Phytomedicine最新文献

{"title":"Lingguizhugan decoction inhibit pulmonary hypertension by regulating macrophage IL-6 secretion via IL-33/ST2 pathway","authors":"Zhengwei Dong ,&nbsp;Zhifeng Xue ,&nbsp;Min Zhang ,&nbsp;Liming Wang ,&nbsp;Qianqian Lu ,&nbsp;Huan Zhao ,&nbsp;Xinlu Wang ,&nbsp;Shanshan Nie ,&nbsp;Jingjing Wei ,&nbsp;Haifeng Yan ,&nbsp;Guanwei Fan ,&nbsp;Yongxia Wang ,&nbsp;Mingjun Zhu","doi":"10.1016/j.phymed.2025.156822","DOIUrl":"10.1016/j.phymed.2025.156822","url":null,"abstract":"<div><h3>Background</h3><div>Lingguizhugan decoction (LGZG), a typical Chinese herbal formula, has remarkable clinical effects for treating pulmonary hypertension (PH) with unclear ingredients and mechanisms. This study aimed to evaluate the efficacy of LGZG and the mechanism of its active ingredients in treating PH.</div></div><div><h3>Methods</h3><div>The PH patient phenotype was characterized by transcriptomic assay of peripheral blood mononuclear cells (PBMCs) and multiplex cytokine profiling of serum. The active ingredients of LGZG were identified by UPLC-Q-TOF-MS. The monocrotaline (MCT)-induced PH model was performed to evaluate the effects of LGZG and its active ingredients <em>in vivo</em>. The interleukin-33 (IL-33)-induced RAW264.7 cells and the mouse pulmonary artery smooth muscle cells (mPASMCs) were applied to explored phenotype and mechanism of the active ingredients of LGZG by immunofluorescence, western blotting and RT-qPCR <em>in vitro.</em></div></div><div><h3>Results</h3><div>Inflammatory receptor activity in PBMCs and serum interleukin-6 (IL-6) levels were elevated in PH patients. Porinic acid B, cinnamic acid, atractylenolide I and glycyrrhizin (PCAG) were characterized and combined to treat the PH, And the IL-33/Growth stimulation expressed gene 2 (ST2) pathway may be the potential mechanism by transcriptomic analysis of lung tissues. Both <em>in vivo</em> and <em>in vitro</em> experiments confirmed that PCAG inhibited the IL-33/ST2 pathway, reduced macrophage polarization, and suppressed IL-6 secretion. Moreover, ST2 overexpression in macrophages attenuated the inhibitory effect of PCAG. Using a co-culture system of macrophages and mPASMCs, we demonstrated that PCAG reduced mPASMCs phenotypic switching by suppressing macrophage-derived IL-6 secretion.</div></div><div><h3>Conclusion</h3><div>The active ingredient of LGZG, PCAG, inhibits the progression of PH by preventing macrophage polarization and IL-6 secretion through the IL-33/ST2 pathway.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156822"},"PeriodicalIF":6.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyphyllin Ⅵ modulates macrophage polarization through autophagy-NLRP3 inflammasome to alleviate inflammatory bowel disease","authors":"Shuo Yuan ,&nbsp;Bao-Hong Liu ,&nbsp;Wen-Wen Cheng ,&nbsp;Huan Meng ,&nbsp;Xiao-Ting Hou ,&nbsp;Jia-Chen Xue ,&nbsp;Hua-Min Zhang ,&nbsp;Qing-Gao Zhang","doi":"10.1016/j.phymed.2025.156640","DOIUrl":"10.1016/j.phymed.2025.156640","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with a rising global prevalence. If left untreated, it can result in severe complications, including colon cancer. Key factors in IBD pathogenesis include macrophages, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), and autophagy. Polyphyllin Ⅵ (PPⅥ), a metanoidal saponin derived from the traditional Chinese herb Chonglou, exhibits significant anti-inflammatory and anti-cancer properties, making it a compound of considerable therapeutic interest.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;The present study investigated the relevant mechanism of PPⅥ on protecting IBD from the perspective of NLRP3 as well as macrophage immunomodulation and laid a theoretical foundation for the development of novel IBD therapeutic drugs.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The IBD mice were prepared by dextran sodium sulfate, and RAW 264.7 inflammatory cells were established through LPS and ATP stimulation. The indicators of macrophage polarization, NLRP3, and autophagy were detected using Western Blot, RT-qPCR, H&amp;E staining, immunofluorescence, and flow cytometry.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;PPⅥ can enhance the inflammatory state of LPS-induced RAW264.7 macrophages, which can reduce weight loss, decrease DAI score, increase colon length, reduce oxidative stress, and decrease intestinal epithelial barrier damage, and thus diminish inflammatory injury in DSS-induced IBD mice. PPⅥ can modify intestinal inflammation and injury by modulating macrophage function. The administration of PPⅥ can maintain the balance between M1-type macrophages and M2-type macrophages while regulating the intestinal macrophage polarization via the NLRP3 inflammasome and autophagy through wildtype mice, cells, and &lt;em&gt;Nlrp3&lt;/em&gt;&lt;sup&gt;-/-&lt;/sup&gt; mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;PPⅥ can regulate macrophage polarization through autophagic modulation of NLRP3 inflammasome to promote the repair of intestinal epithelial damage and maintain the integrity of the mucosal barrier, which contributes to the attenuation of inflammatory injury in DSS-induced IBD mice and provides a database for the development of novel clinical drugs.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Innovations&lt;/h3&gt;&lt;div&gt;1. This subject discovered the protective effect of PPⅥ on IBD mice.&lt;/div&gt;&lt;div&gt;2. This subject proved that macrophages have an important role in the intestinal protection of PPⅥ in IBD mice, and PPⅥ can inhibit the polarization of M1-type macrophages and promote the polarization of M2-type macrophages.&lt;/div&gt;&lt;div&gt;3. This subject demonstrated that PPⅥ could regulate macrophage polarization through NLRP3 inflammasome and ameliorate intestinal inflammation in vitro, in vivo, and in &lt;em&gt;Nlrp3&lt;/em&gt;&lt;sup&gt;-/-&lt;/sup&gt; mice.&lt;/div&gt;&lt;div&gt;4. This subject confirmed that PPⅥ could regulate macrophage polarization to alleviate inflammatory injury by inhibiting NLRP3 inflammasome through m","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156640"},"PeriodicalIF":6.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brevilin A, a novel BNIP3 inhibitor suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss via impairing mitophagy and mitochondrial metabolism","authors":"Rui Zhou ,&nbsp;Yiyuan Wang ,&nbsp;Siyi Liu ,&nbsp;Yuangang Su ,&nbsp;Zhijuan Liu ,&nbsp;Baihui Yang ,&nbsp;Xiangde Li ,&nbsp;Jinmin Zhao ,&nbsp;Jiake Xu ,&nbsp;Qian Liu ,&nbsp;Fangming Song","doi":"10.1016/j.phymed.2025.156774","DOIUrl":"10.1016/j.phymed.2025.156774","url":null,"abstract":"<div><h3>Background</h3><div>The mitochondrial dysfunction and overactive osteoclasts is involved in the progress of osteoporosis. Brevilin A (BA), a sesquiterpene lactone, is a compound extracted and purified from Centipeda minima. It exhibits a range of pharmacological activities, such as anti-inflammatory and antioxidant effects. However, its specific impact on osteoporosis remains unclear. The present study is designed to explore BA as a novel osteoclast inhibitor for the treatment of osteoporosis as well as its molecular mechanisms of action via BNIP3-mediated mitophagy.</div></div><div><h3>Methods</h3><div>The cytotoxicity of BA in vitro was evaluated using the CCK8 assay, while tartrate-resistant acid phosphatase (TRAcP) staining and bone resorption assays were conducted to examine its effects on osteoclastogenesis and osteoclast function. To elucidate the molecular mechanisms by which BA targets BNIP3 in osteoclasts, RNA-seq, molecular docking analysis, Surface plasmon resonance (SPR), qPCR, western blot, mitochondrial oxygen consumption rate (OCR), transmission electron microscopy (TEM), Single cell sequencing and immunofluorescence staining were employed. In addition, a specific BNIP3 agonist IOX5, was used to revalidate the inhibitory effect of BA on BNIP3. To investigate the effects and protective role of BA in modulating BNIP3 on bone loss in osteoporotic mice induced by ovariectomy (OVX), we employed in vivo micro-CT scanning and histological immunostaining techniques.</div></div><div><h3>Results</h3><div>Our study demonstrated that BA inhibited RANKL-induced osteoclastogenesis in a concentration-dependent manner without any cell cytotoxicity. Further, BA abrogated MAPK-related proteins and intracellular and mitochondrial ROS level, subsequently inhibiting NFATc1 activity. RNA-seq analysis revealed that the molecular mechanism by which BA inhibited osteoclasts is closely related to mitophagy and mitochondrial function. Here, we found that BA suppressed oxygen consumption rate and mitochondrial oxidative phosphorylation during osteoclastogenesis. This compound abolished expression of ATG5, SIRT3, Beclin1 and LC3B. RANKL-induced mitophagy associated protein (PINK1 and Parkin) were also suppressed by BA. BA interacted with BNIP3 and IOX5 treatment further verified the targeted inhibition effect of BA on BNIP3. In addition, we found that BNIP3 deficient inhibited osteoclast differentiation related with mitophagy and mitochondrial function. In vivo experiments confirmed that BA significantly prevent OVX-induced bone loss associated with BNIP3-mediated mitophagy.</div></div><div><h3>Conclusions</h3><div>Our study reveals for the first time that BA acts as a novel inhibitor of BNIP3, which ameliorates osteoclast activity and OVX-induced osteoporosis via limiting mitophagy and mitochondrial energy production, suggesting that it could be a novel therapeutic strategy for osteoporosis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156774"},"PeriodicalIF":6.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of emodin on Streptococcus suis by targeting β-ketoacyl-acyl carrier protein synthase Ⅱ","authors":"Jun Wang ,&nbsp;Yongzheng Liu ,&nbsp;Chongxiang Sun ,&nbsp;Long Chen ,&nbsp;Sikai Chen ,&nbsp;Xingyu Huang ,&nbsp;Zhijia Lu ,&nbsp;Chunliu Dong ,&nbsp;Yadan Zheng ,&nbsp;Zhiyun Zhang ,&nbsp;Yanyan Liu ,&nbsp;Qianwei Qu ,&nbsp;Yanhua Li","doi":"10.1016/j.phymed.2025.156821","DOIUrl":"10.1016/j.phymed.2025.156821","url":null,"abstract":"<div><h3>Background</h3><div><em>Streptococcus suis</em> is a zoonotic pathogen that causes meningitis, septicaemia, endocarditis, arthritis, and pneumonia in human beings. With the increasing prevalence of <em>S. suis</em> infections and a general decline in the effectiveness of antibiotics, the development of novel drugs that have effect on <em>S. suis</em> is extremely urgent. Emodin, a natural anthraquinone derivative of <em>Rheum palmatum</em> L., <em>Reynoutria japonica</em> Houtt., <em>Polygonum multiflorum</em> Thunb. and <em>Cassia obtusifolia</em> L., has been reported to exert anti-<em>S. suis</em> effect; however, the specific mechanism of the anti-<em>S. suis</em> action by targeting β-ketoacyl-acyl carrier protein synthase Ⅱ (FabF) in the fatty acid synthesis pathway remains unexplored.</div></div><div><h3>Purpose</h3><div>We sought to reveal the potential role of emodin to prevent <em>S. suis</em> infection, investigate its mechanism of anti-<em>S. suis</em> action, and provide further evidence of emodin as an alternative to traditional antibiotic agents.</div></div><div><h3>Methods</h3><div>The <em>in vitro</em> anti-<em>S. suis</em> properties of emodin were assessed through minimum inhibitory concentration (MIC) assays, and time-kill assays. Subsequently, the mechanisms underlying emodin’s mode of action at the molecular level by targeting FabF were elucidated using molecular docking, site-directed mutagenesis, bio-layer interferometry assays, and cellular thermal shift assays. Finally, metabolomics, cell membrane phospholipid content assay and biochemical parameters assays were used to detect emodin disrupting cell membrane integrity and function by affecting fatty acid biosynthesis.</div></div><div><h3>Results</h3><div>In this study, we have identified that emodin inhibits <em>S. suis</em> by suppressing free fatty acids (FFAs) synthesis and disrupting phospholipid production by targeting FabF, a key enzyme in the fatty acid biosynthesis pathway. This interference compromises the integrity and functionality of the cell membranes of <em>S. suis</em>. Emodin also triggers the dissipation of the proton motive force, accelerates the tricarboxylic acid cycle, and enhances cellular respiration, ultimately leading to <em>S. suis</em> cell death.</div></div><div><h3>Conclusion</h3><div>This study suggested that emodin inhibits the growth of <em>S. suis via</em> targeting FabF and the inhibition of fatty acid biosynthesis through enzyme-targeted drug design. This represents a novel strategy for developing antimicrobial agents against <em>S. suis</em> and addressing the challenge of antibiotic resistance.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156821"},"PeriodicalIF":6.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunomodulatory mechanism of Huangqi-Guizhi-Wuwu Decoction in alleviating autoimmune arthritis based on network pharmacology and experimental validation","authors":"Wenbo Zhang ,&nbsp;Ping Wu ,&nbsp;Yue Song ,&nbsp;Dandan Liang ,&nbsp;Guangxun Meng ,&nbsp;Huasong Zeng","doi":"10.1016/j.phymed.2025.156644","DOIUrl":"10.1016/j.phymed.2025.156644","url":null,"abstract":"<div><h3>Background</h3><div>Juvenile idiopathic arthritis (JIA) is the most common type of childhood autoimmune arthritis. Huangqi Guizhi Wuwu decoction (HGWD), a traditional Chinese herbal formula, is widely used in China to treat patients with autoimmune arthritis. However, the bioactive ingredients and their complex regulatory mechanisms remain unclear.</div></div><div><h3>Purpose</h3><div>To investigate the active components of HGWD using a novel comprehensive strategy and clarify the mechanism underlying immunomodulation.</div></div><div><h3>Methods</h3><div>The main active components of HGWD were determined using ultra-high-performance liquid chromatography-high resolution mass spectrometry (UPLC<img>HRMS). The core target and biological immune regulation mechanism of HGWD in alleviating JIA were predicted using combined network pharmacology and molecular docking analyses, followed by <em>in vitro</em> and <em>in vivo</em> experiments.</div></div><div><h3>Results</h3><div>A total of 1387 active components were identified by UPLC-MS, of which eight were the main active ingredients. Network pharmacology showed that HGWD acted on core targets, such as STAT3. Further combined analysis revealed that regulation of the Th17 differentiation pathway may be an important mechanism by which HGWD relieves JIA. Molecular docking verification showed that the key component of HGWD can stably bind JAK/STAT-related proteins. The induced differentiation of Th17 and Treg <em>in vitro</em> experiment confirmed the immunoregulatory effects of HGWD. <em>in vivo</em> experiments, HGWD significantly alleviated symptoms of arthritis in a mouse model of collagen-induced arthritis (CIA) and was closely associated with restoring the Th17/Treg balance.</div></div><div><h3>Conclusion</h3><div>Taken together, serum components/UPLC-MS, network pharmacology, and molecular biology analyses are feasible strategies for exploring the active ingredients in HGWD. This study highlights the clinical potential of HGWD in alleviating JIA and provides evidence of its therapeutic potential through immune regulation.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156644"},"PeriodicalIF":6.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guiding precision medicine strategy for intravenous ginsenosides via pharmacokinetic-informed bioinformatic approaches: a study on XueShuanTong","authors":"Wei-Wei Jia ,&nbsp;Nan-Nan Tian ,&nbsp;Zi-Jing Song ,&nbsp;Xiao-Fang Lan ,&nbsp;Xi-He Yang ,&nbsp;Fei-Fei Du ,&nbsp;Feng-Qing Wang ,&nbsp;Chen Cheng ,&nbsp;Xiao-Yan Xia ,&nbsp;Yi-Mei Zeng ,&nbsp;Ying Rao ,&nbsp;Jun-Ling Yang ,&nbsp;Chuan Li","doi":"10.1016/j.phymed.2025.156716","DOIUrl":"10.1016/j.phymed.2025.156716","url":null,"abstract":"<div><h3>Background</h3><div>Intravenous ginsenosides, derived from <em>Panax</em> species, are widely used in China. XueShuanTong injection, enriched with ginsenosides Rb₁ and Rg₁, is recommended for unstable angina treatment. Although effective, it may cause adverse effects, especially in patients with renal or hepatic impairment, as these organs are vital in ginsenosides’ systemic exposure.</div></div><div><h3>Purpose</h3><div>This investigation aimed to inform precision medicine by employing a physiologically based pharmacokinetic (PBPK) model to evaluate transporter-mediated interactions between both ginsenosides and their systemic exposure in patients with organ impairment, thereby ensuring safety.</div></div><div><h3>Methods</h3><div>Interactions between ginsenosides Rb₁ and Rg₁, mediated by human and rat transporters, were characterized at both cellular and vesicular levels. Their interactions with human organic anion-transporting polypeptide (OATP)1B3 and rat Oatp1b2 were evaluated when administered together or as part of XueShuanTong in both rats and humans. PBPK models incorporating OATP-mediated hepatobiliary excretion were developed to characterize their interactions and pharmacokinetics, providing guidance for precision medicine in these patients.</div></div><div><h3>Results</h3><div>Ginsenoside Rb₁ was demonstrated to inhibit human OATP1B3 (Oatp1b2 in rats)-mediated cellular uptake, significantly increasing exposure levels of ginsenoside Rg₁ in rats by impairing hepatobiliary elimination. Mechanistic models effectively replicated the pharmacokinetic profiles and the interactions of ginsenosides Rb₁ and Rg₁. These validated models revealed that decreases in GFR, hematocrit, hepatic volume, and/or OATP1B3 expression and activity in patients with renal or hepatic impairment significantly increased the systemic exposure levels of both ginsenosides. Moreover, the models provided valuable insights into the mechanism of “albumin-facilitated dissociation” associated with ginsenoside Rb₁, an OATP1B3 inhibitor. This understanding is crucial for predicting the risk of drug-drug interactions involving drugs with high plasma protein binding.</div></div><div><h3>Conclusions</h3><div>By incorporating these key patient-specific physiological parameters into the models, this investigation provides practical guidance for optimizing dosing strategies and improving the therapeutic efficacy of ginsenoside-containing injections, including XueShuanTong, in patients with complex conditions.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156716"},"PeriodicalIF":6.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Verbenalin protects against coronavirus pneumonia by promoting host immune homeostasis: Evidences for its mechanism of action","authors":"Qiyue Sun ,&nbsp;Ronghua Zhao ,&nbsp;Shuran Li ,&nbsp;Weiqin Zhou ,&nbsp;Jingsheng Zhang ,&nbsp;Bo Pang ,&nbsp;Shilan Ding ,&nbsp;Lei Bao ,&nbsp;Zihan Geng ,&nbsp;Rui Xie ,&nbsp;Dan Xie ,&nbsp;Xiaolan Cui ,&nbsp;Shanshan Guo ,&nbsp;Jing Sun","doi":"10.1016/j.phymed.2025.156820","DOIUrl":"10.1016/j.phymed.2025.156820","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Coronavirus has caused high-mortality viral pneumonia worldwide. The pathogenesis is characterized by hyperinflammatory reactions resulting from immune homeostasis dysregulation. Verbenalin, an iridoid glucoside derived from &lt;em&gt;Verbena officinalis L&lt;/em&gt;., is widely used in Traditional Chinese Medicine (TCM) clinical practice for its antioxidant, anti-inflammatory and antiviral properties.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This study aimed to investigate the pharmacological effects and underlying mechanisms of verbenalin on coronavirus pneumonia both &lt;em&gt;in vivo&lt;/em&gt; and &lt;em&gt;in vitro.&lt;/em&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;A coronavirus pneumonia mouse model and macrophage injury models, including mouse alveolar macrophage cell line (MH-S) cells and primary macrophages, were established to initially confirm the antiviral effects of verbenalin. Time-resolved proteomic were then employed to uncover proteomic changes and identify potential therapeutic targets for coronavirus treatment. Subsequently, flow cytometry and Western blot were employed to investigate verbenalin's effects on NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. Additionally, the targeting regulation of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) / E3 ubiquitin ligase Parkin (Parkin) pathway by verbenalin was validated through molecular docking, surface plasmon resonance (SPR), immunofluorescent staining, RNA interference (RNAi), and mitophagy inhibition both &lt;em&gt;in vivo&lt;/em&gt; and &lt;em&gt;in vitro.&lt;/em&gt;&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Verbenalin reduced cell injury and inflammation in Human coronavirus 229E (HCoV-229E)-infected macrophages and improved lung inflammation in mice. Proteomics analysis highlighted the roles of nucleotide-binding oligomerization domain (NOD)-like receptor signaling and mitophagy pathways in coronavirus pneumonia. Verbenalin bound strongly to PINK1 and Parkin proteins, increased mitochondrial membrane potential (MMP), decreased mitochondrial reactive oxygen species (mtROS) levels, reduced the opening of mitochondrial permeability transition pore (MPTP), maintained mitochondrial mass, promoted mitophagy flux, upregulated the expression of PINK1, Parkin, and microtubule-associated protein 1A/1B-light chain 3BII (LC3BII). Additionally, verbenalin inhibited the activation of the NLRP3 inflammasome and downregulated the expression of Interleukin-1 beta (IL-1β), cysteine aspartate-specific protease 1 (caspase-1), and gasdermin D (GSDMD) both &lt;em&gt;in vivo&lt;/em&gt; and &lt;em&gt;in vitro.&lt;/em&gt; Furthermore, treatment with a mitophagy inhibitor and RNAi attenuated the inhibitory effects of verbenalin on NLRP3 activation, confirming the involvement of the PINK1/Parkin/NLRP3 pathway in verbenalin's protective effects.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Verbenalin enhances PINK1/Parkin-mediated mitophagy to suppress NLRP3 activation, thereby promoting immune homeostasis and mitigating H","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156820"},"PeriodicalIF":6.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel EndMT inhibitor, xanthotoxin, attenuates non-alcoholic fatty liver disease by acting as TGFβR2 antagonist","authors":"Xiaona Zhao ,&nbsp;Fangjie Xia ,&nbsp;Zixu Dong ,&nbsp;Wenyang Huang ,&nbsp;Xinxin Kong ,&nbsp;Zhoujun Cui ,&nbsp;Maocai Yan ,&nbsp;Honggang Gao ,&nbsp;Ruixue Rong ,&nbsp;Minghui Wang ,&nbsp;Guoqing Liu ,&nbsp;Zejin Zhang ,&nbsp;Jing Zhang ,&nbsp;Tao Yuan ,&nbsp;Huiying Cai ,&nbsp;Zhenzhen Yan ,&nbsp;Lin Zhu ,&nbsp;Wei Qin","doi":"10.1016/j.phymed.2025.156823","DOIUrl":"10.1016/j.phymed.2025.156823","url":null,"abstract":"<div><h3>Background</h3><div>Endothelial-to-mesenchymal transition (EndMT) has emerged as a key process contributing to the pathology of non-alcoholic fatty liver disease (NAFLD). Thus, identifying EndMT inhibitors may help impede NAFLD progression.</div></div><div><h3>Purpose</h3><div>Our research aims to identify potent natural EndMT inhibitors and explore their therapeutic potential and mechanisms of action in NAFLD.</div></div><div><h3>Methods</h3><div>A natural compound library was employed to screen potential EndMT inhibitors. High-fat diet (HFD)-induced ApoE^-/- mice and free fatty acid (FFA)-treated human hepatic sinusoidal endothelial cells (HHSECs) were employed as animal and cellular models of NAFLD. EndMT was evaluated by western blotting, qRT-PCR, immunofluorescence staining, tube formation, wound healing, and transwell assays. LC-MS/MS was applied to screen for altered secreted proteins during EndMT. Molecular docking, CETSA, and SPR assays were employed to validate the combination of xanthotoxin with TGFβR2.</div></div><div><h3>Results</h3><div>Xanthotoxin was identified as a novel EndMT inhibitor. Further investigation revealed that xanthotoxin ameliorates NAFLD in ApoE^-/- mice. By inhibiting EndMT, xanthotoxin improves endothelial dysfunction, reduces the pro-NAFLD factor ANGPTL2 secretion, and increases the anti-NAFLD factor SOD2 secretion, thus reducing hepatocyte steatosis, inflammation, and hepatic stellate cell fibrosis. Additional studies demonstrated that xanthotoxin binds to TGFβR2 and acts as its antagonist to block EndMT. In mice, EC-specific overexpression of TGFβR2 negated xanthotoxin’s therapeutic impact on NAFLD.</div></div><div><h3>Conclusion</h3><div>This study reveals for the first time that xanthotoxin attenuates NAFLD by acting as a TGFβR2 antagonist to inhibit EndMT. These findings highlight the significant therapeutic potential of xanthotoxin in NAFLD treatment.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156823"},"PeriodicalIF":6.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gluconic acid alleviates hypertrophic scar formation through binding PLOD1, reducing p-AKT signaling and activating autophagy","authors":"Jingyun Li ,&nbsp;Siqi Zeng ,&nbsp;Yue Sun ,&nbsp;Jijun Zou ,&nbsp;Enyuan Zhang ,&nbsp;Qiyue Yan ,&nbsp;Ling Chen ,&nbsp;Jun Li","doi":"10.1016/j.phymed.2025.156825","DOIUrl":"10.1016/j.phymed.2025.156825","url":null,"abstract":"<div><h3>Background</h3><div>Hypertrophic scarring represents a major clinical challenge worldwide, with current treatment strategies showing limited effectiveness. Gluconic acid (GLA), a naturally occurring glucose metabolite found in fruits, honey, kombucha tea, and wine, may provide new approach for scar treatment.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate the anti-scarring properties of GLA and underlying molecular mechanisms.</div></div><div><h3>Study design</h3><div>A comprehensive experimental study combined <em>in vitro</em> hypertrophic scar fibroblasts and <em>in vivo</em> rabbit ear scar model assays.</div></div><div><h3>Methods</h3><div>Hypertrophic scar fibroblasts were treated with GLA. Cell counting kit-8 (CCK-8) and flow cytometry were used to evaluate cell viability and apoptosis. The collagen and ACTA2 (actin alpha 2, smooth muscle) expressions were analyzed by qPCR and western blot. A rabbit ear scar model was applied to assess GLA’s effects on scar formation and collagen deposition. Transcriptome sequencing, pull-down assays, western blotting and rescue experiments using AKT agonist SC79 were employed to identify GLA-regulated pathways. Molecular docking, pull-down, cellular thermal shift assays and co-localization studies were used to assess GLA’s interaction with PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1). E64d, MG132 and QX77 were added to analyze GLA’s function mechanisms on PLOD1 protein expression. Autophagy activation was evaluated through autophagic flux assay, transmission electron microscopy and autophagy related protein expression analysis. Mitochondrial membrane potential was detected by JC-1 staining.</div></div><div><h3>Results</h3><div>GLA suppresses collagen and ACTA2 expressions and exerted a mild inhibitory effect on cell proliferation or apoptosis in hypertrophic scar fibroblasts. And it diminishes scar formation and collagen content in the rabbit ear scar model. AKT (protein kinase B) and phosphorylated AKT (p-AKT) levels were significantly reduced after GLA treatment. Rescue experiments confirmed that GLA’s effects are mediated through the AKT pathway. Moreover, GLA interacts with PLOD1, resulting in its autophagy-lysosomal degradation. Additionally, GLA treatment activated autophagy, reduced mTOR protein expressions, and had no significant effect on mitochondrial membrane depolarization, further contributing to its anti-scarring effects.</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate that GLA attenuates hypertrophic scarring through multi-modal mechanisms involving PLOD1 targeting, AKT/mTOR pathway inhibition, and autophagy activation. This study provides both mechanistic insights and therapeutic potential for GLA in scar treatment.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156825"},"PeriodicalIF":6.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of Chinese herbal medicines combined with high-intensity focused ultrasound for patients with uterine fibroids: A meta-analysis with core herbs exploration","authors":"Yu-Ting Huang ,&nbsp;Meng-Chun Wang ,&nbsp;Jian-An Liao ,&nbsp;Wei-Chun Chen ,&nbsp;Yu-Ting Chou ,&nbsp;Wei-Jen Cheng","doi":"10.1016/j.phymed.2025.156811","DOIUrl":"10.1016/j.phymed.2025.156811","url":null,"abstract":"<div><h3>Background</h3><div>Uterine fibroids (UFs) are prevalent benign tumours affecting women; they often present with symptoms such as excessive menstrual bleeding, pelvic discomfort, recurrent pregnancy loss, and infertility. High-intensity focused ultrasound (HIFU) has emerged as a non-invasive treatment option. Recent studies suggest that Chinese herbal medicines (CHMs) may enhance the efficacy of HIFU, but a comprehensive evaluation of their combined effects is lacking.</div></div><div><h3>Aim</h3><div>To evaluate the effectiveness of CHMs combined with HIFU for UFs through a meta-analysis on randomised controlled trials (RCTs) and identify core herbal patterns that may potentiate HIFU outcomes.</div></div><div><h3>Materials and methods</h3><div>English and Chinese databases were searched to identify relevant studies until May 2024. The risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. A meta-analysis was performed using RevMan 5.4 software. The primary outcomes were changes in UF volume and clinical efficacy; secondary outcomes were changes in uterus volume, Traditional Chinese Medicine syndrome scores, incidence of recurrences and adverse reactions. Network analysis was performed to identify core herbs.</div></div><div><h3>Results</h3><div>Nineteen RCTs were included. The effects of reducing UFs volumes in the CHM group were more significant than those in the control group (SMD:0.34; 95 % CI:0.44 to -0.23, <em>p</em> &lt; 0.001, I² = 0 %). The clinical effectiveness rate was higher in the CHM group than with HIFU therapy alone (risk ratio: 1.13; 95 % CI: 1.08 to 1.18; <em>p</em> &lt; 0.001; I² = 37 %). Core pattern analysis revealed a total of 26 single herbs and 93 commonly used herbal combinations. Among these, Curcumae Rhizoma, Sparganii Rhizoma, Astragalus membranaceus, Poria cocos, Paeonia suffruticosa, and Trionyx sinensis were the most frequently utilized herbs.</div></div><div><h3>Conclusions</h3><div>This is the first meta-analysis to evaluate the clinical effectiveness of combining CHMs with HIFU for UFs, integrating both quantitative outcome and computational core herb pattern analyses to identify CHMs that may enhance the efficacy of HIFU. In addition to demonstrating superior clinical effectiveness, this study proposes a novel hypothesis: core CHMs may enhance HIFU efficacy through a dual-phase mechanism—promoting apoptosis during thermal ablation and modulating fibrotic and proliferative signaling pathways in the post-ablation phase. These findings provide an evidence-based foundation for developing integrated therapeutic strategies.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"143 ","pages":"Article 156811"},"PeriodicalIF":6.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927810","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}