BALB/c mice through ovalbumin (OVA) sensitization and repeated exposure, followed by ICAII administration at various doses. Pulmonary function tests, histological analyses, ELISA, flow cytometry, and immunohistochemistry were employed to assess inflammation, airway remodeling, and macrophage polarization. In vitro experiments using RAW264.7 and MHS macrophage lines further investigated ICAII’s impact on M2 differentiation. Transcriptome sequencing, network pharmacology, molecular docking analyses, and validation were integrated to identify key regulatory pathways.</div></div><div><h3>Results</h3><div>ICAII improved airway resistance and compliance, alleviated inflammatory infiltration and collagen deposition, and lowered Th2 cytokines, serum IgE, and pro-fibrotic markers, with the most pronounced effects observed at 40 mg/kg. In vivo, ICAII suppressed M2 macrophage accumulation, and in vitro, it inhibited M2 differentiation, while with a divergent impact on M1 marker expression. Network pharmacology and molecular docking predicted a moderate affinity interaction between ICAII and SIRT1, which was experimentally confirmed by SPR and enzymatic activity assays. Combined with transcriptomic and pharmacological analyses, these results identified the SIRT1/NLRP3 and TGF-β/Smad3/VEGF axes as principal pathways mediating the protective effects of ICAII against chronic asthma. Specifically, the SIRT1/NLRP3 axis refers to Sirtuin1 (SIRT1)-mediated suppression of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, whereas the TGF-β/Smad3/VEGF axis represents a transforming growth factor beta-driven profibrotic signaling cascade associated with vascular endothelial growth factor. Mechanistically, ICAII enhanced SIRT1 activity, suppressed NLRP3 inflammasome-associated inflammation, and inhibited the profibrotic TGF-β/Smad3 signaling cascade and its remodeling-associated downstream effector VEGF, thereby restraining M2 macrophage polarization and tissue remodeling.</div></div><div><h3>Conclusion</h3><div>We provide the first integrated mechanistic evidence in chronic asthma that ICAII reprograms M2 macrophages via a dual-axis strategy, simultaneously activating SIRT1 to suppre
慢性哮喘以持续气道炎症、气道高反应性和气道结构重塑为特征。巨噬细胞，尤其是M2细胞，是2型免疫和纤维化的关键驱动因素。Icariside II （ICAII）是一种来自淫羊藿的类黄酮，具有已知的抗炎特性，但其对哮喘中M2巨噬细胞的精确免疫调节作用尚不清楚。目的通过模拟慢性哮喘的小鼠模型来评估ICAII的潜在治疗作用，并确定其潜在机制，重点是巨噬细胞极化和免疫介导的组织重塑。方法对BALB/c小鼠进行卵清蛋白致敏和重复暴露，然后给药不同剂量的ICAII，建立慢性哮喘模型。采用肺功能测试、组织学分析、ELISA、流式细胞术和免疫组织化学来评估炎症、气道重塑和巨噬细胞极化。RAW264.7和MHS巨噬细胞体外实验进一步研究了ICAII对M2分化的影响。转录组测序、网络药理学、分子对接分析和验证相结合，以确定关键的调控途径。结果icaii改善气道阻力和顺应性，减轻炎症浸润和胶原沉积，降低Th2细胞因子、血清IgE和促纤维化标志物，以40mg /kg剂量效果最显著。在体内，ICAII抑制M2巨噬细胞的聚集，在体外，ICAII抑制M2的分化，但对M1标记物的表达有不同的影响。网络药理学和分子对接预测了ICAII和SIRT1之间的中等亲和力相互作用，并通过SPR和酶活性实验证实了这一点。结合转录组学和药理学分析，这些结果确定SIRT1/NLRP3和TGF-β/Smad3/VEGF轴是介导ICAII对慢性哮喘保护作用的主要途径。具体来说，SIRT1/NLRP3轴是指Sirtuin1 （SIRT1）介导的NLR家族pyrin domain containing 3 （NLRP3）炎性体激活的抑制，而TGF-β/Smad3/VEGF轴则代表了与血管内皮生长因子相关的转化生长因子β驱动的促纤维化信号级联。机制上，ICAII增强SIRT1活性，抑制NLRP3炎性小体相关炎症，抑制促纤维化TGF-β/Smad3信号级联及其重塑相关下游效应因子VEGF，从而抑制M2巨噬细胞极化和组织重塑。我们提供了慢性哮喘中ICAII通过双轴策略重编程M2巨噬细胞的第一个综合机制证据，同时激活SIRT1以抑制NLRP3炎性体并减弱TGF-β/Smad3/ vegf驱动的重构。不同于以往的报道只描述了ICAII广泛的抗炎作用，我们的研究独特地将免疫调节与结构保护联系起来，并进一步提供了直接的靶点接合验证。这种药物-靶标-功能连续体不仅描绘了以巨噬细胞为中心的慢性哮喘病理生物学范式，而且还引入了一种可翻译的可操作机制，以解决持续气道重塑和t2高炎症的长期挑战。
{"title":"Icariside II targets M2 macrophages by regulating the inflammasome and profibrotic signaling in chronic asthma","authors":"Mengmeng Chen , Huijie Zhang , Congcong Li , Jiaqi Liu , Huahe Zhu , Weifeng Tang , Xueyi Zhu , Jiemin He , Yuting Shi , Yalikun Maimaititusun , Na Wang , Jingcheng Dong","doi":"10.1016/j.phymed.2026.157787","DOIUrl":"10.1016/j.phymed.2026.157787","url":null,"abstract":"<div><h3>Background</h3><div>Chronic asthma features persistent airway inflammation, airway hyper-responsiveness, and structural remodeling. Macrophages, especially alternatively activated M2 cells, are key drivers of type-2 immunity and fibrosis. Icariside II (ICAII), a flavonoid from <em>Epimedium</em>, exhibits known anti-inflammatory properties, but its precise immunomodulatory effects on M2 macrophages in asthma remain elusive.</div></div><div><h3>Objective</h3><div>This work sought to evaluate the potential therapeutic role of ICAII using a mouse model that mimics chronic asthma and define the underlying mechanisms, with emphasis on macrophage polarization and immune-mediated tissue remodeling.</div></div><div><h3>Methods</h3><div>Chronic asthma was established in BALB/c mice through ovalbumin (OVA) sensitization and repeated exposure, followed by ICAII administration at various doses. Pulmonary function tests, histological analyses, ELISA, flow cytometry, and immunohistochemistry were employed to assess inflammation, airway remodeling, and macrophage polarization. In vitro experiments using RAW264.7 and MHS macrophage lines further investigated ICAII’s impact on M2 differentiation. Transcriptome sequencing, network pharmacology, molecular docking analyses, and validation were integrated to identify key regulatory pathways.</div></div><div><h3>Results</h3><div>ICAII improved airway resistance and compliance, alleviated inflammatory infiltration and collagen deposition, and lowered Th2 cytokines, serum IgE, and pro-fibrotic markers, with the most pronounced effects observed at 40 mg/kg. In vivo, ICAII suppressed M2 macrophage accumulation, and in vitro, it inhibited M2 differentiation, while with a divergent impact on M1 marker expression. Network pharmacology and molecular docking predicted a moderate affinity interaction between ICAII and SIRT1, which was experimentally confirmed by SPR and enzymatic activity assays. Combined with transcriptomic and pharmacological analyses, these results identified the SIRT1/NLRP3 and TGF-β/Smad3/VEGF axes as principal pathways mediating the protective effects of ICAII against chronic asthma. Specifically, the SIRT1/NLRP3 axis refers to Sirtuin1 (SIRT1)-mediated suppression of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, whereas the TGF-β/Smad3/VEGF axis represents a transforming growth factor beta-driven profibrotic signaling cascade associated with vascular endothelial growth factor. Mechanistically, ICAII enhanced SIRT1 activity, suppressed NLRP3 inflammasome-associated inflammation, and inhibited the profibrotic TGF-β/Smad3 signaling cascade and its remodeling-associated downstream effector VEGF, thereby restraining M2 macrophage polarization and tissue remodeling.</div></div><div><h3>Conclusion</h3><div>We provide the first integrated mechanistic evidence in chronic asthma that ICAII reprograms M2 macrophages via a dual-axis strategy, simultaneously activating SIRT1 to suppre","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157787"},"PeriodicalIF":8.3,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980914","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 : 2026-01-06DOI: 10.1016/j.phymed.2026.157785
Chao Wang , Weihang Zhu , Ziran Wei , Zihan Cui , Yunqing Chen , Ronghan Liu , Tianrui Wang , Lu Zhang
Background
Autophagy plays a crucial role in the recovery of neural function after spinal cord injury (SCI) by modulating the inflammatory microenvironment. Naringenin (NGN) is a flavanone with anti-inflammatory activity; however, the effects and specific mechanisms of NGN on autophagy in SCI remain unclear.
Purpose
To elucidate the therapeutic effect of NGN on SCI and its role in modulating macrophage/microglia autophagy by stabilising progranulin (PGRN).
Methods
A traumatic SCI mouse model was established via spinal cord clamping. Motor function was assessed by the Basso Mouse Scale, inclined grid test, and footprint analysis. Tissue inflammation, apoptosis, and autophagy were evaluated via enzyme linked immunosorbent assay, western blotting, and immunofluorescence analysis. The LC3-GFP-mCherry system and transmission electron microscopy were used to assess autophagic flux in vitro, and the neuroprotective effects of NGN were evaluated using a cell co-culture system. Interactions between NGN and PGRN were analysed by molecular docking, thermal shift, and protein degradation assays. The PGRN-dependent therapeutic potential of NGN was validated using Grn-/- mice.
Results
Administration of NGN orally ameliorated the recovery of locomotor function in SCI mice; attenuated the inflammatory response and improved autophagic flux in injured spinal cord tissue. In vitro, NGN enhanced cell proliferation, improved autophagic flux, and suppressed the inflammatory response in BV2 cells. Chloroquine pretreatment abolished NGN’s anti-inflammation and neuroprotective effects, highlighting the involvement of autophagy. Mechanistically, we identified PGRN as a novel binding protein with NGN. NGN upregulated PGRN at the post-translational level in BV2. Furthermore, PGRN deficiency blocked the therapeutic effects of NGN in SCI mice.
Conclusion
These findings highlight a novel mechanism by which NGN critically regulates autophagy-related inflammation in macrophage/microglia through interaction with PGRN. Overall, NGN shows promising potential as a therapeutic SCI drug.
{"title":"Naringenin alleviates spinal cord injury by ameliorating macrophage/microglia autophagy via progranulin stabilisation","authors":"Chao Wang , Weihang Zhu , Ziran Wei , Zihan Cui , Yunqing Chen , Ronghan Liu , Tianrui Wang , Lu Zhang","doi":"10.1016/j.phymed.2026.157785","DOIUrl":"10.1016/j.phymed.2026.157785","url":null,"abstract":"<div><h3>Background</h3><div>Autophagy plays a crucial role in the recovery of neural function after spinal cord injury (SCI) by modulating the inflammatory microenvironment. Naringenin (NGN) is a flavanone with anti-inflammatory activity; however, the effects and specific mechanisms of NGN on autophagy in SCI remain unclear.</div></div><div><h3>Purpose</h3><div>To elucidate the therapeutic effect of NGN on SCI and its role in modulating macrophage/microglia autophagy by stabilising progranulin (PGRN).</div></div><div><h3>Methods</h3><div>A traumatic SCI mouse model was established via spinal cord clamping. Motor function was assessed by the Basso Mouse Scale, inclined grid test, and footprint analysis. Tissue inflammation, apoptosis, and autophagy were evaluated via enzyme linked immunosorbent assay, western blotting, and immunofluorescence analysis. The LC3-GFP-mCherry system and transmission electron microscopy were used to assess autophagic flux <em>in vitro</em>, and the neuroprotective effects of NGN were evaluated using a cell co-culture system. Interactions between NGN and PGRN were analysed by molecular docking, thermal shift, and protein degradation assays. The PGRN-dependent therapeutic potential of NGN was validated using <em>Grn<sup>-/-</sup></em> mice.</div></div><div><h3>Results</h3><div>Administration of NGN orally ameliorated the recovery of locomotor function in SCI mice; attenuated the inflammatory response and improved autophagic flux in injured spinal cord tissue. <em>In vitro</em>, NGN enhanced cell proliferation, improved autophagic flux, and suppressed the inflammatory response in BV2 cells. Chloroquine pretreatment abolished NGN’s anti-inflammation and neuroprotective effects, highlighting the involvement of autophagy. Mechanistically, we identified PGRN as a novel binding protein with NGN. NGN upregulated PGRN at the post-translational level in BV2. Furthermore, PGRN deficiency blocked the therapeutic effects of NGN in SCI mice.</div></div><div><h3>Conclusion</h3><div>These findings highlight a novel mechanism by which NGN critically regulates autophagy-related inflammation in macrophage/microglia through interaction with PGRN. Overall, NGN shows promising potential as a therapeutic SCI drug.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157785"},"PeriodicalIF":8.3,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952957","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 : 2026-01-06DOI: 10.1016/j.phymed.2026.157791
Xingyong Zhang , Xuan Jiang , Lejing Jiang , Haotian Zhang , Yuanyuan Xu , Fangfang Cheng , Yudan Cao , Kaifeng Wei , Hui Yan , Weifeng Yao , Mingliang Gao , Li Zhang , Peidong Chen
Background
Carbonized Typhae Pollen (CTP) is a class of herbs that resolves blood stasis and stops bleeding. Blood stasis syndrome (BSS) is a pathological state associated with blood circulation disorders and vascular injury, which contributes to the development of cardiovascular diseases. The metabolic microenvironment of endothelial cells (ECs) plays a pivotal role in maintaining vascular homeostasis and is highly sensitive to pathological disturbances. CTP positively enhances the hemostatic phase via the vascular endothelial growth factor (VEGF)/phospholipase C gamma 1 (PLCγ1)/Ca2⁺/cyclooxygenase 2 (COX-2) pathway. Excessive hemostasis may increase the risk of vascular disease. Therefore, the dual pharmacological effect of CTP in achieving “stop bleeding without leaving stasis” implies the involvement of additional regulatory pathways that contribute to vascular protection.
Purpose
This study aims to elucidate the protective mechanisms of CTP against BSS-induced circulatory disorders and vascular injury.
Methods
Models of BSS rats, zebrafish thrombosis model, and hypoxia-induced ECs model were used to evaluate vascular protection. Bioinformatics, metabolomic analyses, and molecular biology studies were integrated to investigate underlying mechanisms.
Results
Treatment with CTP promoted blood circulation, and ameliorated thrombosis in zebrafish. Furthermore, CTP markedly attenuated hypoxia and inflammation caused by blood stasis and facilitated vascular remodeling. Bioinformatics and metabolomic analyses suggested that VEGF and downstream arginine metabolism were key pathways. CTP enhanced vascular protection and promoted remodeling through the VEGF/PI3K/AKT signalling pathway, thereby facilitating vascular repair following injury.
Conclusions
CTP mediated haemostasis through the VEGF/PLCγ1/Ca²⁺/COX-2 pathway while improving vascular function following haemostasis via the VEGF/PI3K/AKT pathway. These pathways function independently yet remain interconnected, jointly contributing to the vascular homeostasis.
{"title":"Carbonized Typhae Pollen coordinates VEGF-dependent hemostatic and vascular protective pathways in blood stasis syndrome","authors":"Xingyong Zhang , Xuan Jiang , Lejing Jiang , Haotian Zhang , Yuanyuan Xu , Fangfang Cheng , Yudan Cao , Kaifeng Wei , Hui Yan , Weifeng Yao , Mingliang Gao , Li Zhang , Peidong Chen","doi":"10.1016/j.phymed.2026.157791","DOIUrl":"10.1016/j.phymed.2026.157791","url":null,"abstract":"<div><h3>Background</h3><div>Carbonized Typhae Pollen (CTP) is a class of herbs that resolves blood stasis and stops bleeding. Blood stasis syndrome (BSS) is a pathological state associated with blood circulation disorders and vascular injury, which contributes to the development of cardiovascular diseases. The metabolic microenvironment of endothelial cells (ECs) plays a pivotal role in maintaining vascular homeostasis and is highly sensitive to pathological disturbances. CTP positively enhances the hemostatic phase via the vascular endothelial growth factor (VEGF)/phospholipase C gamma 1 (PLCγ1)/Ca<sup>2</sup>⁺/cyclooxygenase 2 (COX-2) pathway. Excessive hemostasis may increase the risk of vascular disease. Therefore, the dual pharmacological effect of CTP in achieving “stop bleeding without leaving stasis” implies the involvement of additional regulatory pathways that contribute to vascular protection.</div></div><div><h3>Purpose</h3><div>This study aims to elucidate the protective mechanisms of CTP against BSS-induced circulatory disorders and vascular injury.</div></div><div><h3>Methods</h3><div>Models of BSS rats, zebrafish thrombosis model, and hypoxia-induced ECs model were used to evaluate vascular protection. Bioinformatics, metabolomic analyses, and molecular biology studies were integrated to investigate underlying mechanisms.</div></div><div><h3>Results</h3><div>Treatment with CTP promoted blood circulation, and ameliorated thrombosis in zebrafish. Furthermore, CTP markedly attenuated hypoxia and inflammation caused by blood stasis and facilitated vascular remodeling. Bioinformatics and metabolomic analyses suggested that VEGF and downstream arginine metabolism were key pathways. CTP enhanced vascular protection and promoted remodeling through the VEGF/PI3K/AKT signalling pathway, thereby facilitating vascular repair following injury.</div></div><div><h3>Conclusions</h3><div>CTP mediated haemostasis through the VEGF/PLCγ1/Ca²⁺/COX-2 pathway while improving vascular function following haemostasis via the VEGF/PI3K/AKT pathway. These pathways function independently yet remain interconnected, jointly contributing to the vascular homeostasis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157791"},"PeriodicalIF":8.3,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980747","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 : 2026-01-05DOI: 10.1016/j.phymed.2026.157778
Yun-Yuan Tian, Lin-Yu Chen, Fei-Yu Xie, Juan Wang, Jia-Hui Xu, Yao Li, Hai-Feng Tang, Si-Wang Wang
Background: Endometriosis (EMs) is a chronic inflammatory disease often treated with blood-activating and stasis-resolving therapies. Anxiety and depression are common mental comorbidities in patients with EMs. There are no medications available for treating EMs with anxiety/depression. Paeonia × suffruticosa Andrews leaves (PSL) has blood-activating and stasis-resolving effects, which are commonly used to treat inflammation and gynecological conditions.
Purpose: The purpose of this study was to explore the therapeutic effect of PSL on EMs with anxiety/depression and elucidate its mechanisms.
Methods: This study evaluated the inhibitory effect of PSL on EMs through pathological assessment of EMs tissue. Behavioral experiments and pathological characteristics of the brain demonstrated that PSL improved brain damage in EMs mice. Further molecular-level detection and analysis in the hippocampus and prefrontal cortex investigated the mechanism of PSL treatment for EMs with anxiety/depression.
Results: PSL inhibited the growth of EMs lesions and reduced Ki67 expression of EMs lesions. PSL improved anxiety/depression-like behavior in EMs mice. Furthermore, PSL treatment contributed to restore neuronal damage in the hippocampus and prefrontal cortex of EMs mice, consistent with behavioral changes. PSL reduced the mRNA and protein expression of IL-1β, IL-6, TNF-α and iNOS in the brain tissue of EMs mice, and promoted the expression of IL-4, CD163, and Arg-1. In addition, the inflammation-related JAK2/STAT3 signaling pathway was activated in the brain of EMs mice with anxiety/depression. PSL downregulated the expression of M1-type microglia and upregulated the expression of M2-type microglia by inhibiting the activation of the JAK2/STAT3 pathway in the hippocampus and prefrontal cortex.
Conclusions: PSL suppressed neuroinflammation through JAK2/STAT3 pathway to treat EMs with anxiety/depression.
{"title":"Paeonia × suffruticosa Andrews leaves improve endometriosis with anxiety/depression by regulating microglial polarization via JAK2/STAT3 pathway.","authors":"Yun-Yuan Tian, Lin-Yu Chen, Fei-Yu Xie, Juan Wang, Jia-Hui Xu, Yao Li, Hai-Feng Tang, Si-Wang Wang","doi":"10.1016/j.phymed.2026.157778","DOIUrl":"https://doi.org/10.1016/j.phymed.2026.157778","url":null,"abstract":"<p><strong>Background: </strong>Endometriosis (EMs) is a chronic inflammatory disease often treated with blood-activating and stasis-resolving therapies. Anxiety and depression are common mental comorbidities in patients with EMs. There are no medications available for treating EMs with anxiety/depression. Paeonia × suffruticosa Andrews leaves (PSL) has blood-activating and stasis-resolving effects, which are commonly used to treat inflammation and gynecological conditions.</p><p><strong>Purpose: </strong>The purpose of this study was to explore the therapeutic effect of PSL on EMs with anxiety/depression and elucidate its mechanisms.</p><p><strong>Methods: </strong>This study evaluated the inhibitory effect of PSL on EMs through pathological assessment of EMs tissue. Behavioral experiments and pathological characteristics of the brain demonstrated that PSL improved brain damage in EMs mice. Further molecular-level detection and analysis in the hippocampus and prefrontal cortex investigated the mechanism of PSL treatment for EMs with anxiety/depression.</p><p><strong>Results: </strong>PSL inhibited the growth of EMs lesions and reduced Ki67 expression of EMs lesions. PSL improved anxiety/depression-like behavior in EMs mice. Furthermore, PSL treatment contributed to restore neuronal damage in the hippocampus and prefrontal cortex of EMs mice, consistent with behavioral changes. PSL reduced the mRNA and protein expression of IL-1β, IL-6, TNF-α and iNOS in the brain tissue of EMs mice, and promoted the expression of IL-4, CD163, and Arg-1. In addition, the inflammation-related JAK2/STAT3 signaling pathway was activated in the brain of EMs mice with anxiety/depression. PSL downregulated the expression of M1-type microglia and upregulated the expression of M2-type microglia by inhibiting the activation of the JAK2/STAT3 pathway in the hippocampus and prefrontal cortex.</p><p><strong>Conclusions: </strong>PSL suppressed neuroinflammation through JAK2/STAT3 pathway to treat EMs with anxiety/depression.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"157778"},"PeriodicalIF":8.3,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998520","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 : 2026-01-05DOI: 10.1016/j.phymed.2026.157770
Yiwen Deng , Leilei Zhou , Na Li , Fan Huang , Guanhuan Du , Yufeng Wang , Jian Meng , Shijie Chen , Xiufeng Wei , Wenmei Wang , Guoyao Tang
Background
Refractory oral lichen planus (OLP) poses a treatment challenge due to its chronic nature, symptoms, and potential for malignant transformation. Total glucosides of paeony (TGP), a botanical immunomodulator that targets NF-κB and Th17 pathways, have demonstrated promise in managing OLP. However, robust clinical evidence from real-world settings remains lacking.
Purpose
This study aimed to assess the effectiveness and safety of TGP as an add-on therapy for patients with symptomatic refractory OLP in a real-world clinical trial setting.
Study Design
This multicenter, pragmatic, randomized, active-controlled trial (Chinese Clinical Trial Registry: ChiCTR-IPR-16,010,156) enrolled 448 adults with symptomatic refractory OLP from five Chinese centers between January 2017 and December 2020. The pragmatic design assessed TGP under real-world conditions.
Methods
Participants were randomly assigned in a 1:1 ratio to receive basic therapy (tapering prednisone from 15 mg to 5 mg over 4 weeks plus standardized oral hygiene; n = 222) or basic therapy plus TGP (0.6 g three times daily for 12 months; n = 226). The primary endpoint was the time from randomization to complete response (CR), defined as reducing the VAS pain score and Thongprasom sign score to 0 or 1 (or to 0 if the baseline score was 1).
Results
The TGP group demonstrated significantly faster achievement of CR and higher CR rates compared to controls (53.9% vs. 34.4%; hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.52–2.82; p < 0.0001) and better overall response rates at 12 months (70.6% vs. 44.4%; odds ratio [OR] 2.99; 95% CI 2.01–4.44; p < 0.0001). Patients receiving TGP also experienced greater improvements in sleep quality (PSQI responder rate: HR 1.49, p = 0.038). The safety analysis primarily showed mild adverse events, with a higher incidence of diarrhea in the TGP group (5.5% vs. 0.9%), but no severe events or treatment discontinuations.
Conclusion
As an add-on therapy, TGP significantly improved clinical outcomes in refractory OLP in a real-world setting, demonstrating immunomodulatory effects and a favorable safety profile. These pragmatic trial results support TGP as a promising and effective long-term add-on therapy for the long-term management of this potentially malignant disorder.
难治性口腔扁平苔藓（OLP）由于其慢性、症状和潜在的恶性转化，给治疗带来了挑战。牡丹总糖苷（TGP）是一种靶向NF-κB和Th17通路的植物性免疫调节剂，在治疗OLP方面表现出了希望。然而，来自现实世界的可靠临床证据仍然缺乏。目的：本研究旨在评估TGP作为治疗难治性OLP的辅助疗法的有效性和安全性。这项多中心、实用、随机、主动对照试验（中国临床试验注册：ChiCTR-IPR-16,010,156）在2017年1月至2020年12月期间从中国五个中心招募了448名有症状的难治性OLP成人。实用设计评估了真实世界条件下的TGP。方法受试者按1:1的比例随机分配，接受基础治疗（强的松从15 mg逐渐减少到5 mg，持续4周，加上标准化口腔卫生，n = 222）或基础治疗加TGP （0.6 g，每天3次，持续12个月，n = 226）。主要终点是从随机化到完全缓解（CR）的时间，定义为将VAS疼痛评分和Thongprasom体征评分降至0或1（如果基线评分为1，则降至0）。结果与对照组相比，TGP组实现CR的速度更快，CR率更高（53.9% vs. 34.4%；风险比[HR] 2.07, 95%可信区间[CI] 1.52-2.82; p < 0.0001）， 12个月时总有效率更高（70.6% vs. 44.4%；优势比[OR] 2.99; 95% CI 2.01-4.44; p < 0.0001）。接受TGP治疗的患者睡眠质量也有较大改善（PSQI应答率：HR 1.49, p = 0.038）。安全性分析主要显示轻度不良事件，TGP组腹泻发生率较高（5.5%对0.9%），但没有严重事件或治疗中断。结论：作为一种附加治疗，TGP在现实世界中显著改善了难治性OLP的临床结果，显示出免疫调节作用和良好的安全性。这些实用的试验结果支持TGP作为一种有希望和有效的长期附加治疗，用于长期管理这种潜在的恶性疾病。
{"title":"Clinical effectiveness and safety of total glucosides of paeony as an immunomodulator in patients with refractory oral lichen planus: A multicenter, pragmatic, randomized controlled trial","authors":"Yiwen Deng , Leilei Zhou , Na Li , Fan Huang , Guanhuan Du , Yufeng Wang , Jian Meng , Shijie Chen , Xiufeng Wei , Wenmei Wang , Guoyao Tang","doi":"10.1016/j.phymed.2026.157770","DOIUrl":"10.1016/j.phymed.2026.157770","url":null,"abstract":"<div><h3>Background</h3><div>Refractory oral lichen planus (OLP) poses a treatment challenge due to its chronic nature, symptoms, and potential for malignant transformation. Total glucosides of paeony (TGP), a botanical immunomodulator that targets NF-κB and Th17 pathways, have demonstrated promise in managing OLP. However, robust clinical evidence from real-world settings remains lacking.</div></div><div><h3>Purpose</h3><div>This study aimed to assess the effectiveness and safety of TGP as an add-on therapy for patients with symptomatic refractory OLP in a real-world clinical trial setting.</div></div><div><h3>Study Design</h3><div>This multicenter, pragmatic, randomized, active-controlled trial (Chinese Clinical Trial Registry: ChiCTR-IPR-16,010,156) enrolled 448 adults with symptomatic refractory OLP from five Chinese centers between January 2017 and December 2020. The pragmatic design assessed TGP under real-world conditions.</div></div><div><h3>Methods</h3><div>Participants were randomly assigned in a 1:1 ratio to receive basic therapy (tapering prednisone from 15 mg to 5 mg over 4 weeks plus standardized oral hygiene; <em>n</em> = 222) or basic therapy plus TGP (0.6 g three times daily for 12 months; <em>n</em> = 226). The primary endpoint was the time from randomization to complete response (CR), defined as reducing the VAS pain score and Thongprasom sign score to 0 or 1 (or to 0 if the baseline score was 1).</div></div><div><h3>Results</h3><div>The TGP group demonstrated significantly faster achievement of CR and higher CR rates compared to controls (53.9% vs. 34.4%; hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.52–2.82; <em>p</em> < 0.0001) and better overall response rates at 12 months (70.6% vs. 44.4%; odds ratio [OR] 2.99; 95% CI 2.01–4.44; <em>p</em> < 0.0001). Patients receiving TGP also experienced greater improvements in sleep quality (PSQI responder rate: HR 1.49, <em>p</em> = 0.038). The safety analysis primarily showed mild adverse events, with a higher incidence of diarrhea in the TGP group (5.5% vs. 0.9%), but no severe events or treatment discontinuations.</div></div><div><h3>Conclusion</h3><div>As an add-on therapy, TGP significantly improved clinical outcomes in refractory OLP in a real-world setting, demonstrating immunomodulatory effects and a favorable safety profile. These pragmatic trial results support TGP as a promising and effective long-term add-on therapy for the long-term management of this potentially malignant disorder.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157770"},"PeriodicalIF":8.3,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980909","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 : 2026-01-05DOI: 10.1016/j.phymed.2026.157777
Han Yang , Yuzhan Xu , Yufei Feng , Haiyang Ling , Zhiliang Liu , Yaqin Ma , Xiaoli Chen , Shengxiang Ge , Huiming Ye
Background
While bleeding associated with anticoagulants is often predictable and manageable, non-anticoagulant induced bleeding poses greater clinical challenges due to unclear mechanisms. These disorders primarily arise from coagulation factor dysfunction, with emerging evidence implicating off-target disruption of the vitamin K cycle. However, existing research on Traditional Chinese Medicines (TCMs) has largely focused on their antiplatelet effects and direct inhibition of coagulation proteases. Given the complex, multi-component nature of TCMs, a comprehensive evaluation of their potential to interfere with vitamin K cycle remains critically needed.
Purpose
This study aims to systematically investigate TCM-derived compounds that interfere with the vitamin K cycle, thereby elucidating novel mechanisms underlying TCM-induced coagulopathy and informing their safety assessment.
Study Design
A high-throughput vitamin K-dependent (VKD) carboxylation assay was employed to screen 1931 pharmacologically characterized bioactive compounds derived from TCMs. Lead candidates were further validated through in vivo mouse experiments.
Methods
The VKD carboxylation assay quantified compound-induced inhibition of γ-carboxylation. Positive hits were evaluated for dose-dependent effects, and mechanism of potential inhibitors were investigated using vitamin K recue assay and molecular docking analysis. Their anticoagulant activity was validated in vivo in mice following oral administration.
Results
Screening identified two ginger (Zingiber officinale Roscoe)-derived compounds—6-paradol and 10-gingerol—as first-in-class natural vitamin K antagonists that inhibited γ-carboxylation in a dose-dependent manner. Vitamin K rescue assays and molecular docking analyses demonstrated that both compounds directly target vitamin K epoxide reductase (VKOR), thereby disrupting the vitamin K cycle. Oral administration in mice significantly prolonged prothrombin and tail bleeding times, confirming their anticoagulant effects.
Conclusion
Our study establishes 6-paradol and 10-gingerol, derived from ginger, as the first natural inhibitors of VKOR. This finding provides a novel mechanistic basis for understanding bleeding risks associated with TCMs, thereby highlighting the "double-edged sword" nature of their bioactive components. Consequently, this study underscores the critical need to balance the exploration of TCM's therapeutic potential with rigorous safety assessments, including the specific evaluation of VKOR inhibition.
{"title":"Ginger (Zingiber officinale Roscoe)-derived natural compounds inhibit vitamin K-dependent carboxylation: a novel possibility for traditional Chinese medicine-induced bleeding risk","authors":"Han Yang , Yuzhan Xu , Yufei Feng , Haiyang Ling , Zhiliang Liu , Yaqin Ma , Xiaoli Chen , Shengxiang Ge , Huiming Ye","doi":"10.1016/j.phymed.2026.157777","DOIUrl":"10.1016/j.phymed.2026.157777","url":null,"abstract":"<div><h3>Background</h3><div>While bleeding associated with anticoagulants is often predictable and manageable, non-anticoagulant induced bleeding poses greater clinical challenges due to unclear mechanisms. These disorders primarily arise from coagulation factor dysfunction, with emerging evidence implicating off-target disruption of the vitamin K cycle. However, existing research on Traditional Chinese Medicines (TCMs) has largely focused on their antiplatelet effects and direct inhibition of coagulation proteases. Given the complex, multi-component nature of TCMs, a comprehensive evaluation of their potential to interfere with vitamin K cycle remains critically needed.</div></div><div><h3>Purpose</h3><div>This study aims to systematically investigate TCM-derived compounds that interfere with the vitamin K cycle, thereby elucidating novel mechanisms underlying TCM-induced coagulopathy and informing their safety assessment.</div></div><div><h3>Study Design</h3><div>A high-throughput vitamin K-dependent (VKD) carboxylation assay was employed to screen 1931 pharmacologically characterized bioactive compounds derived from TCMs. Lead candidates were further validated through <em>in vivo</em> mouse experiments.</div></div><div><h3>Methods</h3><div>The VKD carboxylation assay quantified compound-induced inhibition of γ-carboxylation. Positive hits were evaluated for dose-dependent effects, and mechanism of potential inhibitors were investigated using vitamin K recue assay and molecular docking analysis. Their anticoagulant activity was validated <em>in vivo</em> in mice following oral administration.</div></div><div><h3>Results</h3><div>Screening identified two ginger (<em>Zingiber officinale</em> Roscoe)-derived compounds—6-paradol and 10-gingerol—as first-in-class natural vitamin K antagonists that inhibited γ-carboxylation in a dose-dependent manner. Vitamin K rescue assays and molecular docking analyses demonstrated that both compounds directly target vitamin K epoxide reductase (VKOR), thereby disrupting the vitamin K cycle. Oral administration in mice significantly prolonged prothrombin and tail bleeding times, confirming their anticoagulant effects.</div></div><div><h3>Conclusion</h3><div>Our study establishes 6-paradol and 10-gingerol, derived from ginger, as the first natural inhibitors of VKOR. This finding provides a novel mechanistic basis for understanding bleeding risks associated with TCMs, thereby highlighting the \"double-edged sword\" nature of their bioactive components. Consequently, this study underscores the critical need to balance the exploration of TCM's therapeutic potential with rigorous safety assessments, including the specific evaluation of VKOR inhibition.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157777"},"PeriodicalIF":8.3,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941420","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}
Diabetic nephropathy (DN) serves as the major etiological factor of end-stage renal disease (ESRD) in DM patients. Balanophora involucrata Hook.f. & Thomson (BI) is a traditional medicine of the Tujia ethnic group in China, with good therapeutic effects on kidney diseases. However, both its effectiveness in the context of DN and the regulatory mechanism remain to be further clarified.
Purpose
To elucidate the role of BI in DN mice, with a focus on exploring the intrinsic mechanism responsible for this process.
Methods
UPLC-MS/MS was employed to identify the main ingredients of BI. The DN model was established using C57BLKS/J db/db mice, which received BI treatment. Serum/urine parameters, renal histology, and ultrastructure were assessed. Intrinsic microbial composition and corresponding metabolites were analyzed via 16S rDNA gene sequencing and nontargeted metabolomics. HK-2 cells were treated with high glucose to simulate DN and then treated with BI-containing drug serum and ferrostatin-1 (fer-1). Cell viability was assessed by CCK-8 assay, and lipid peroxidation was evaluated using the Bodipy 581/591 C11 fluorescence assay. Commercial kits were used to detect MDA and other ferroptosis-related indicators. Protein levels were analyzed by Western blotting.
Results
Terpenoids and flavonoids were the main identified components of BI. Fasting blood glucose was reduced, and lipid metabolism disorders were corrected by BI in DN mice. It also ameliorated renal injury in these mice. Meanwhile, BI regulated serum metabolites, and remodeled gut microbiota in DN mice. Furthermore, Nrf2, GPX4, FPN1, FTH1, and SLC7A11 were activated by BI, whereas TFR1 and ACSL4 were suppressed.
Conclusions
BI ameliorates DN by regulating serum metabolites, remodeling the gut microbiota, and inhibiting ferroptosis.
{"title":"Balanophora involucrata alleviates diabetic nephropathy by inhibiting ferroptosis, modulating serum metabolites and gut microbiota","authors":"Chaoxi Tian , Yawen Chen , Jing Huang , Fangyu Zhao , Xiane Tang , Jianhong Gao , Xianbing Chen , Xiuxue Yuan","doi":"10.1016/j.phymed.2026.157773","DOIUrl":"10.1016/j.phymed.2026.157773","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic nephropathy (DN) serves as the major etiological factor of end-stage renal disease (ESRD) in DM patients. <em>Balanophora involucrata</em> Hook.f. & Thomson (BI) is a traditional medicine of the Tujia ethnic group in China, with good therapeutic effects on kidney diseases. However, both its effectiveness in the context of DN and the regulatory mechanism remain to be further clarified.</div></div><div><h3>Purpose</h3><div>To elucidate the role of BI in DN mice, with a focus on exploring the intrinsic mechanism responsible for this process.</div></div><div><h3>Methods</h3><div>UPLC-MS/MS was employed to identify the main ingredients of BI. The DN model was established using C57BLKS/J db/db mice, which received BI treatment. Serum/urine parameters, renal histology, and ultrastructure were assessed. Intrinsic microbial composition and corresponding metabolites were analyzed via 16S rDNA gene sequencing and nontargeted metabolomics. HK-2 cells were treated with high glucose to simulate DN and then treated with BI-containing drug serum and ferrostatin-1 (fer-1). Cell viability was assessed by CCK-8 assay, and lipid peroxidation was evaluated using the Bodipy 581/591 C11 fluorescence assay. Commercial kits were used to detect MDA and other ferroptosis-related indicators. Protein levels were analyzed by Western blotting.</div></div><div><h3>Results</h3><div>Terpenoids and flavonoids were the main identified components of BI. Fasting blood glucose was reduced, and lipid metabolism disorders were corrected by BI in DN mice. It also ameliorated renal injury in these mice. Meanwhile, BI regulated serum metabolites, and remodeled gut microbiota in DN mice. Furthermore, Nrf2, GPX4, FPN1, FTH1, and SLC7A11 were activated by BI, whereas TFR1 and ACSL4 were suppressed.</div></div><div><h3>Conclusions</h3><div>BI ameliorates DN by regulating serum metabolites, remodeling the gut microbiota, and inhibiting ferroptosis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"151 ","pages":"Article 157773"},"PeriodicalIF":8.3,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941422","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：