Phytomedicine最新文献

{"title":"Edaravone dexborneol exerts anti-epileptic effects on rodent temporal lobe epilepsy by promoting NMDAR deactivation and inhibiting oxidative stress","authors":"Wanhua Qiu ,&nbsp;Roumeng Chen ,&nbsp;Lechen Pan ,&nbsp;Yiqian Li ,&nbsp;Yuchen Xu ,&nbsp;Yuqian Li ,&nbsp;Ang Guo ,&nbsp;Wenting Huang ,&nbsp;Tao Tan ,&nbsp;Peijun Li ,&nbsp;Chenglong Xie ,&nbsp;Huiqin Xu ,&nbsp;Li Lin ,&nbsp;Xinshi Wang","doi":"10.1016/j.phymed.2025.156558","DOIUrl":"10.1016/j.phymed.2025.156558","url":null,"abstract":"<div><h3>Background</h3><div>Disease-modifying treatments with anti-epileptic effects are currently unavailable and urgently required for temporal lobe epilepsy (TLE). Combined therapy targeting multiple mechanisms may offer a promising anti-epileptic strategy, given the complex processes underlying epileptogenesis.</div></div><div><h3>Purpose</h3><div>This study evaluates the effects of Edaravone Dexbroneol, a combination of Edaravone and Dexborneol in 4:1, on rat and mouse TLE models and an in vitro epileptiform activity model.</div></div><div><h3>Methods</h3><div>The Pilocarpine-induced rat TLE model and the Kainic acid-induced mouse TLE model were used to assess the in vivo effect of Edaravone and/or Dexbornel. Primary neurons were utilized to evaluate the in vitro effect of drugs using calcium imaging, electrophysiological and biochemical analyses, as well as RNA sequencing.</div></div><div><h3>Results</h3><div>Treatment of Edaravone Dexbornel during the latent period significantly alleviated epileptic seizures in rodents, mitigated cognitive impairment, and inhibited neuronal loss and astrocytic activation. In vitro, Edaravone Dexborneol inhibited the action potentials and protected primary hippocampal neurons from Mg²⁺-free-induced neurite injury. All these effects were significantly more pronounced in the group treated with the Edaravone Dexborneol mixture compared to either drug used individually. Furthermore, Edaravone can significantly inhibit Mg²⁺-free-induced calcium oscillations in primary neurons, probably by promoting the deactivation of NMDA receptors. RNA sequencing and RT-PCR analysis revealed that synergetic regulation of lipid metabolism, oxidative stress, apoptosis, and calcium signaling probably underlay the neuroprotective effect of Edaravone Dexbornel on epileptic neurons.</div></div><div><h3>Conclusion</h3><div>Edaravone Dexborneol exhibits antiepileptic effects and may fill the gap in disease-modifying treatments for TLE.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"140 ","pages":"Article 156558"},"PeriodicalIF":6.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550270","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":"Ginseng in delaying brain aging: Progress and Perspectives","authors":"Jingwen Niu ,&nbsp;Guoqi Zhu ,&nbsp;Junjie Zhang","doi":"10.1016/j.phymed.2025.156587","DOIUrl":"10.1016/j.phymed.2025.156587","url":null,"abstract":"<div><h3>Background</h3><div>The <em>Shennong Bencao Jing</em> (Shennong's Classic of Materia Medica) records that <em>Panax ginseng</em> C. A. Mey (ginseng) ‘lightens the body and prolongs life’. Many investigations have documented that ginseng exerts neuroprotective effects by mitigating the aging of the brain. However, a comprehensive review of the impacts of ginseng on brain aging remains lacking.</div></div><div><h3>Purpose</h3><div>This study aims to review the advances in ginseng research regarding its role in delaying brain aging, focusing on its bioactive constituents, underlying mechanisms and potential side effects. The findings provide scientific pieces of evidence to support the medical utilization of ginseng in the delaying senescence and the management of aging-related diseases.</div></div><div><h3>Methods</h3><div>This review includes studies on ginseng and brain aging in humans, retrieved from English-language research articles published between 2017 and the present in the PubMed and Web of Science databases. The work focused on ginseng, brain aging, and aging-related diseases, utilizing keywords such as “Ginseng”, “Brain aging”, “central nervous system”, “intracellular homeostasis”, “peripheral system”, <em>etc</em>.</div></div><div><h3>Results</h3><div>Ginseng comprises a varied spectrum of biologically bioactive constituents, such as ginsenosides, Maillard reaction products, ginseng polysaccharides, volatile oils, amino acids, proteins, <em>etc</em>. These components work to contribute to their significant medicinal value. Based on the traditional Chinese medicine (TCM) theory that “the heart and brain are interconnected, the liver and brain are mutually supportive, the brain and spleen are related, the brain and lung are linked, and the brain and kidney work in harmony,” we summarize that ginseng may sustain neural homeostasis through both central and peripheral perspectives. Additionally, the potential toxic side effects of ginseng are minimal.</div></div><div><h3>Conclusion</h3><div>Ginseng and its bioactive constituents exhibit considerable promise in delaying brain aging and treating neurodegenerative diseases. Future research should prioritize exploring the direct targets of ginseng and its active ingredients, and work toward establishing precise drug-target-efficacy relationships. This approach will facilitate the translation of these findings into clinically viable therapeutic approaches.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"140 ","pages":"Article 156587"},"PeriodicalIF":6.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549432","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":"13-Methylpalmatine alleviates bleomycin-induced pulmonary fibrosis by suppressing the ITGA5/TGF-β/Smad signaling pathway","authors":"Qin Mao ,&nbsp;Jiajing Liu ,&nbsp;Yu Yan ,&nbsp;Gang Wang ,&nbsp;Miao Zhang ,&nbsp;Zhuo Wang ,&nbsp;Xiaowei Wen ,&nbsp;Zefeng Jiang ,&nbsp;Haijing Li ,&nbsp;Jing Li ,&nbsp;Mingyang Xu ,&nbsp;Rong Zhang ,&nbsp;Baofeng Yang","doi":"10.1016/j.phymed.2025.156545","DOIUrl":"10.1016/j.phymed.2025.156545","url":null,"abstract":"<div><h3>Background</h3><div>Idiopathic pulmonary fibrosis (IPF) is an irreversible lung disease for which there is a lack of effective and safe therapeutic drugs. 13-Methylpalmatine (13-Me-PLT) is an active compound from <em>Coptis chinensis</em>, and no study has yet been reported on its pharmacological effects in pulmonary fibrotic diseases. The group has previously demonstrated the antimyocardial fibrosis efficacy of 13-Me-PLT but its effect on pulmonary fibrosis and its potential mechanism has not yet been investigated.</div></div><div><h3>Purpose</h3><div>The present research is designed to clarify the therapeutic potential and mechanism of action of 13-Me-PLT in IPF using a bleomycin (BLM)-induced mouse model of IPF.</div></div><div><h3>Methods</h3><div><em>In vivo</em>, mice were administrated with BLM to establish the IPF model, and IPF mice were treated with 13-Me-PLT (5, 10, and 20 mg/kg) and pirfenidone (PFD, 300 mg/kg) by gavage. <em>In vitro</em>, we employed TGF-β1 (10 ng/ml)-induced MRC5 cells, which were then treated with 13-Me-PLT (5, 10, 20 μM) and PFD (500 μM). High-throughput transcriptome sequencing, molecular dynamics simulations, molecular docking and Surface plasmon resonance (SPR) were employed to elucidate the underlying mechanisms of 13-Me-PLT in mitigating IPF.</div></div><div><h3>Result</h3><div><em>In vivo</em> experiments showed that 13-Me-PLT significantly ameliorated BLM-induced lung fibrosis in mice. <em>In vitro</em> studies, 13-Me-PLT showed good antifibrotic potential by inhibiting fibroblast differentiation. Transcriptomic analysis of mouse lung tissues identified ITGA5 and TGF-β/Smad signaling pathways as key targets for the antifibrotic effects of 13-Me-PLT. Molecular docking and kinetic analyses further supported these findings. Functional studies involving ITGA5 silencing and overexpression confirmed that 13-Me-PLT down-regulated ITGA5 expression and inhibited the activation of the TGF-β/Smad signaling pathway, confirming its mechanism of action.</div></div><div><h3>Conclusion</h3><div>To our best knowledge, these results provide the first insight that 13-Me-PLT is protective against BLM-induced IPF in mice. Unlike existing antifibrotic drugs, 13-Me-PLT specifically targets the ITGA5/TGF-β/Smad signaling pathway, offering a novel and potentially more effective therapeutic approach. This study not only validates the antifibrotic efficacy of 13-Me-PLT but also elucidates its unique mechanism of action, these findings may provide an opportunity to develop new drugs to treat IPF.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"140 ","pages":"Article 156545"},"PeriodicalIF":6.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apigenin ameliorates inflamed ulcerative colitis by regulating mast cell degranulation via the PAMP-MRGPRX2 feedback loop","authors":"Yihan Huang ,&nbsp;Na Wang ,&nbsp;Xiaolan Ji ,&nbsp;Shiqiong Luo ,&nbsp;Ling Gong ,&nbsp;Chenrui Zhao ,&nbsp;Guodong Zheng ,&nbsp;Rui Liu ,&nbsp;Tao Zhang","doi":"10.1016/j.phymed.2025.156564","DOIUrl":"10.1016/j.phymed.2025.156564","url":null,"abstract":"<div><h3>Purpose</h3><div>The aim of this study was to investigate the therapeutic effect of API on UC via the regulation of PAMP-MRGPRX2-mediated mast cells (MCs) degranulation.</div></div><div><h3>Background</h3><div>The pro-inflammatory positive feedback loop mediated by Mas-related G-protein-coupled receptor X2 (MRGPRX2) and its endogenous ligand, PAMP-12, is associated with ulcerative colitis (UC) progression. However, the therapeutic strategies that target MRGPRX2 in the treatment of UC are less reported. Apigenin (API), a natural flavonoid, can relieve inflammation.</div></div><div><h3>Method</h3><div>A dextran sodium sulfate (DSS)-induced mouse UC model was used to elucidate the therapeutic effects of API. Animal behavior assessment, serological assays, and histological analysis were performed in wild-type (WT) and MC MrgprB2-conditional knockout (CKO) mouse model. mRNA sequencing analysis, PCR, ELISA, and western blotting were performed <em>in vitro</em> and <em>in vivo</em> to elucidate the mechanism underlying the effect of API by a PAMP-12 triggered MC degranulation model.</div></div><div><h3>Results</h3><div>MC degranulation via MrgprB2 was critical for the persistence of inflammation in colitis. API attenuated colonic tissue damage, splenomegaly, and myeloperoxidase (MPO) activity in the colonic tissues. It also ameliorated colonic crypt structure damage and inflammatory cell infiltration. Moreover, API suppressed MCs degranulation, and the level of carboxypeptidases A3 (CPA3), in DSS-induced colitis, thereby blocking the pro-inflammatory positive feedback loop induced by PAMP-MrgprB2. Lastly, API effectively inhibited PAMP-12-triggered mast cell degranulation by regulating Akt1/XBP-1S/CHOP/TXNIP and NF-κB/IL-1β signaling pathways.</div></div><div><h3>Conclusion</h3><div>API alleviates inflammatory symptoms in UC by suppressing PAMP-MRGPRX2/B2 mediated MC sustained degranulation feedback loop.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"140 ","pages":"Article 156564"},"PeriodicalIF":6.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549533","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":"Draconis Sanguis (DS) from the fruit of Daemonorops draco Bl. ameliorates cardiac function through optimizing myocardial energy metabolism by promoting angiogenesis in ischemic heart failure","authors":"Junjun Li ,&nbsp;Boyang Jiao ,&nbsp;Keyan Wang ,&nbsp;Shungang Jiao ,&nbsp;Ran Wang ,&nbsp;Ying Sun ,&nbsp;Lingwen Cui ,&nbsp;Xiangning Liu ,&nbsp;Yujie Pei ,&nbsp;Pengfei Tu ,&nbsp;Jun Li ,&nbsp;Chun Li","doi":"10.1016/j.phymed.2025.156583","DOIUrl":"10.1016/j.phymed.2025.156583","url":null,"abstract":"<div><h3>Backgroud</h3><div>Draconis Sanguis (DS), a precious traditional Chinese medicine for activating blood and dissolving stasis, has been used in treating ischemic cardiovascular diseases. However, the underlying mechanism of DS against heart failure after myocardial ischemia (MI) remains unclear, especially concerning angiogenesis and energy metabolism, which have never been elucidated.</div></div><div><h3>Purpose</h3><div>This study aimed to explore the protective mechanism of DS in ischemic heart failure (IHF) from the perspectives of angiogenesis and energy metabolism.</div></div><div><h3>Methods</h3><div>We investigated the effects of DS on an <em>in vivo</em> model of IHF induced by ligation of the left anterior descending coronary artery (LADCA) and an <em>in vitro</em> model of HUVECs injury induced by hypoxia. High-performance liquid chromatography (HPLC) was performed to identify components of DS. Echocardiography, histopathology, and cardiac enzymes analysis were used to examine the anti-ischemic heart failure effect of DS. Transcriptome sequencing, positron emission tomography (PET), HPLC, and chocardiography were performed on heart tissues to explore the underlying mechanism. Furthermore, the relevant targets were investigated by real-time quantitative PCR (RT-qPCR), Western blotting, immunohistochemistry, and immunofluorescence. Finally, potential pharmacodynamic substances were identified with a cell model and molecular docking.</div></div><div><h3>Results</h3><div>The results showed DS increased survival of rats with IHF for 28 days by 10 %, significantly ameliorated cardiac function in rats with IHF, increased left ventricular ejection fraction by 20 %, and it reduced pathological changes and cardiac enzymes levels. These results indicated that DS alleviated myocardial ischaemia injury. The effects described above were related to the regulation of the HIF-1α/VEGF signallings pathway to promote angiogenesis in the ischemic myocardium, increase the local oxygen supply and optimize myocardial energy metabolism \"promoting lipid and inhibiting glucose\" and increasing local ATP production. Moreover, DS compounds were identified; these compounds protected HUVECs from hypoxia and glucose deprivation, significantly upregulated HIF-1α gene expression, and were shown to be related to this mechanism <em>in vitro</em> experiments.</div></div><div><h3>Conclusions</h3><div>DS ameliorates cardiac function by optimizing myocardial energy metabolism after promoting angiogenesis via HIF-1α/VEGF signalling pathway regulation.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"140 ","pages":"Article 156583"},"PeriodicalIF":6.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating untargeted/targeted metabolomics and network pharmacology association analysis to study the mechanism of safflower regulating C18:0 sphingolipid metabolism to treat acute myocardial ischemia","authors":"Zhixin Jia ,&nbsp;Cong Fang ,&nbsp;Mingxia Pan ,&nbsp;Ping Zhang ,&nbsp;Hua Yan ,&nbsp;Jia Chen ,&nbsp;Mengjiao Liu ,&nbsp;Xianlong Cheng ,&nbsp;Feng Wei","doi":"10.1016/j.phymed.2025.156594","DOIUrl":"10.1016/j.phymed.2025.156594","url":null,"abstract":"<div><h3>Background</h3><div>Safflower extract (SE) has been reported to treat acute myocardial ischemia (AMI); however, its underlying mechanism remains unclear.</div></div><div><h3>Purpose</h3><div>To investigate the ameliorative effects of SE on rats with AMI and the underlying mechanism.</div></div><div><h3>Methods</h3><div>UPLC-Q-TOF-MS/MS method was used to analyze the drug-derived components in the serum of rats following SE administration. We treated the ISO-induced rat model of AMI with different doses. Echocardiography and histopathology (HE staining) were used to evaluate the effect, alongside biochemical parameters. SE medicinal serum (SEMS) was used to assess its protective effect on H9C2 cells against hypoxic reoxygenation injury <em>in vitro</em>. We explored the mechanism of SE in improving AMI through non-targeted metabolomics combined with network pharmacological analysis based on <em>in vivo</em> components, and further integrated with targeted sphingolipomics. RT-qPCR was used to evaluate the gene expression levels of the key enzymes involved in ceramide synthesis (CERS1 and CERS4).</div></div><div><h3>Results</h3><div>Nineteen compounds were identified following oral administration of SE. Echocardiography showed that different doses of SE significantly improved cardiac function in AMI rats. The serum levels of CK, HBDH, AST, LDH, and SOD were significantly reduced in AMI rats. HE staining results showed that SE significantly improved pathological injury in AMI rats. <em>In vitro</em> experiments results showed that SEMS protects against OGD/R injury in H9C2 cells. Non-targeted metabolomics and network pharmacology results indicated that SE regulates glycosphingolipid and glycerophospholipid metabolism to improve acute myocardial ischemic injury. Targeted sphingolipomics have shown that SE had significant regulatory effects on 18:0 acyl-chain ceramides, dihydroceramides, 1-phosphorylated ceramides, glycosylated ceramides, Sph and S1P. RT-qPCR results showed that SE significantly down-regulates the expression of mCERS4.</div></div><div><h3>Conclusions</h3><div>SE significantly improves AMI in rats, with the mechanism related to the regulation of CERS4 and then the modulation of C18:0 sphingolipid metabolism.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"140 ","pages":"Article 156594"},"PeriodicalIF":6.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549433","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":"Novel anti-inflammatory compounds that alleviate experimental autoimmune encephalomyelitis","authors":"Mengjiao Sun ,&nbsp;Ning Liu ,&nbsp;Jing Sun ,&nbsp;Wenjing Zhang ,&nbsp;Panpan Gong ,&nbsp;Manxia Wang ,&nbsp;Zhenxing Liu","doi":"10.1016/j.phymed.2025.156544","DOIUrl":"10.1016/j.phymed.2025.156544","url":null,"abstract":"<div><h3>Background</h3><div>Multiple sclerosis (MS) is an autoimmune disease primarily characterized by inflammatory demyelination. Despite significant research efforts, effective therapies for MS remain limited. Drug screening offers a promising approach to rapidly identifying potential therapeutic compounds.</div></div><div><h3>Purpose</h3><div>This study aimed to screen compounds that can exert anti-inflammatory effects and alleviate experimental autoimmune encephalomyelitis (EAE), an animal model of MS.</div></div><div><h3>Study design</h3><div>A fundamental research <em>in vitro</em> and <em>in vivo</em>. A high-throughput screen was performed to screen drugs that can mitigate EAE and the molecular mechanism was explored.</div></div><div><h3>Methods</h3><div>Based on our previous research highlighting the crucial role of AXL, a receptor tyrosine kinase, in microglial function, we constructed an AXL-GFP reporter gene in BV2 microglia cells. A high-throughput screen of an FDA-approved compound library was performed to identify potential AXL-targeting compounds. The effects of candidate compounds on cellular morphology, cell cycle, apoptosis, mitochondrial function, inflammatory cytokine production, polarization, and phagocytic activity of BV2 cells were assessed. To investigate the <em>in vivo</em> effects of AXL modulation, EAE mice were generated. AXL was either upregulated using recombinant Gas6 protein or knocked out using CRISPR/Cas9. The impact of AXL modulation on disease progression and underlying molecular mechanisms was explored.</div></div><div><h3>Results</h3><div>Primary and secondary screenings identified three potential AXL-targeting compounds: Betulin, Clofibric acid, and Isosorbide. Molecular docking analysis revealed that Isosorbide exhibited poor binding affinity with AXL at the molecular level and was excluded from further studies. Betulin and Clofibric acid were found to promote M2 polarization, reduce inflammation, enhance phagocytosis, extend the S phase of the cell cycle, inhibit apoptosis, and improve mitochondrial structure in BV2 cells. <em>In vivo</em> studies demonstrated that Betulin (20 mg/kg) alleviated EAE, while <em>AXL</em> gene knockout reversed its protective effects.</div></div><div><h3>Conclusion</h3><div>This study elucidates the molecular mechanism underlying Betulin's therapeutic effects in MS, both <em>in vitro</em> and <em>in vivo</em>. Betulin exerts its beneficial effects by upregulating the AXL/SOCS3 pathway and inhibiting the JAK2/STAT1 signaling pathway. These findings suggest that Betulin holds significant promise as a potential therapeutic agent for multiple sclerosis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156544"},"PeriodicalIF":6.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512679","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":"Liang-Ge-San attenuates virus-induced acute lung injury by targeting FXR-mediated ACE2 downregulation to modulate the formation of the cytokine storm","authors":"Liling Yang ,&nbsp;Xiangjun Zhou ,&nbsp;Junshan Liu ,&nbsp;Guangli Yang ,&nbsp;Jingtao Yu ,&nbsp;Weifu Tan ,&nbsp;Xiaochuan Fang ,&nbsp;Wei Li ,&nbsp;Jiayang He ,&nbsp;Qinhai Ma ,&nbsp;Linzhong Yu ,&nbsp;Zibin Lu","doi":"10.1016/j.phymed.2025.156584","DOIUrl":"10.1016/j.phymed.2025.156584","url":null,"abstract":"<div><h3>Background</h3><div>Traditional Chinese medicine has been recognized for its significant role in treating acute lung injury (ALI) due to its distinct therapeutic advantages. Liang-Ge-San (LGS), a formulation from the ancient “Taiping Huimin Hejiju Fang”, is believed to possess beneficial effects for treating ALI. However, LGS's precise mechanisms and efficacy in addressing viral ALI remain inadequately explored.</div></div><div><h3>Purpose</h3><div>To evaluate LGS's therapeutic effects and underlying mechanisms in treating viral-induced ALI.</div></div><div><h3>Methods</h3><div>The protective effects of LGS were examined in a Polyinosinic-polycytidylic acid [Poly(I:C)]-induced ALI model using real-time quantitative PCR, enzyme-linked immunosorbent assay, and histopathological analysis. A bioinformatics approach combined with network pharmacology was utilized to ascertain the key targets of LGS in viral pneumonia. The pharmacodynamic mechanisms of LGS in viral ALI were further validated through immunofluorescence, overexpression, short hairpin RNA, chromatin immunoprecipitation, and target agonist assays.</div></div><div><h3>Results</h3><div>LGS administration resulted in a reduction of IL-1β, IL-6, and TNF-α levels, along with a decrease in macrophage infiltration, pulmonary damage, and pneumonedema following the Poly(I:C) challenge. Bioinformatics and network pharmacology analyses suggested that Farnesyl X receptor (FXR) and angiotensin converting enzyme 2 (ACE2) are potential therapeutic targets for LGS in viral pneumonia. Further experiments revealed that LGS suppressed the expression of FXR, ACE2, and NF-κB-p65 in Poly(I:C)-infected cells. Notably, overexpression of FXR counteracted the repressive effects of LGS, while ACE2 expression remained unchanged in FXR-knockdown RAW264.7 cells upon treatment with Poly(I:C) or LGS. Additionally, LGS inhibited the interaction between FXR and ACE2 transcriptional promoters. <em>In vivo</em>, LGS attenuated the Poly(I:C)-induced upregulation of FXR, ACE2, IL-1β, IL-6, and TNF-α in ALI zebrafish and mice models, effects that could be reversed by chenodeoxycholic acid (CDCA), an FXR agonist. Moreover, LGS markedly alleviated weight loss, improved survival rates, reduced lung index, diminished viral load, and inhibited lung pathological changes in H1N1-PR8-induced ALI mice. IL-1β, IL-6, TNF-α, INF-γ, FXR, ACE2, small heterodimer partner, and NF-κB-p65 levels were markedly reduced by LGS, with these effects being reversed by CDCA.</div></div><div><h3>Conclusion</h3><div>This investigation provides the first evidence that FXR/ACE2 signaling is pivotal in acute respiratory viral infections, while LGS demonstrates antiviral activity against viral-induced ALI. LGS inhibits ACE2 expression induced by viral infection via FXR inhibition and modulates the cytokine storm, thus alleviating viral ALI. These findings suggest that LGS may be a promising treatment strategy for treating viral ALI.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"140 ","pages":"Article 156584"},"PeriodicalIF":6.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578311","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":"Toosendanin-induced liver damage through irreparable DNA damage and autophagy flow blockade","authors":"Yifan Lin ,&nbsp;Jian Zhang ,&nbsp;Xinyue Gao ,&nbsp;Zekai Wu ,&nbsp;Lele Yang ,&nbsp;Kun Tian ,&nbsp;Xiaoqi Lv ,&nbsp;Jiaqi Li ,&nbsp;Kunqi Chen ,&nbsp;Youbo Zhang ,&nbsp;Hong Hu ,&nbsp;An Zhu","doi":"10.1016/j.phymed.2025.156586","DOIUrl":"10.1016/j.phymed.2025.156586","url":null,"abstract":"<div><h3>Objective</h3><div>The fruit of <em>Melia toosendan</em> Sieb. et Zucc<em>.</em> (MT) is known for its efficacy in relieving pain and treating roundworms. Toosendanin (TO) has been identified as a bioactive marker of MT, with hepatotoxic properties. This study offers a comprehensive investigation into the toxic mechanisms, involving TO-induced remaining DNA damage, cell cycle arrest, and the synergistic effect of autophagy flow disruption. It provides new insights into the clinical applications of MT and TO.</div></div><div><h3>Methods</h3><div>TO was prepared at 50, 100, and 200 μM for a 48 h treatment of HepG2 cells, while zebrafish were administered at 50, 75, and 100 μM for 72 h. Transcriptomics and computational molecular simulations, including network pharmacology, molecular docking, and molecular dynamics simulation, were used for target prediction. Fluorescent probes, flow cytometry, quantitative real-time polymerase chain reaction, and western blotting were employed for mechanism verification.</div></div><div><h3>Results</h3><div>TO disrupted the balance between reactive oxygen species and cellular antioxidant defense, resulting in mitochondrial damage and repression of DNA-dependent protein kinase catalytic subunit. This led to the inability to repair DNA damage and caused cell cycle arrest in the G1/S phase. As shown in computational molecular simulations and transcriptomics analysis, the repression of damaged organelle removal through autophagy flow disruption resulted in excessive injury and hepatocyte death.</div></div><div><h3>Conclusion</h3><div>By impairing DNA damage responses (DDRs) and autophagy, TO causes unrepaired DNA damage, which disrupts cell cycle progression through complex interactions with cyclin proteins and tumour suppressor genes, ultimately contributing to hepatotoxicity.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"140 ","pages":"Article 156586"},"PeriodicalIF":6.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginsenoside CK inhibits EMT and overcomes oxaliplatin resistance in gastric cancer by targeting the PI3K/Akt pathway","authors":"Li Zhang,&nbsp;Xiao-Lan Zhao,&nbsp;Zhang-Jing Cao,&nbsp;Ke-Di Li,&nbsp;Li-Yue Xu,&nbsp;Fei Tang,&nbsp;Jing-Nan Zhang,&nbsp;Cheng Peng,&nbsp;Hui Ao","doi":"10.1016/j.phymed.2025.156516","DOIUrl":"10.1016/j.phymed.2025.156516","url":null,"abstract":"<div><h3>Background</h3><div>Gastric cancer remains a leading cause of cancer mortality, with oxaliplatin (L-OHP) resistance posing a major therapeutic challenge. Ginsenosides have shown potential in addressing chemoresistance.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate whether ginsenoside Compound K (CK), a derivative of protopanaxadiol ginsenosides, could overcome L-OHP resistance in gastric cancer cells.</div></div><div><h3>Methods</h3><div>The anti-cancer effects of CK were investigated using L-OHP-resistant HGC27/L cells through comprehensive in vitro experiments. Cell viability, migration, invasion, apoptosis, and colony formation were evaluated under CK treatment alone or combined with L-OHP. Drug efflux was specifically assessed using Rhodamine 123 staining. To understand the molecular mechanism, network pharmacology and molecular docking analyses were employed, which identified the PI3K/Akt pathway as a crucial target of CK. This finding was further validated through Western blotting and RT-qPCR analyses, focusing on PI3K/Akt signaling components and EMT markers. Finally, drug-resistant gastric cancer xenograft models were established to evaluate the therapeutic efficacy of CK alone and in combination with L-OHP in vivo.</div></div><div><h3>Results</h3><div>CK effectively suppressed cell viability, migration, invasion, drug efflux, and colony formation while enhancing apoptosis in resistant cells. Mechanistically, CK inhibited the PI3K/Akt pathway, leading to reduced P-glycoprotein (P-gp) expression and EMT reversal. These effects were confirmed using PI3K pathway modulators. In xenograft models, CK significantly inhibited tumor growth and reduced PI3K/Akt activity, P-gp expression, and EMT markers.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that CK overcomes L-OHP resistance through PI3K/Akt pathway inhibition and EMT prevention, suggesting that combining CK with L-OHP may improve outcomes in chemoresistant gastric cancer patients.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"140 ","pages":"Article 156516"},"PeriodicalIF":6.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563526","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}