Phytomedicine最新文献

{"title":"A multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of Tongmai Yangxin pill on ventricular remodeling in acute anterior STEMI patients after primary PCI.","authors":"Yongxia Wang, Xinlu Wang, Jianru Wang, Chunjie Li, Guoan Zhao, Chaoyang Zheng, Xiaochi Shi, Xiaolong Wang, Ke Wang, Wei Wu, Zhenpeng Zhang, Hengliang Liu, Hao Zhou, Fei Lin, Xiaofen Ruan, Jia Zhao, Shichao Wang, Xingyuan Li, Shanshan Nie, Xiaohui Li, Jinyu Huang, Heng Sun, Linping Pian, Wei Xing, Bin Li, Rui Yu, Zuoying Xing, Yankun Song, Yutian Luo, Duolao Wang, Yanming Xie, Junhua Zhang, Mingjun Zhu","doi":"10.1016/j.phymed.2024.156133","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156133","url":null,"abstract":"<p><strong>Background: </strong>Acute ST-segment elevation myocardial infarction (STEMI) is a severe form of coronary heart disease and a leading cause of mortality and morbidity. This can mainly be ascribed to adverse ventricular remodeling (VR). However, the efficacy of existing treatment strategies for STEMI is not entirely satisfactory. Tongmai Yangxin Pill (TMYX), a patented traditional Chinese medicine (TCM), has been approved for treating various cardiovascular diseases.</p><p><strong>Purpose: </strong>The purpose was to assess the effect of TMYX on VR in acute STEMI patients undergoing primary percutaneous coronary intervention (PPCI).</p><p><strong>Study design: </strong>A multicenter, randomized, double-blinded, and placebo-controlled trial conducted across 11 hospitals in China.</p><p><strong>Method: </strong>A total of 270 patients with acute anterior STEMI, undergoing PPCI within 10 days of symptom onset were enrolled and randomly assigned to receive either a placebo or TMYX, in addition to guideline-directed treatments for STEMI. The primary endpoint was a change in left ventricular end-diastolic volume index (LVEDVI) at 12 weeks.</p><p><strong>Result: </strong>Among the 270 randomized patients, 218 (TMYX: 109 and placebo: 109) were included in the per-protocol analysis. At 4 and 12 weeks, TXMY significantly improved LVEDVI than the placebo group ([-2.17(-9.24, 8.28) vs. 3.76(-2.38, 11.48), p < 0.05] and [-1.17 (-12.19, 12.88) vs. 4.46 (-2.89, 11.99), p < 0.05]). Changes in left ventricular end-diastolic volume (LVEDV) at 4 weeks were superior in the TMYX group than the placebo group (-4.37 (-17, 13.99) vs. 7.41 (-4.56, 21.79), p < 0.05). Cardiac magnetic resonance imaging (CMRI) showed that left ventricular ejection fraction (LVEF) was significantly greater in the TMYX group than in the placebo group at 4 weeks. There were no statistically significant differences between groups for left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), 6 min walking distance (6MWD), and major adverse cardiac and cerebrovascular events (MACCEs) (p > 0.05).</p><p><strong>Conclusion: </strong>TMYX, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly delayed VR in patients with acute anterior STEMI undergoing PPCI within 10 days of symptom onset.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156133"},"PeriodicalIF":6.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569421","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":"Gut microbiota mediate the alleviation effect of Xiehuo-Guzheng granules on β cell dedifferentiation in type 2 diabetes mellitus","authors":"Zebiao Cao ,&nbsp;Xianzhe Wang ,&nbsp;Huijun Liu ,&nbsp;Zhaojun Yang ,&nbsp;Zhili Zeng","doi":"10.1016/j.phymed.2024.156151","DOIUrl":"10.1016/j.phymed.2024.156151","url":null,"abstract":"<div><h3>Background</h3><div>Type 2 diabetes mellitus (T2DM) is a worldwide public health problem characterized by a progressive decline in β cell function. In traditional Chinese medicine (TCM) theory, ‘fire’ and ‘healthy qi deficiency’ are important pathogeneses of T2DM, and purging ‘fire’ and reinforcing the ‘healthy qi’ (Pinyin name: Xiehuo-Guzheng, XHGZ) are important method of treatment. Over the years, we have observed its benefit for diabetes. However, the underlying mechanisms remain unclear.</div></div><div><h3>Purpose</h3><div>To investigate the mechanism of XHGZ granules against β cell dedifferentiation in T2DM based on gut microbiota.</div></div><div><h3>Methods</h3><div>Rats with T2DM, induced by intraperitoneal injection of streptozotocin after eight weeks of high-fat diet, were randomly allocated to receive XHGZ granules, metformin, or distilled water for eight consecutive weeks. Changes in metabolic parameters, β cell dedifferentiation, inflammatory cytokines, gut microbiota, and microbial metabolites (lipopolysaccharide (LPS) and short-chain fatty acids (SCFAs)), were detected. Furthermore, faecal microbiota transplantation (FMT) was performed to confirm the anti-diabetic effect of XHGZ granule-regulated gut microbiota in pseudo-germ-free T2DM rats.</div></div><div><h3>Results</h3><div>XHGZ granules significantly ameliorated hyperglycaemia, improved islet function and pathology, and reduced β cell dedifferentiation and pro-inflammatory cytokines in T2DM rats. 16S rRNA sequencing revealed that XHGZ granules decreased the LPS-containing microbiota (e.g., <em>Colidextribacter, Desulfovibrionaceae</em>, and <em>Morganella</em>) and increased the SCFAs-producing bacteria (e.g., <em>Prevotella, Alloprevotella</em>, and <em>Muribaculaceae</em>) and <em>Lactobacillus_intestinalis</em>. Correspondingly, it strengthened intestinal barrier, lowered LPS, and elevated acetic and butyric acids. Tax4Fun analysis indicated that XHGZ granules restored abnormal metabolism, lipopolysaccharide biosynthesis, and pantothenate and CoA biosynthesis. Moreover, the XHGZ granule-regulated microbiota also exhibited the effects of anti-diabetes, anti-β cell dedifferentiation, and anti-inflammation along with the reduction of LPS and the increase of SCFAs in pseudo-germ-free T2DM rats.</div></div><div><h3>Conclusion</h3><div>Our results show that XHGZ granules alleviate β cell dedifferentiation via regulating gut microbiota and their metabolites in T2DM, suggesting its potential as a promising complementary treatment for T2DM. As far as we know, there are very few studies on the alleviation of β cell dedifferentiation by TCM, and investigations into the mechanism from the perspective of intestinal flora and microbial metabolites are yet to be reported.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"Article 156151"},"PeriodicalIF":6.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506467","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":"Cepharanthine-mediated endoplasmic reticulum stress inhibits Notch1 via binding GRP78 for suppressing hepatocellular carcinoma metastasis","authors":"Jun Hu ,&nbsp;Nan-Nan Chen ,&nbsp;Liu-Gen Li ,&nbsp;Ting-Ting Yu ,&nbsp;Yufei Qin ,&nbsp;Xing-Chun Peng ,&nbsp;Hai-Tao Li ,&nbsp;Xian-Yu Li ,&nbsp;Tian-Qi Ma ,&nbsp;Yao-Hua Lu ,&nbsp;Ning Han ,&nbsp;Zhijie Xu ,&nbsp;Yuan-Jian Hui ,&nbsp;Tong-Fei Li","doi":"10.1016/j.phymed.2024.156162","DOIUrl":"10.1016/j.phymed.2024.156162","url":null,"abstract":"<div><h3>Background</h3><div>The metastasis of hepatocellular carcinoma (HCC) leads to a poor prognosis, wherein the activation of Notch1 is an essential contributor. Cepharanthine (Cep) has been identified for its effective antiviral function and versatile intracellular targets. Our previous study has only reported the anti-cancer efficacy of Cep in lung cancer, without an in-depth exploration. Herein, the present study aims to investigate the anti-metastasis effect in HCC, the target involved, and the molecular mechanism of Cep.</div></div><div><h3>Methods</h3><div>Stable over-expression of Notch1-N1ICD yielded C5WN1 cells compared with C5WBF344 cells. The C5WN1 cells and C5WN1 cell-bearing mice were applied as the HCC model. The bioinformatics analysis, RNA sequencing, molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), microscale thermophoresis (MST), and transient knockdown techniques were carried out to identify the underlying target. The apoptosis assay, immunofluorescent staining, qRT-PCR, Western blots, Elisa, flow cytometry, migration and scratching experiments, Transmission electron microscopy (TEM), laser scanning confocal microscopy (LSCM), micro-computed tomography (micro-CT), and histopathological experiments were conducted to assay the anti-HCC efficacy, functions, and mechanism.</div></div><div><h3>Results</h3><div>Notch1 had an increased expression in HCC and contributed to metastasis thereupon. Surprisingly, Cep (2 μg/ml <em>in vitro</em>, 5 mg kg^-1 <em>in vivo</em>) presented potent Notch1 signaling pathway inhibitory effect and anti-metastasis efficacy in C5WN1 cells and in situ mice models as evidenced by reduced Notch1/MMP-2/MMP-9 expression, TGF-β release, decreased cell migration, diminished pulmonary metastases, and prolonged survival. RNA sequencing showed that the differential gene of Cep-treated HCC cells was positioned in the endoplasmic reticulum (ER). Molecular docking, CETSA, DARTS, and MST further identified that the possible target of Cep was GRP78, which was distributed in the ER. As expected, Cep (2 μg/ml) up-regulated the critical molecules of ER stress such as GRP78, induced β-amyloid accumulation, and promoted calcium burst in HCC. In contrast, suppression of GRP78 attenuated Cep-induced ER stress. Furthermore, inhibition of ER stress abated Cep-induced Notch1 inactivation and HCC cells’ migration.</div></div><div><h3>Conclusions</h3><div>Taken together, the present study finds that Cep possesses excellent anti-metastasis of HCC, wherein the GRP78 could be directly bound and activated by Cep, leading to ER stress and Notch1 blockage. This study reveals for the first time the effect, critical target, and mechanism of the Cep-mediated anti-cancer effect, providing novel insights into the molecular target therapy by phytomedicine.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"Article 156162"},"PeriodicalIF":6.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472882","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":"Cepharanthine sensitizes gastric cancer cells to chemotherapy by targeting TRIB3-FOXO3-FOXM1 axis to inhibit autophagy","authors":"Yang-yang Lu ,&nbsp;Yuan-yuan Fang ,&nbsp;Sha-sha Wang ,&nbsp;Jing Guo ,&nbsp;Jia-lin Song ,&nbsp;Liang Zhu ,&nbsp;Zhong-kun Lin ,&nbsp;Rui Wang ,&nbsp;Si-yi Zhang ,&nbsp;Wen-sheng Qiu ,&nbsp;Wei-wei Qi","doi":"10.1016/j.phymed.2024.156161","DOIUrl":"10.1016/j.phymed.2024.156161","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Gastric cancer is among the common solid tumors. Chemotherapy resistance is the most common issue in gastric cancer treatment. Inhibiting intracellular autophagy may be a feasible method for overcoming chemotherapy resistance. Cepharanthine (CEP), a natural small molecule extracted from the &lt;em&gt;stephania cephalantha&lt;/em&gt; Hayata plant, has been demonstrated to significantly inhibit cancer growth and can regulate autophagy. Although CEP can significantly inhibit cancer growth, it remains unclear whether CEP can regulate autophagy in gastric cancer. This study aimed to investigate whether CEP can enhance the sensitivity of gastric cancer to chemotherapy and elucidate its molecular mechanism.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Three gastric cancer cell lines (AGS, SGC7901, and MFC) and one normal gastric mucosal epithelial cell line (GES-1) were used for &lt;em&gt;in vitro&lt;/em&gt; experiments. The characterization of autophagy in gastric cancer cells included the detection of autophagy markers and autophagy flux through immunofluorescence staining and Western blotting, as well as the assessment of lysosomal function using fluorescence staining (LysoTracker Red DND-99, Acridine Orange staining) and Western blotting. The cytotoxicity of CEP, autophagy inhibitors (chloroquine [CQ] and 3-methyladenine [3MA]), and chemotherapy drugs (doxorubicin [DOX] and cisplatin [CIS]) was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell colony formation, and fluorescence staining techniques (H2DCFDA, Dihydroethidium, and JC-1 staining). The interaction between CEP and autophagy inhibitors was tested in a 615 mice model, and changes in the gut microbiota were determined through accurate 16S absolute quantification sequencing. The signaling pathway and autophagy regulatory target TRIB3-FOXO3-FOXM1 were confirmed through molecular docking, RNA sequencing, bioinformatic analysis, transfection techniques, and Western blotting.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;CEP blocked autophagic flux in gastric cancer cells without affecting lysosomal function. As a novel autophagy inhibitor, CEP could combine with conventional autophagy inhibitors (CQ and 3MA) to block intracellular autophagy, thereby inhibiting gastric cancer growth. During this process, changes in the gut microbiota were observed, including low-level changes in &lt;em&gt;Odoribacterium, Erysipelatoclostridium&lt;/em&gt;, and &lt;em&gt;ParaPrevotella&lt;/em&gt; and high-level changes in &lt;em&gt;Ileibacterium, Enterorhabdus&lt;/em&gt;, and &lt;em&gt;Bifidobacterium&lt;/em&gt;. Additionally, CEP synergistically inhibited the growth of gastric cancer when combined with chemotherapy drugs. Mechanistically, the TRIB3-FOXO3-FOXM1 signaling axis was found to be involved in the inhibition of gastric cancer by CEP combined with autophagy inhibitors and chemotherapy drugs, thereby mediating cell apoptosis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;This study links the TRIB3-FOXO3-FOXM1 axis with chemothera","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"Article 156161"},"PeriodicalIF":6.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506462","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":"Effects of metformin and curcumin in women with polycystic ovary syndrome: A factorial clinical trial","authors":"Fatemeh Feghhi ,&nbsp;Habib Ghaznavi ,&nbsp;Roghayeh Sheervalilou ,&nbsp;Maryam Razavi ,&nbsp;Mahdi Sepidarkish","doi":"10.1016/j.phymed.2024.156160","DOIUrl":"10.1016/j.phymed.2024.156160","url":null,"abstract":"<div><h3>Background</h3><div>Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women, associated with dyslipidemia, insulin resistance, and hormonal imbalances. Metformin and curcumin have shown promise in improving these metabolic and hormonal parameters individually, but their combined effects in PCOS remain unclear.</div></div><div><h3>Methods</h3><div>We conducted a randomized, double-blind, placebo-controlled, 12-week factorial trial involving 200 women with PCOS. Participants were randomly assigned in a 1:1:1:1 ratio to receive metformin (500-mg/8 h) + placebo, nanocurcumin soft gel capsule (80-mg/8 h) + placebo, metformin (500-mg/8 h) + nanocurcumin (80-mg/8 h), or double placebo. Lipid profiles, glucose metabolism markers, hormonal parameters, body weight, and body mass index (BMI) were assessed at baseline and week 12.</div></div><div><h3>Results</h3><div>The combination of metformin and curcumin demonstrated significant improvements in lipid profiles, glucose metabolism, hormonal parameters, body weight, and BMI compared to individual agents or placebo. Greater reductions in low-density lipoproteins (LDL) cholesterol, total cholesterol (TC), and triglyceride (TG) levels were observed with the combination therapy, along with increased high-density lipoproteins (HDL) cholesterol. Additionally, the combination therapy significantly improved markers of glucose metabolism and showed synergistic effects in reducing body weight and BMI. Reductions in testosterone and improvements in Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) levels were also observed with combination therapy.</div></div><div><h3>Conclusion</h3><div>The combination of metformin and curcumin demonstrates superior efficacy in improving lipid profiles, glucose metabolism, hormonal parameters, body weight, and BMI in women with PCOS compared to individual agents or placebo. This highlights the potential synergistic effects of combining these agents for the management of PCOS.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"Article 156160"},"PeriodicalIF":6.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506465","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":"An endophenotype network strategy uncovers YangXue QingNao Wan suppresses Aβ deposition, improves mitochondrial dysfunction and glucose metabolism.","authors":"Xue Wang, Jinna Yang, Xiaolian Zhang, Jinyong Cai, Jieqi Zhang, Chuipu Cai, Yue Zhuo, Shuhuan Fang, Xinxin Xu, Hui Wang, Peng Liu, Shuiping Zhou, Wenjia Wang, Yunhui Hu, Jiansong Fang","doi":"10.1016/j.phymed.2024.156158","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156158","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Alzheimer's disease (AD), an escalating global health issue, lacks effective treatments due to its complex pathogenesis. YangXue QingNao Wan (YXQNW) is a China Food and Drug Administration (CFDA)- approved TCM formula that has been repurposed in clinical Phase II for the treatment of AD. Identifying YXQNW's active ingredients and their mechanisms is crucial for developing effective AD treatments.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;This study aims to elucidate the anti-AD effects of YXQNW and to explore its potential therapeutic mechanisms employing an endophenotype network strategy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Herein we present an endophenotype network strategy that combines active ingredient identification in rat serum, network proximity prediction, metabolomics, and in vivo experimental validation in two animal models. Specially, utilizing UPLC-Q-TOF-MS/MS, active ingredients are identified in YXQNW to build a drug-target network. We applied network proximity to identify potential AD pathological mechanisms of YXQNW via integration of drug-target network, AD endophenotype gene sets, and human protein interactome, and validated related mechanisms in two animal models. In a d-galactose-induced senescent rat model, YXQNW was administered at varying doses for cognitive and neuronal assessments through behavioral tests, Nissl staining, and transmission electron microscopy (TEM). Metabolomic analysis with LC-MS revealed YXQNW's influence on brain metabolites, suggesting therapeutic pathways. Levels of key proteins and biochemicals were measured by WB and ELISA, providing insights into YXQNW's neuroprotective mechanisms. In addition, 5×FAD model mice were used and administered YXQNW by gavage for 14 days at two doses. Amyloid-β levels, transporter expression, and cerebral blood flow have been detected by MRI and biochemical assays.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The network proximity analysis showed that the effect of YXQNW on AD was highly correlated with amyloid β, synaptic function, glucose metabolism and mitochondrial function. The results of metabolomics combined with in vivo experimental validation suggest that YXQNW has the potential to ameliorate glucose transport abnormalities in the brain by upregulating the expression of GLUT1 and GLUT3, while further enhancing glucose metabolism through increased O-GlcNAcylation and mitigating mitochondrial dysfunction via the AMPK/Sirt1 pathway, thereby improving d-galactose-induced cognitive deficits in rats. Additionally, YXQNW treatment significantly decreased Aβ&lt;sub&gt;1-42&lt;/sub&gt; levels and enhanced cerebral blood flow (CBF) in the hippocampus of 5×FAD mice. while mechanistic findings indicated that YXQNW treatment increased the expression of ABCB1, an Aβ transporter, in 5×FAD model mice to promote the clearance of Aβ from the brain and alleviate AD-like symptoms.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study reveals that YXQNW may mitigate AD by inhibiting Aβ depositio","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156158"},"PeriodicalIF":6.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506404","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":"https://doi.org/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":"2024-10-13","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":"Formononetin alleviates ulcerative colitis via reshaping the balance of M1/M2 macrophage polarization in a gut microbiota-dependent manner","authors":"Qiuping Xiao ,&nbsp;Lin Luo ,&nbsp;Xiyan Zhu ,&nbsp;Yuhao Yan ,&nbsp;Shanshan Li ,&nbsp;Liling Chen ,&nbsp;Xiaomin Wang ,&nbsp;Jie Zhang ,&nbsp;Duanyong Liu ,&nbsp;Ronghua Liu ,&nbsp;Youbao Zhong","doi":"10.1016/j.phymed.2024.156153","DOIUrl":"10.1016/j.phymed.2024.156153","url":null,"abstract":"<div><h3>Background</h3><div>Ulcerative colitis (UC), a type of inflammatory bowel disease, presents substantial challenges in clinical treatment due to the limitations of current medications. Formononetin (FN), a naturally compound with widespread availability, exhibits anti-inflammatory, antioxidant, and immunomodulatory properties.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate the efficacy of FN against UC and its potential regulatory mechanism.</div></div><div><h3>Methods</h3><div>Here, dextran sulfate sodium (DSS) was employed to replicate experimental colitis in mice with concomitant FN treatment. The distribution and localisation of CD68 and F4/80 macrophages in colonic tissues were visualized by immunofluorescence, their chemokine and inflammatory cytokine concentrations were determined by ELISA, and macrophages and M1/M2 subpopulations were determined by flow cytometry. Additionally, 16 s rRNA and LC-MS techniques were used to detect the colonic intestinal microbiota and metabolite profiles, respectively. Correlation analyses was performed to clarify the interactions between differential bacteria, metabolites and M1/M2 macrophages, and pseudo sterile mice were constructed by depletion of gut flora with quadruple antibiotics, followed by faecal microbial transplantation to evaluate its effects on colitis and M1/M2 macrophage polarisation.</div></div><div><h3>Results</h3><div>FN dose-dependently alleviated clinical symptoms and inflammatory injury in colonic tissues of colitis mice, with its high-dose efficacy comparable to that of 5-ASA. Concurrently, FN not only inhibited inflammatory infiltration of macrophages and their M1/M2 polarisation balance in colitis mice, but also improved the composition of colonic microbiota and metabolite profiles. However, FN lost its protective effects against DSS-induced colitis and failed to restore the equilibrium of M1/M2 macrophage differentiation following intestinal flora depletion through quadruple antibiotic treatment. Importantly, fecal microbiota transplantation from FN-treated mice restored FN's protective effects against DSS-induced colitis and reestablished its regulatory role in M1/M2 macrophage polarization.</div></div><div><h3>Conclusion</h3><div>Collectively, FN ameliorated UC through modulating the balance of M1/M2 macrophage polarization in a gut microbiota-dependent manner.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"Article 156153"},"PeriodicalIF":6.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445955","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":"Kunduan Yimu Decoction affected Th17/Treg balance through microRNA-124 to improve rheumatoid arthritis pathology","authors":"Qiang Xu ,&nbsp;Mei-Feng Shi ,&nbsp;Yu-Feng Han ,&nbsp;Min-Ying Liu ,&nbsp;Xiao-bao Liu ,&nbsp;Xiao-Na Ma ,&nbsp;Wei Feng ,&nbsp;Chang-Song Lin ,&nbsp;Qing-Ping Liu","doi":"10.1016/j.phymed.2024.156129","DOIUrl":"10.1016/j.phymed.2024.156129","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is an autoimmune condition characterized by inflammation and the deterioration of joints. Current treatments often have side effects, highlighting the need for safer options. This study investigates the therapeutic effects of Kunduan Yimu Decoction (KDYMD) on RA, focusing on the role of miR-124 in regulating Th17/Treg differentiation.</div></div><div><h3>Methods</h3><div>PBMCs from RA patients were analyzed before and after KDYMD treatment. RT-qPCR was used to measure the miR-124 expressions. Flow cytometry was used to assess the ratios of Th17 to Treg cells. ELISA was used to quantify the cytokine concentrations. The effects of KDYMD on JAK2/STAT3 signaling were evaluated by western blot analysis. A CIA mouse model was used to validate the in vivo effects of KDYMD.</div></div><div><h3>Results</h3><div>MiR-124 expression was significantly upregulated in PBMCs of RA patients after KDYMD treatment. This upregulation was associated with increased Tip60 and Foxp3 expression and decreased RORγt expression. In the cytokine analysis, IL-1, IL-6, and IL-17A were decreased, and IL-10 and TGF- were increased after treatment. Flow cytometry showed a restoration of the Th17/Treg balance, with a decrease in Th17 and an increase in Treg cells. In vivo, KDYMD treatment ameliorated ankle swelling and arthritis index in CIA mice, comparable to methotrexate (MTX). In addition, KDYMD modulated JAK2/STAT3 signaling and enhanced anti-inflammatory responses.</div></div><div><h3>Conclusions</h3><div>KDYMD exerts significant anti-inflammatory effects in RA by upregulating miR-124, which in turn regulates Th17/Treg differentiation and modulates JAK2/STAT3 signaling. A novel mechanism involving miR-124 and immune cell balance suggests KDYMD could be a promising therapeutic agent for RA.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"Article 156129"},"PeriodicalIF":6.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472883","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":"Fangchinoline suppresses hepatocellular carcinoma by regulating ROS accumulation via the TRIM7/Nrf2 signaling pathway","authors":"Yange Liu ,&nbsp;Yawen Wang ,&nbsp;Juan Wang ,&nbsp;Xingxing Wang ,&nbsp;Luoting Chen ,&nbsp;Tianyu Han ,&nbsp;Hang Lian ,&nbsp;Mingxi Gan ,&nbsp;Jianbin Wang","doi":"10.1016/j.phymed.2024.156143","DOIUrl":"10.1016/j.phymed.2024.156143","url":null,"abstract":"<div><h3>Background</h3><div>Dysregulation of redox homeostasis is associated with developing hepatocellular carcinoma (HCC). Oxidative stress (OS) is distinguished by the accumulation of ROS, which plays a variety of roles in cancer pathology. Fangchinoline (FAN), a bis-benzylisoquinoline alkaloid, has anti-cancer pharmacological activity. However, the regulatory mechanism of FAN on OS and whether it can inhibit HCC by mediating OS are still unclear.</div></div><div><h3>Hypothesis/Purpose</h3><div>This paper aims to explore the effectiveness of FAN in preventing HCC via regulating OS and identify the underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>We used the primary HCC mouse model and hepatoma cell line to explore the suppressive effect of FAN on hepatocarcinogenesis. To study the role of ROS in the anti-hepatocarcinoma effect of FAN in cell model and mouse model. The mechanism of FAN-induced nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation was studied through various techniques, including generation of Nrf2 and tripartite motif containing 7 (TRIM7) gene overexpressing or knockdown cell model, co-immunoprecipitation, immunohistochemistry and subcutaneous tumor xenograft models constructed by the stable TRIM7-overexpression HLE cells, etc.</div></div><div><h3>Results</h3><div>We showed that FAN significantly inhibited cell proliferation and hepatocarcinogenesis in HCC cells and primary HCC mouse model. The FAN-induced mitochondrial dysfunction promoted ROS accumulation, and using N-Acetylcysteine to clear ROS reversed the anti-HCC effects of FAN. We observed that FAN is capable of activating the Nrf2 pathway. This effect was thought to be due to the fact that, in response to the FAN-induced OS, the cancer cells created a feedback loop to stable Nrf2 via depressing the K48-linkage ubiquitination of it, which was caused by reduced binding of kelch-like ECH-associated protein 1 (Keap1) and Nrf2 and elevated TRIM7 expression. Indeed, overexpression of TRIM7 suppressed the anti-hepatocarcinoma effect of FAN.</div></div><div><h3>Conclusion</h3><div>The study determines the anti-liver cancer effect of FAN and first describes the positive regulatory effect of TRIM7 on Nrf2 signaling. We reveal that TRIM7/Nrf2 signaling served as a target of FAN-induced ROS accumulation in HCC, which helps to clarify the mechanism of action of FAN against HCC and provides a theoretical basis for FAN as an anti-cancer drug.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"Article 156143"},"PeriodicalIF":6.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506466","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}