Phytomedicine最新文献

{"title":"Efficacy and safety of yangxinshi versus trimetazidine on exercise tolerance in patients with coronary heart disease after percutaneous coronary intervention: Multicenter, double-blind clinical trial.","authors":"Yang Li, Yi Li, Zhijie Zhang, Jian Zhang, Hong Chen, Haichu Yu, Xiaoping Meng, Haitao Yuan, Lili Shao, Yan Lu, Bin Liu, Jiayao Xu, Yi Zhang, Jing Li, Yaling Han","doi":"10.1016/j.phymed.2024.156198","DOIUrl":"10.1016/j.phymed.2024.156198","url":null,"abstract":"<p><strong>Background: </strong>Optimizing medication to improve exercise tolerance in patients with coronary heart disease (CHD) after percutaneous coronary intervention (PCI) is limited. Yangxinshi tablets, an herbal-based oral medicine, relieve symptoms of angina might be that they can improve energy metabolism of the ischemic myocardium. We conducted a randomized trial to assess the efficacy and safety of Yangxinshi vs. trimetazidine in improving exercise tolerance in patients with CHD after PCI.</p><p><strong>Methods: </strong>This prospective, randomized, double-blind, double-dummy, multicenter, non-inferiority study enrolled patients aged 18-75 years with CHD who underwent their first PCI within 2 months of diagnosis. Patients were randomized to Yangxinshi plus trimetazidine-placebo or trimetazidine plus Yangxinshi-placebo for 24 weeks. The primary endpoint was the change in metabolic equivalents (METs) assessed by cardiopulmonary exercise test (CPET) between 0 and 24 weeks. Secondary endpoints were comprehensive variables of the CPET, health status and adverse events. This study has been registered at ClinicalTrials. gov (NCT03809273).</p><p><strong>Results: </strong>Between August 1, 2019, and March 31, 2022, a total of 681 patients were randomized to Yangxinshi (n = 341) or trimetazidine (n = 340). After 24 weeks, the exercise tolerance of patients increased by 0.77±1.25 METs in the Yangxinshi group and 0.76±1.00 METs in the trimetazidine group (difference, 0.01; 95 % confidence interval [CI], -0.17 to 0.19), meeting the predefined non-inferiority threshold. Better outcomes were observed in the Yangxinshi group compared with the trimetazidine group for patient-reported depression (PHQ-9; -1.88±3.32 vs. -0.93±3.68; p < 0.001) and anxiety (GAD-7; -1.70±3.26 vs. -0.39±3.29; p < 0.001). Adverse events were similar in both groups.</p><p><strong>Conclusions: </strong>In patients with CHD after PCI, Yangxinshi was non-inferior to trimetazidine in improving exercise tolerance during the 24-week treatment period. Notably, patients in the Yangxinshi group showed a better mental health profile compared with trimetazidine recipients.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156198"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682545","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":"Bushen Huoxue Yiqi formula alleviates cardiac fibrosis in ischemic heart failure through SIRT1/Notch1 pathway-mediated EndMT.","authors":"Cong Chen, Jie Wang, Chengzhi Hou, Wenjing Lian, Xueying Zhu, Jun Hu, Chao Liu","doi":"10.1016/j.phymed.2024.156252","DOIUrl":"10.1016/j.phymed.2024.156252","url":null,"abstract":"<p><strong>Background: </strong>Cardiac fibrosis plays a crucial role in the development of heart failure (HF) following myocardial infarction (MI). Endothelial-mesenchymal transition (EndMT) is one of the key drivers of cardiac fibrosis and subsequent cardiac dysfunction. The traditional Chinese medicine formula Bushen Huoxue Yiqi Formula (BHYF) is an effective prescription for treating HF, significantly improving cardiac function in patients. However, the underlying mechanisms of BHYF's efficacy remain inadequately understood.</p><p><strong>Objective: </strong>This study aims to determine whether BHYF ameliorates HF by inhibiting cardiac fibrosis and to elucidate the intrinsic mechanisms involved.</p><p><strong>Methods: </strong>A post-MI HF model was established by ligating the left anterior descending coronary artery in rats, and human umbilical vein endothelial cells (HUVEC) were stimulated with hypoxia/reoxygenation (H/R) in vitro. Active compounds in BHYF were identified using HPLC. Cardiac function and morphology were assessed using echocardiography, TTC staining, HE staining, Masson's trichrome, and Sirius Red staining. The mechanism of action of BHYF was evaluated using Western blotting, immunohistochemistry, and immunofluorescence.</p><p><strong>Results: </strong>A total of 98 compounds, including glycosides, phenolic compounds, carboxylic acids, and others, were identified or preliminarily identified. BHYF improved cardiac function and myocardial damage in rats with MI-induced HF and mitigated cardiac fibrosis by inhibiting EndMT. Mechanistically, BHYF treatment inhibited EndMT by modulating the SIRT1/Notch1 pathway, thereby exerting anti-fibrotic effects in the heart.</p><p><strong>Conclusion: </strong>Targeting EndMT based on the SIRT1/Notch1 pathway, BHYF may represent a novel antifibrotic therapeutic strategy, providing a scientific basis for the development of new cardiovascular drugs.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156252"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682486","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":"Isoliquiritin targeting m5C RNA methylation improves mitophagy in doxorubicin-induced myocardial cardiotoxicity.","authors":"Jiaqi Fu, Li Cheng, Jie Zhang, Runjie Sun, Manya Yu, Muyun Wu, Suzhen Li, Xing Cui","doi":"10.1016/j.phymed.2024.156293","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156293","url":null,"abstract":"<p><strong>Background: </strong>Doxorubicin (DOX)-induced myocardial cardiotoxicity (DIC) severely limits its clinical application, and there is no optimal therapeutic agent available. Recent studies revealed that activation of BNIP3-mediated mitophagy and the inhibition of m5C RNA methylation played a crucial role in DIC. Isoliquiritin (ISL) has remarkable cardiac protective effect. But its potential mechanisms against DIC still remains unknown.</p><p><strong>Purpose: </strong>To investigate the therapeutic effect and potential mechanism of Isoliquiritin(ISL) on doxorubicin(DOX)-induced myocardial cardiotoxicity(DIC).</p><p><strong>Methods: </strong>Bioinformatics analyses and network pharmacology were carried out to identify effective target of ISL against DIC. Molecular docking and surface-plasmon resonance (SPR) were used to confirm the predict. The mechanism of ISL regulating mitophagy through M5C methylation to improve DIC was demonstrated in vitro and in vivo experiments. The methylation modification was verified by MeRIP-qPCR. Cell model of DIC was constructed to evaluate mitochondrial function by measuring cell viability, myocardial enzyme level, mitochondrial quality, mCherry-EGFP analysis and TEM morphometry with the application of mitophagy inhibitor (Baf A1) and inducer (CCCP). Myocardial injury in mice with DIC was assessed by survival rate, myocardial enzyme level, HE staining, echocardiography and detection of mitophagy markers.</p><p><strong>Results: </strong>The decreased level of m5C writer TRDMT1 and mitochondrial marker (BNIP3) were chosen for the research. After the docking and SPR verification between ISL and TRDMT1, the improvement of ISL on TRDMT1 and TRDMT1-associated m5C level of BNIP3 was identified. In vitro and in vivo experiments showed that the cardiac markers, heart function, and mitochondrial function were recovered after ISL application. Meanwhile, the results manifested that there was blocked autophagy flow indicated by mCherry-EGFP analysis, then the suppressed mitophagy caused the mitochondria damage associated cell death. ISL could alleviate the autophagy block, and Baf A1 couldn't influnce the ISL effect. Compared to CCCP group, Mitochondrial maker TOMM20 significantly elevated treated with both CCCP and DOX, indicating that DOX impaired mitophagy for clearing damaged mitochondrial proteins. After ISL treated, a higher level of co-localization between mitochondrial and BNIP3 was observed, inducing restoration of mitochondrial function.</p><p><strong>Conclusion: </strong>This study showed that ISL may exert cardioprotective role restoring BNIP3-mediated mitophagy by targeting TRDMT1 to alleviate DOX-induced macro-autophagy-dependent protein homeostasis and acquired blocking of mitophagy, providing a new idea for the clinical treatment of DIC.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156293"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807583","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 combined treatment with Ursolic acid and Solasodine inhibits colorectal cancer progression through the AKT1/ERK1/2-GSK-3β-β-catenin axis.","authors":"Yiren Yang, Pengyu Liu, Yue Jin, Huilin Zhu, Miao Wang, Xiaowen Jiang, Huiyuan Gao","doi":"10.1016/j.phymed.2024.156068","DOIUrl":"10.1016/j.phymed.2024.156068","url":null,"abstract":"<p><strong>Background: </strong>Conventional chemotherapy medications are inadequate for managing the primary or acquired drug resistance, high toxicity, and adverse effects of colorectal cancer (CRC) treatment. Ursolic acid (UA) and Solasodine (Sol) are natural compounds found in a wide variety of traditional medicinal plants, as well as in many fruits and vegetables, such as Actinidia arguta (Sieb. & Zucc) Planch and Solanum nigrum L.. These compounds exhibit significant anti-tumor activity. Recent investigations have demonstrated that a combination strategy using natural products exhibits greater potential in CRC treatment compared to a single-drug strategy.</p><p><strong>Purpose: </strong>This study aimed to elucidate the potential of UA-Sol synergy against CRC and to investigate the mechanism of action involved in inducing apoptosis and inhibiting metastasis through the AKT1/ERK1/2-GSK-3β-β-catenin axis.</p><p><strong>Methods: </strong>The optimal ratio of UA-Sol and its synergistic effects were explored using an MTT assay combined with the technique of Chou Talalay. The effects of UA-Sol on the apoptosis, autophagy, and metastasis of CRC cells were assessed using Annexin V-FITC/PI, TUNEL, Immunofluorescence, Wound healing, Transwell migration, and western blotting. The core mechanism of action of UA-Sol against CRC was investigated employing network pharmacology prediction combined with CETSA and plasmid transfection. Finally, in vivo validation was conducted using mouse xenograft tumor and lung metastasis models.</p><p><strong>Results: </strong>The combination of UA and Sol synergistically inhibited CRC cell viability at a molar ratio of 6:24. UA-Sol induced the expression of pro-apoptotic and autophagy genes such as Bax/Bcl-2 and LC3, ultimately leading to apoptosis and autophagy in CRC cells in vitro. In addition, this combination inhibited MMP-9 and promoted the expression of the adhesion protein E-cadherin, thereby inhibiting CRC cell metastasis. Mechanistically, UA-Sol regulated the expression of a downstream protein GSK-3β by targeting AKT1 and ERK1/2 inhibition. This induced a cross-talk between the MAPK cascade pathway and the PI3K/AKT pathway, thereby inhibiting the nuclear translocation of β-catenin and participating in the regulation of CRC cell processes.</p><p><strong>Conclusion: </strong>UA-Sol inhibited the AKT1/ERK1/2-GSK-3β-β-catenin axis to induce apoptosis, autophagy and anti-metastasis by targeting AKT1 and ERK1/2 inhibition. This dual-target drug combination strategy provides promising insights into the development of novel, safe, and efficient drugs for the treatment of CRC.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156068"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606006","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":"Licorice-regulated gut-joint axis for alleviating collagen-induced rheumatoid arthritis.","authors":"Di Yang, Guangfu Lv, Yongxi Wu, Wentao Guo, Yuchen Wang, Jiannan Hu, Nian Li, Fei Zheng, Yulin Dai, Zifeng Pi, Hao Yue","doi":"10.1016/j.phymed.2024.156203","DOIUrl":"10.1016/j.phymed.2024.156203","url":null,"abstract":"<p><strong>Background: </strong>Rheumatoid arthritis (RA) is partially affected by the integrity of the intestinal barrier. Licorice (GC), a medicinal and food-related herb, exhibits potent anti-inflammatory activity; however, studies on its mechanisms of action in RA are limited.</p><p><strong>Method: </strong>Using a bovine type-II collagen-induced arthritis rat model, this study examined how GC influences the gut-joint axis to decrease RA. The Th17/Treg cell ratios in the blood, colon, and joints were also measured. Metabolomics and 16S rRNA sequencing were applied to explore the effects of variations in gut flora and metabolites.</p><p><strong>Results: </strong>The arthropathological slices, inflammation markers, and joint inflammation index scores in the GC treatment group significantly differed from those in the CIA group. Studies on the effect of GC on the gut-joint axis showed changes in the levels of lipopolysaccharide and diamine oxidase, both directly associated with intestinal permeability. ZO-1, occludin, and claudin-1, three intestinal tight-junction proteins, may express themselves more when exposed to GC. By maintaining an appropriate Th17/Treg cell ratio in the blood, colon, and joints, GC may reduce impaired to the intestinal barrier. An imbalance in the intestinal microenvironment, caused by modifications in gut flora and endogenous substances, can damage the intestinal barrier. GC may modify the relative abundances of Papillibacter, Clostridium, Eubacterium, Helicobacter, Provotella, and Barnesiella during RA treatment by repairing the intestinal barrier. The metabolic differences were mainly related to primary bile acid biosynthesis, pyrimidine metabolism, steroid biosynthesis, biotin metabolism, and sphingolipid metabolism. A fecal microbiota transplantation experiment confirmed the involvement of the gut microbiota and its metabolites in GC-mediated RA therapy.</p><p><strong>Conclusion: </strong>The results demonstrated that GC repairs the intestinal barrier and adjusts the gut-joint axis to manage immunological imbalance in RA.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156203"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606123","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":"Gnetupendin A protects against ischemic stroke through activating the PI3K/AKT/mTOR-dependent autophagy pathway.","authors":"Danyang Mu, Jingyu Liu, Yan Mi, Dequan Wang, Libin Xu, Yuxin Yang, Yueyang Liu, Dong Liang, Yue Hou","doi":"10.1016/j.phymed.2024.156233","DOIUrl":"10.1016/j.phymed.2024.156233","url":null,"abstract":"<p><strong>Background: </strong>Autophagy has been recently emerged as a prominent factor in the pathogenesis of ischemic stroke (IS) and is increasingly being considered as a potential therapeutic target for IS. Gnetum parvifolium has been identified as a potential therapeutic agent for inflammatory diseases such as rheumatism and traumatic injuries. However, the pharmacological effects of Gnetupindin A (GA), a stilbene compound isolated from Gnetum parvifolium, have not been fully elucidated until now.</p><p><strong>Objective: </strong>Here we identified the therapeutic potential of GA for IS, deeply exploring the possible mechanisms related to its regulation of autophagy.</p><p><strong>Methods: </strong>The mouse model of middle cerebral artery occlusion-reperfusion (MCAO/R) and the oxygen-glucose deprivation reperfusion (OGD/R)-exposed cells served as models to study the protection of GA against IS. The adeno-associated virus (AAV) encoding shAtg5, in conjunction with autophagy inhibitor 3-Methyladenine (3-MA) were utilized to explore the role of GA in regulating autophagy following IS. Molecular docking, CETSA, and DARTS were used to identify the specific therapeutic target of GA. PI3K inhibitor LY294002 was employed to test the participation of PI3K in GA-mediated autophagy and neuroprotective effects following IS.</p><p><strong>Results: </strong>Our findings revealed that treatment with GA significantly alleviated the brain infract volume, edema, improved neurological deficits and attenuated apoptosis. Mechanistically, we found that GA promoted autophagic flow both in vivo and in vitro after IS. Notably, neural-targeted knockdown of Atg5 abolished the neuroprotective effects mediated by GA. Inhibition of autophagy using 3-MA blocked the attenuation on apoptosis induced by GA. Moreover, molecular docking, CETSA, and DARTS analysis demonstrated that GA specifically targeted PI3K and further inhibited the activation of PI3K/AKT/mTOR signaling pathway. LY294002, which inhibits PI3K, reversed GA-induced autophagy and neuroprotective effects on OGD/R-treated cells.</p><p><strong>Conclusion: </strong>We demonstrated, for the first time, that GA protects against IS through promoting the PI3K/AKT/mTOR-dependent autophagy pathway. Our findings provide a novel mechanistic insight into the anti-IS effect of GA in regulating autophagy.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156233"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648377","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":"Targeting and degradation of OTUB1 by Erianin for antimetastasis in esophageal squamous cell carcinoma.","authors":"Yuan Zhu, Ningning Kang, Li Zhang, Jianju Tao, Wen Xue, Hui Li, Yingcan Li, Xucai Zheng, Wei He, Junting Ma","doi":"10.1016/j.phymed.2024.155969","DOIUrl":"10.1016/j.phymed.2024.155969","url":null,"abstract":"<p><strong>Background: </strong>Metastasis is a major contributor to mortality in patients with esophageal squamous cell carcinoma (ESCC); effective treatment is currently lacking. Erianin, a bioactive ingredient of traditional Chinese medicine, Dendrobium chrysotoxum, has anti-tumor activity against multiple human tumors. However, the effect and associated underlying mechanism of Erianin on ESCC antimetastasis remain unclear.</p><p><strong>Purpose: </strong>To investigate the anti-metastatic properties of Erianin in ESCC both in vitro and in vivo and associated molecular mechanisms.</p><p><strong>Methods: </strong>Wound healing assay, Transwell assay, CCK-8 assay, immunohistochemistry, and lung metastasis mouse model were carried out to examine ESCC cell migration and viability in vitro and in vivo. Drug affinity responsive target stability (DARTS), cellular thermal migration assay (CETSA), molecular docking, and Surface plasmon resonance (SPR) assay were used to confirm Erianin binding to ovarian tumor ubiquitin aldehyde-binding protein 1 (OTUB1) protein. Protein stability assay, cell transfection, and western blotting were used to confirm Erianin-mediated degradation of OTUB1 and Snail via the ubiquitin-proteasome pathway. qRT-PCR and western blotting were used to assess OTUB1expression in ESCC tissues.</p><p><strong>Results: </strong>Erianin suppressed the migration/invasion of ESCC cells without modulating cell viability in vitro and in vivo, bound to OTUB1 through DARTS, CETSA, and molecular docking, and SPR assay, and enhanced OTUB1 degradation via the ubiquitin-proteasome system. Moreover, Erianin inhibited the ESCC epithelial-mesenchymal transition by enhancing the ubiquitination and degradation of Snail via targeting OTUB1.</p><p><strong>Conclusion: </strong>Erianin inhibited ESCC metastasis through ubiquitination and degradation of Snail via targeting OTUB1. Our findings suggest Erianin as a novel OTUB1 inhibitor for preventing ESCC metastasis.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"155969"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682554","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":"Yes-associated protein indispensably mediates hirsutine-induced inhibition on cell growth and Wnt/β-catenin signaling in colorectal cancer.","authors":"Zehao Ren, Ruixin Su, Donghui Liu, Qian Wang, Shanshan Liu, Dexin Kong, Yuling Qiu","doi":"10.1016/j.phymed.2024.156156","DOIUrl":"10.1016/j.phymed.2024.156156","url":null,"abstract":"<p><strong>Background and purpose: </strong>Targeting Wnt/β-catenin signaling emerges as one of the promising strategies for colorectal cancer (CRC) treatment, as this signaling is highly activated in CRC progression. Despite reports on the cytotoxic effects of hirsutine (HT), an indole alkaloid found in herbal medicines from the genus Uncaria, its therapeutic potential for CRC and the involved mechanisms are poorly understood. This study investigates the anticancer efficacy and the probable mechanisms of HT against CRC.</p><p><strong>Methods: </strong>To evaluate in vitro anticancer activity of HT, cell growth examined by MTT and colony formation assay, and apoptosis examined by flow cytometry were analyzed. To explore the mechanisms, RNA-sequencing, western blotting, dual-luciferase reporter assays, immunofluorescence, and co-immunoprecipitation were performed. Mouse model of azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colon cancer was utilized to assess HT's in vivo anticancer efficacy.</p><p><strong>Results: </strong>HT significantly inhibited CRC cell proliferation with IC₅₀ values of 22.25 ± 3.27 μM for SW620 cells and 22.24 ± 2.36 μM for HCT116 cells, and induced apoptosis. HT decreased protein levels of Wnt3a and β-catenin dose- and time-dependently, and inhibited TOP/FOP FLASH reporter activity, nuclear travel of β-catenin, and downstream targets like c-Myc, Cyclin D1, VEGF. HT reduced β-catenin protein half-life, and the reversal of this effect by MG132 indicated that HT facilitated proteasome-dependent degradation of β-catenin in these two cell lines. HT also increased β-catenin ubiquitination without affecting Axin and β-TrCP levels. HT treatment for 24 h induced YAP cytoplasmic retention, enhanced YAP interacting with β-catenin and β-TrCP, triggering destruction complex formation and β-catenin ubiquitination and degradation, while YAP siRNA impaired these effects. Additionally, β-catenin overexpression and LiCl treatment counteracted HT-induced inhibition on cell growth and Wnt/β-catenin cascade. In model of AOM/DSS-induced mouse colon cancer, compared with AOM/DSS treatment group, HT recovered colon length, reduced tumor numbers and radius, and downregulated β-catenin and Ki-67, while upregulated cleaved PARP in the colorectal tissue with tumors.</p><p><strong>Conclusion: </strong>HT exhibits anticancer activity against CRC probably by inhibiting Wnt/β-catenin signaling, with YAP playing an indispensible role during the process, highlighting HT as a potential novel candidate drug for CRC therapy.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156156"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506420","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":"The role of METTL3-mediated CircStk4 modification in the treatment of chronic glomerulonephritis with Qi Teng Xiao Zhuo granule.","authors":"Xiujuan Qin, Huiyu Chen, Wenjia Zheng, Wenjie Hu, Xianjin Xu, Jiarong Gao","doi":"10.1016/j.phymed.2024.156183","DOIUrl":"10.1016/j.phymed.2024.156183","url":null,"abstract":"<p><strong>Background: </strong>Qi Teng Xiao Zhuo granule (QTXZG), a compound preparation used in traditional Chinese medicine, is a highly effective treatment for chronic glomerulonephritis (CGN). Previously, the mechanism of circStk4 and the N⁶-methyladenosine (m⁶A) modification of circStk4 in CGN was elucidated in vivo. Nevertheless, there hasn't been any research done on the connection between circStk4 and QTXZG's mechanism in CGN treatment.</p><p><strong>Purpose: </strong>The current study intended to clarify the molecular mechanism of QTXZG in CGN therapy by both in vitro and in vivo investigations.</p><p><strong>Methods: </strong>Mouse mesangial cells (MMCs) were used to measure the rate of proliferation and apoptosis using flow cytometry and the Cell Counting Kit-8 (CCK-8) assay. The expression of markers associated with proliferation, apoptosis, and autophagy was analysed using reverse transcription quantitative PCR (RT-qPCR), western blotting (WB), and immunofluorescence (IF), respectively. Methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) was utilized to analyse the m⁶A modification of circStk4, and METTL3 expression was assessed using RT-qPCR. Subsequently, miR-133a-3p and C1 expression was examined using RT-qPCR, WB, and IF. Adeno-associated virus 9 (AAV9)-circStk4 knockdown vector and a METTL3 inhibitor were used to explore the roles of METTL3 and circStk4 in CGN. Additionally, molecular docking and cellular thermal shift assays (CETSAs) were performed to assess the binding affinity between METTL3 and the active compounds in QTXZG.</p><p><strong>Results: </strong>Mechanistically, QTXZG reduced METTL3 expression and decreased circStk4 m⁶A levels while decreasing circStk4 levels and regulating the miR-133a-3p/C1 axis. Functionally, QTXZG inhibited MMCs and renal tissue proliferation, promoted apoptosis and autophagy, and reduced inflammation. In vivo experiments further confirmed that downregulated ircStk4 and METTL3 expression were accompanied by the therapeutic effects of QTXZG, resulting in a significant attenuation of renal injury, reduction in inflammation, inhibition of renal tissue proliferation and promotion of apoptosis and autophagy.</p><p><strong>Conclusion: </strong>The present study revealed that QTXZG reduced circStk4 m⁶A and METTL3 expression to regulate the circStk4/miR-133a-3p/C1 axis in the treatment of CGN and thus inhibited glomerular tissue/membrane cell proliferation and promoted autophagy and apoptosis; these results uncovered a new mechanism by which QTXZG reduced CGN and imply that METTL3 might be a target for innovative therapeutic approaches.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156183"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569444","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":"Yi-Fei-San-Jie Chinese medicine formula reverses immune escape by regulating deoxycholic acid metabolism to inhibit TGR5/STAT3/PD-L1 axis in lung cancer.","authors":"Zhiqiang Chen, Xiwu Rao, Lingling Sun, Xiangjun Qi, Jingrui Wang, Shujing Wang, Bo An, Jietao Lin, Lizhu Lin","doi":"10.1016/j.phymed.2024.156175","DOIUrl":"10.1016/j.phymed.2024.156175","url":null,"abstract":"<p><strong>Background: </strong>Yi-Fei-San-Jie Formula (YFSJF), a proprietary medicine of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, has been widely used in clinical practice for several years and is currently being tested in randomized controlled trials for early-stage lung cancer in China. However, the mechanisms by which YFSJF affects lung cancer biology, particularly the immune microenvironment and metabolic processes, remain poorly understood.</p><p><strong>Purpose: </strong>This study aims to explore how YFSJF modulates the immune microenvironment and metabolism in lung cancer, specifically its unique role in inhibiting immune evasion by targeting the TGR5/STAT3/PD-L1 pathway, which has not previously been reported.</p><p><strong>Methods: </strong>Computed Tomography (CT) scan was used to assess YFSJF efficacy in patients with lung cancer and a mouse model of urethane-induced lung cancer. Histopathological evaluation, flow cytometry, and metabolomic analysis were used to assess lung tissue structure, immune cell subset changes, and metabolism modulation, respectively. Western blotting and immunohistochemistry were used to detect Ki67, TTF-1, TGR5, STAT3, p-STAT3, and PD-L1 protein expression. Serum cytokines were detected by ELISA.</p><p><strong>Results: </strong>YFSJF effectively reduced the size of human lung cancer lesions and decreased the tumor burden and improved survival rates in mice. Lung tissue structure was also improved after YFSJF treatment. YFSJF regulated T-cell subsets, particularly by downregulating cells with PD-1-positive expression of CD3⁺, CD4⁺, and CD8⁺, and elevated serum TNF-α, IFN-γ, and GzmB levels. In addition, YFSJF modulated bile acid metabolism, particularly by inhibiting deoxycholic acid metabolism, which participates in immune regulation in lung cancer by acting on the G protein-coupled bile acid receptor TGR5.</p><p><strong>Conclusion: </strong>Finally, YFSJF inhibited immune evasion by blocking the TGR5-mediated STAT3/PD-L1 pathway, weakening PD-L1 and PD-1 binding and reviving T-cell immune activity, thereby countering lung cancer immune evasion and exerting anti-tumor effects.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156175"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606130","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}