Phytomedicine最新文献

{"title":"Nuciferine activates intestinal TAS2R46 to attenuate metabolic disorders and hyperlipidemia via hepatic VLDL regulation","authors":"Chen Ding ,&nbsp;Jian Ruan ,&nbsp;Jingxian Huang ,&nbsp;Limin Liu ,&nbsp;Yu Li ,&nbsp;Yuan Du ,&nbsp;Yan Zhao","doi":"10.1016/j.phymed.2025.156800","DOIUrl":"10.1016/j.phymed.2025.156800","url":null,"abstract":"<div><h3>Background</h3><div>Dysregulated blood lipid metabolism, a primary driver of hyperlipidemia, is closely associated with excessive very low-density lipoprotein (VLDL) synthesis and secretion. Nuciferine, a bioactive compound isolated from lotus leaves, demonstrates remarkable hypolipidemic efficacy; however, its limited bioavailability challenges existing mechanistic explanations for this pronounced therapeutic effect.</div></div><div><h3>Purpose</h3><div>This research aims to investigate the disease-modifying effect and underlying mechanism of nuciferine against hyperlipidemia from a novel perspective by modulating the synthesis and secretion of VLDL.</div></div><div><h3>Methods</h3><div>High-fat diet-induced hyperlipidemic rats were assessed by biochemical assays and histopathological examinations to assess the therapeutic effect of nuciferine. Untargeted metabo-lipidomics were launched to obtain the metabolic and lipid profiles, and explainable machine learning algorithms were innovatively utilized in screening differentially expressed metabolites for pathway analysis. A hyperlipidemic two-layer cell co-culture model was analyzed using quantitative polymerase chain reaction, molecular docking, immunofluorescence, cellular thermal shift assay, western blotting, and flow cytometry to delineate VLDL regulatory mechanisms.</div></div><div><h3>Results</h3><div>Nuciferine significantly attenuated lipid accumulation and metabolic dysfunction in a hyperlipidemic rat model, with the biosynthesis and metabolism of phenylalanine, tyrosine, and tryptophan as pivotal metabolic pathways. Mechanistically, nuciferine activated intestinal type 2 taste receptor 46 (TAS2R46), promoting Ca²⁺-dependent secretion of glucagon-like peptide-1 (GLP-1). Subsequently, the hepatic GLP-1 receptor was cascaded to upregulate expression of liver X receptor alpha and ATP-binding cassette transporter A1, thereby reducing pathological VLDL overproduction.</div></div><div><h3>Conclusion</h3><div>This investigation establishes nuciferine’s therapeutic potential in metabolic disorders and hyperlipidemia by activating intestinal TAS2R46 to regulate hepatic VLDL synthesis and secretion.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156800"},"PeriodicalIF":6.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886301","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":"Luteolin alleviates estrogen deficiency-induced muscle atrophy via targeting SLC7A11-mediated ferroptosis","authors":"Yu Liu ,&nbsp;Honglin Chen ,&nbsp;Kun Chen ,&nbsp;Qi Shang ,&nbsp;Feng Lin ,&nbsp;Peng Zhang ,&nbsp;You Zhang ,&nbsp;Weicheng Qin ,&nbsp;Huiwen Liu ,&nbsp;Weiyu Qiu ,&nbsp;Xingda Chen ,&nbsp;Yan Gong ,&nbsp;Yixuan Jiang ,&nbsp;Yuzhuo Zhang ,&nbsp;Jiahui He ,&nbsp;Wenhua Zhao ,&nbsp;Hui Ren ,&nbsp;Gengyang Shen ,&nbsp;Xiaobing Jiang","doi":"10.1016/j.phymed.2025.156799","DOIUrl":"10.1016/j.phymed.2025.156799","url":null,"abstract":"<div><h3>Background</h3><div>Skeletal muscle atrophy, which is a debilitating condition exacerbated by estrogen deficiency, lacks effective therapeutic interventions. Although ferroptosis (an iron-dependent form of cell death driven by lipid peroxidation) has emerged as a contributor to muscle degeneration, its regulatory mechanisms remain poorly defined. In this study, we identified luteolin, which is a natural flavonoid, as a potent inhibitor of ferroptosis that mitigates estrogen deficiency-induced muscle atrophy by targeting SLC7A11.</div></div><div><h3>Purpose</h3><div>The aim of this study was to investigate the role of ferroptosis in the anti-muscle atrophy effects of luteolin.</div></div><div><h3>Methods</h3><div>Via database screening, luteolin was identified as a potential drug for improving muscle atrophy, and the promotion of C2C12 myogenic differentiation by luteolin was detected by using immunofluorescence (IF), quantitative reverse transcription PCR (RT-qPCR) and western blot (WB). The mechanism of luteolin-mediated ferroptosis in muscle atrophy was confirmed by RNA-seq, transmission electron microscopy (TEM), and GSH, MDA, SOD and Fe²⁺ assays. Molecular docking, molecular dynamics simulation, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and siRNA-mediated gene knockout were applied to validate the notion that the mechanism of luteolin treatment of muscle atrophy involves target binding to SLC7A11. In addition, this study confirmed the role of luteolin in ameliorating muscle atrophy via the modulation of the SLC7A11-mediated ferroptosis pathway <em>in vivo</em>. Finally, the effect of luteolin on the myogenic differentiation of HsKMCs was investigated.</div></div><div><h3>Results</h3><div>Luteolin promotes myogenic differentiation and significantly inhibits myotube atrophy, with the main mechanism of these effects involving the direct binding of luteolin to the SLC7A11 protein to inhibit the occurrence of ferroptosis. We confirmed that luteolin can inhibit ferroptosis in muscle tissue and improve the loss of muscle mass and strength due to muscle atrophy <em>in vivo</em>. In addition, luteolin significantly inhibited myotube atrophy in HsKMCs and promoted their myogenic differentiation by modulating the SLC7A11-mediated ferroptosis.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that luteolin regulates myogenesis and prevents muscle atrophy ​​through binding to SLC7A11 and subsequently inhibiting ferroptosis. This study elucidates the critical role of the SLC7A11-ferroptosis axis in preserving muscle physiology during atrophy, while identifying luteolin as a therapeutic agent capable of targeting SLC7A11 to suppress ferroptosis and alleviate muscle atrophy.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156799"},"PeriodicalIF":6.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881688","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":"Tea residue protein-derived oligopeptides attenuate DSS-induced acute colitis complicated with hepatic injury in C57BL/6J mice by regulating the gut-microbiome-liver axis","authors":"Fengxue Qi ,&nbsp;Ziyi Shen ,&nbsp;Simeng Zhou ,&nbsp;Yuan Zhang ,&nbsp;Yaru Zhang ,&nbsp;Hongyan Wang ,&nbsp;Yiqun Du ,&nbsp;Zhongwen Xie ,&nbsp;Daxiang Li ,&nbsp;Huifang Ge","doi":"10.1016/j.phymed.2025.156792","DOIUrl":"10.1016/j.phymed.2025.156792","url":null,"abstract":"<div><h3>Background</h3><div>Impairment of the intestinal mucosal barrier is a prevalent feature of acute colitis, and untreated acute colitis can lead to extra-intestinal manifestations, including hepatic injury. Previous research has demonstrated that large-leaf yellow tea residue protein-derived oligopeptides (TPP) can alleviate ulcerative colitis symptoms and hepatic injury in mice. However, the underlying regulatory mechanisms by which TPP improves colitis complicated with liver injury are unknown.</div></div><div><h3>Purpose</h3><div>To explore the potential mechanism by which TPP alleviates acute colitis complicated with hepatic injury.</div></div><div><h3>Methods</h3><div>Acute colitis with hepatic injury was induced in mice using 3.5 % dextran sodium sulfate. Both 16S rRNA sequencing and transcriptomic analyses were utilized to investigate the impact of TPP on mitigating symptoms in mice.</div></div><div><h3>Results</h3><div>It indicated that TPP administration effectively reduced inflammatory symptoms in the colon and liver, enhanced the secretion of mucin occluding, claudin-1, ZO-1, and MUC-2, decreased intestinal mucosal permeability, and restored homeostasis within the gut microbiome of mice. Moreover, transcriptomic analysis has evidenced the effectiveness of TPP in mitigating liver-related effects. RNA-seq KEGG enrichment and RT-qPCR analyses validated TPP could modulate the “gut-microbiome-liver” axis, and participate in signaling pathways related to inflammatory regulation, as well as bile acid metabolism and synthesis.</div></div><div><h3>Conclusion</h3><div>These findings suggest that TPP administration is a promising novel approach for preventing and treating acute colitis complicated with hepatic injury.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156792"},"PeriodicalIF":6.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886264","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":"Palmitic acid enhances the sensitivity of ferroptosis via endoplasmic reticulum stress mediated the ATF4/TXNIP Axis in polycystic ovary syndrome","authors":"Xumin Zhang ,&nbsp;Jianrong Liu ,&nbsp;Chunmei Bai ,&nbsp;Yanxin Fan ,&nbsp;Haixia Song ,&nbsp;Ziwei Huang ,&nbsp;Yang Li ,&nbsp;Ting Luo","doi":"10.1016/j.phymed.2025.156777","DOIUrl":"10.1016/j.phymed.2025.156777","url":null,"abstract":"<div><h3>Background</h3><div>Palmitic acid (PA), the most prevalent saturated fatty acid in humans, is closely associated with ovarian dysfunction. Elevated PA levels in the follicular fluid of patients with polycystic ovary syndrome (PCOS) are correlated with the outcomes of assisted reproductive technology (ART), though the underlying mechanism remains unclear.</div></div><div><h3>Methods</h3><div>Multi-omics analysis identified PA and TXNIP as potential pathogenic factors in PCOS. CCK-8 and apoptosis assay were conducted to detect the cytotoxicity of PA. To further investigate the molecular mechanisms underlying PA-induced ferroptosis, we established COV434 cell models with both TXNIP overexpression and knockdown. Transmission electron microscopy (TEM), western blot (WB), ELISA assays, and flow cytometry were employed to assess ferroptosis-related markers. A PCOS mouse model was also developed, and histopathological staining, TEM, ELISA, and WB were performed to evaluate clinical parameters related to PCOS ovarian ferroptosis levels. To clarify the targeting relationship between <em>ATF4</em> and <em>TXNIP</em>, we utilized luciferase reporter gene assays, chromatin immunoprecipitation (ChIP), and RT-qPCR for a comprehensive analysis.</div></div><div><h3>Results</h3><div>In vivo and in vitro, PA enhanced the sensitivity of PCOS ovarian ferroptosis. The protein levels of TXNIP and ACSL4 were upregulated in both PCOS patients and mouse models after PA treatment. PA also induces the expression of the ferroptosis inhibitor SLC7A11 as part of an adaptive response. Elevated intracellular ROS levels, increased MDA content, decreased GSH/GSSG ratios, elevated ferrous iron levels, and TEM findings collectively indicated that PA induces ferroptosis in KGN/COV434 cells. The ER stress inhibitor 4-PBA reduces PA-induced ferroptosis in PCOS ovaries by suppressing ER stress, thereby improving PA-induced PCOS-like traits. Moreover, the UPR gene ATF4 regulates cellular ferroptosis by activating the transcriptional expression of TXNIP.</div></div><div><h3>Conclusion</h3><div>PA stimulated ovarian ferroptosis by activating ER stress, a process mediated by the ATF4/TXNIP axis, which might represent a potential mechanism underlying the progression of PCOS. The application of ER stress inhibitors improved PCOS traits by reducing the sensitivity of ovarian ferroptosis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156777"},"PeriodicalIF":6.7,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144084201","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":"Bioactive components of Jiedu Sangen decoction against colorectal cancer: A novel and comprehensive research strategy for natural drug development","authors":"Xueer Zheng ,&nbsp;Chao Shi ,&nbsp;Ying Xie ,&nbsp;Qing Wen ,&nbsp;Tongdan Lyu ,&nbsp;Hao Li ,&nbsp;Zhenru Wang ,&nbsp;Minhe Shen ,&nbsp;Ying Zhu ,&nbsp;Shanming Ruan","doi":"10.1016/j.phymed.2025.156795","DOIUrl":"10.1016/j.phymed.2025.156795","url":null,"abstract":"<div><h3>Background</h3><div>Jiedu Sangen Decoction (JSD) is widely used in the treatment of colorectal cancer (CRC) patients in southern China due to its good clinical efficacy, but the effective active ingredients are still unknown.</div></div><div><h3>Purpose</h3><div>This study fully explored the bioactive components of JSD based on an innovative and comprehensive research strategy. Using advanced computer technology (e.g., machine learning AHP-SOM algorithm and molecular dynamics simulation) to identify the most promising bioactive components and key targets in JSD, in order to provide new perspectives for the development of natural drugs.</div></div><div><h3>Methods</h3><div>UPLC-MS/MS was used to screen bioactive components in JSD and rat plasma, and network pharmacology analysis combined with machine learning yielded the most promising bioactive components. RNA-seq was used to screen therapeutic targets before and after JSD acted on SW620 cells, and bioinformatics was used to analyze the clinical significance of these key targets. Molecular docking, molecular dynamics simulation, and experiments verified the most promising bioactive components and their therapeutic targets.</div></div><div><h3>Results</h3><div>JSD exhibited a strong pro-apoptotic effect on CRC in <em>vitro</em>. UPLC-MS/MS screened out 18 prototype components and 8 possible metabolites of JSD entering the blood. Network pharmacology combined with machine learning identified the three most promising bioactive components. RNA sequencing and bioinformatics analysis revealed six key targets of JSD against CRC. Molecular docking and molecular dynamics simulations proposed the most promising \"small molecule drug-target protein\" combinations, and SPR and MST demonstrated the direct binding between them: Resveratrol - CA9, Genistein - NOTUM, and Afzelin - DPEP1. Molecular biology experiments found that resveratrol may promote CRC apoptosis through the CA9/PI3K/AKT signaling pathway, and genistein targets NOTUM to downregulate β-catenin expression to inhibit CRC proliferation.</div></div><div><h3>Conclusion</h3><div>It is feasible to develop a novel and comprehensive research strategy to fully explore bioactive components of JSD and provide full support for natural drug development.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156795"},"PeriodicalIF":6.7,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868327","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":"Geniposide via enema alleviates colitis by modulating intestinal flora and bile acid metabolites, inhibiting S100A8/S100A9/NF-κB, and promoting TGR5 inhibition of NLRP3 inflammasome","authors":"Bao-Xin Zheng ,&nbsp;Yan Yi ,&nbsp;Xing-Wen Wang ,&nbsp;Chun-Ying Li ,&nbsp;Yong Zhao ,&nbsp;Jing-Zhuo Tian ,&nbsp;Lian-Mei Wang ,&nbsp;Jia-Yin Han ,&nbsp;Chen Pan ,&nbsp;Su-Yan Liu ,&nbsp;Chen-Yue Liu ,&nbsp;Sha-Sha Qin ,&nbsp;Xuan Tang ,&nbsp;Mei-Ting Liu ,&nbsp;Ai-Hua Liang","doi":"10.1016/j.phymed.2025.156791","DOIUrl":"10.1016/j.phymed.2025.156791","url":null,"abstract":"<div><h3>Background</h3><div>Geniposide (GE) has potential efficacy in treating ulcerative colitis (UC). However, its reactivity can be affected by rapid degradation after oral administration. Furthermore, increasing oral doses may lead to hepatotoxicity. Thus, We used enema administration, characterized by smaller dose and higher localized concentration in the lesion, to improve the above situation.</div></div><div><h3>Purpose</h3><div>We aimed to confirm that enema administration is a better modality than oral administration for GE against UC and to explore its mechanism.</div></div><div><h3>Study design/Method</h3><div>We established UC mouse model, monitoring Disease Activity Index (DAI), inflammatory cytokines levels, and histopathology. Macrogenomics and bile acid (BAs) metabolomics analysed the major intestinal flora and BAs. Simultaneouslly, we conducted quantitative proteomics analysis and screened core proteins and pathway. In vitro validation was taken by qPCR, immunofluorescence and immunoblotting experiments.</div></div><div><h3>Results</h3><div>GE via enema alleviate UC by inhibiting inflammatory factor production through downregulating S100A8/S100A9/NF-κB pathway. Analysis of the intestinal flora and BAs revealed that the enhanced abundance of <em>Lachnospiraceae</em>, which improves the ratio of primary to secondary BAs, and the reduced abundance of <em>Provocaceae</em>, which increases intestinal permeability and promotes inflammation, favored the restoration of the intestinal barrier. In addition, in vitro experiments confirmed that the key BA metabolites (mainly UDCA, DCA, and LCA) stimulated TGR5 signal to inhibit the assembly of the NLRP3 inflammasome and alleviated inflammation.</div></div><div><h3>Conclusion</h3><div>We firstly confirmed that GE alleviates UC via the enema route in a better manner than the oral route, through enhancing the intestinal barrier, restoring intestinal flora and BAs homeostasis, and inhibiting inflammatory injury. This study initially revealed that GE can alleviate UC through elevating UDCA, DCA, and LCA levels at the colonic site to activate TGR5 receptor for inhibiting the NLRP3 inflammasome, in addition to downregulating the S100A8/S100A9/-TLR4-NF-κB pathway related inflammatory response directly. The evidences offer a promising strategy and profround meaning for UC treatment.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156791"},"PeriodicalIF":6.7,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868393","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":"Crataegus pinnatifida polysaccharide alleviates DSS-induced colitis in mice by regulating the intestinal microbiota and enhancing arginine biosynthesis","authors":"Fan-Hao Wei ,&nbsp;Wen-Yin Xie ,&nbsp;Pei-Sen Zhao,&nbsp;Zhong-Hao Ji,&nbsp;Fei Gao,&nbsp;Cheng-Zhen Chen,&nbsp;Zhe Zhang,&nbsp;Wei Gao,&nbsp;Bao Yuan","doi":"10.1016/j.phymed.2025.156794","DOIUrl":"10.1016/j.phymed.2025.156794","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;The development of effective and safe dietary supplements is essential for both the prevention and management of ulcerative colitis (UC), as its pathogenesis is intricate and difficult to completely resolve. Crataegus pinnatifida, a medicinal food with a long history of use, has broad medicinal value. Recent research has revealed promising insights into the role of polysaccharide derived from Crataegus pinnatifida on modulating short-chain fatty acids (SCFAs) to alleviate UC inflammation. However, the mechanisms by which CPP regulates the intestinal microbiota and key metabolites during the antagonistic phase of UC have yet to be elucidated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;This research elucidated the protective role of CPP in relation to UC, highlighted the mechanisms through which CPP operates, particularly regarding gut microbiota and metabolism, and offered a theoretical foundation for the potential use of CPP as a dietary supplement aimed at preventing UC.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The impact of CPP on acute UC induced by 3 % DSS in mice was examined through the evaluation of the disease activity index, measurement of colon length, and observation of body weight changes. Enzyme-linked immunosorbent assay (ELISA) was used to measure inflammatory factor levels in both serum and colon, as well as to assess oxidative stress mediators. The intestinal histological damage, mucus layer damage and the level of tight junction protein were analyzed by histopathological staining and western blot (WB). The impact of gut microbiota on CPP in colitis was evaluated using 16S rRNA sequencing, microbiota depletion experiments, and fecal microbiota transplantation (FMT) studies. The key metabolic pathways and key metabolites affected by CPP in the treatment of UC were analyzed through untargeted metabolomics sequencing, ELISA, and WB assays.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Prophylactic dietary supplementation with Crataegus pinnatifida polysaccharide (CPP) notably reduced the fundamental clinical manifestations of UC induced by DSS, including DAI score, reduced colon length, and weight loss, as well as inflammation and oxidative stress. CPP promoted the expression of Claudin-1, ZO-1 and Occludin and promoted mucin secretion, which contributed to the mitigation of intestinal barrier damage caused by DSS. 16S sequencing results and metabolomics results revealed that CPP intervention upregulated the relative abundance of Lactobacillus, thereby reshaping the intestinal microbiota and activate the arginine biosynthesis pathway. The results of fecal microbiota transplantation and antibiotic clearance experiments indicated that the alleviating effect of CPP on UC was dependent on the intestinal microbiota and this alleviating effect was transferred through fecal microbiota transplantation. Mechanistically, CPP indirectly promoted the expression of the rate-limiting enzyme argininosuccinate synthase 1 (ASS1) in the i","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156794"},"PeriodicalIF":6.7,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895553","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 STING and protecting mitochondrial function with Nephropathy Ⅱ decoction to alleviate renal fibrosis","authors":"Yujiu Gao ,&nbsp;Tingting Wei ,&nbsp;Linjie Mu ,&nbsp;Chen Liu ,&nbsp;Yini Zeng ,&nbsp;Xingrong Guo ,&nbsp;Yong Zhang ,&nbsp;Zhengzhong Yuan ,&nbsp;Jinguo Cheng","doi":"10.1016/j.phymed.2025.156785","DOIUrl":"10.1016/j.phymed.2025.156785","url":null,"abstract":"<div><h3>Background</h3><div>Nephrology II Decoction (NED), a compound from traditional Chinese medicine, has been used in the clinical treatment of chronic kidney disease (CKD) for a long time. However, the specific active ingredients and the mechanisms by which they operate are not yet fully understood.</div></div><div><h3>Objective</h3><div>The study aims to explore how NED eases CKD, with an emphasis on its influence on stimulator of interferon genes (STING)-mediated mitochondrial balance within kidney cells.</div></div><div><h3>Methods</h3><div>Various CKD mouse models, including folic acid nephropathy (FAN), unilateral ureteral obstruction (UUO), and bilateral renal ischemia-reperfusion injury (bIRI), were administered with NED via oral gavage for three weeks. This study evaluated kidney function, pathological alterations, and fibrosis markers (fibronectin, collagen I, TGF-β, α-SMA) were assessed. Bulk RNA-sequencing of kidney tissues identified key targets, with molecular docking, dynamics simulations, and microscale thermophoresis were used to predict active components and pathways. These components and pathways were confirmed in renal tissues from CKD mice and renal tubular cells induced by folic acid. Additionally, oxidative stress induced by Tert‑butyl hydroperoxide (t-BHP) in HK2 cells was used to replicate CKD-induced renal fibrosis <em>in vitro</em>.</div></div><div><h3>Results</h3><div>NED significantly improved renal function, reduced pathological damage, and decreased fibrosis in mice with CKD. Bulk RNA-seq identified STING as a pivotal target, and molecular docking demonstrated a strong binding affinity between NED's active components and murine STING. NED inhibited the cGAS/STING/TBK1/IRF3/IFN-β pathway, thereby alleviating renal fibrosis. It also corrected defects in mitochondrial oxidative phosphorylation, diminished inflammatory responses, and reduced apoptosis in fibrotic kidneys. <em>In vitro</em>, NED prevented mitochondrial DNA leakage induced by t-BHP, preserved mitochondrial function, and suppressed STING activation. STING inhibitor C176 effectively reduced fibrosis in both FAN mice and folic acid -induced cells, whereas the STING agonist DMXAA intensified fibrosis. There were potential interactions observed when DMXAA was combined with NED.</div></div><div><h3>Conclusions</h3><div>This study clarified the anti-fibrotic mechanisms of NED through the cGAS/STING pathway, highlighting STING as a primary target and the involvement of mitochondrial phosphorylation. NED appears to be a promising candidate for the treatment of CKD and reductions of renal fibrosis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156785"},"PeriodicalIF":6.7,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868325","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 comprehensive pharmacology study reveals the molecular mechanisms underlying the antidepressant effects of Gastrodiae Rhizoma","authors":"Pei Liu ,&nbsp;Zhihuang Zhao ,&nbsp;Haili Zhang ,&nbsp;Chenghong Xiao ,&nbsp;Meidan Wang ,&nbsp;Chengyan Yang ,&nbsp;Yu-e Liu ,&nbsp;Lulu Wang ,&nbsp;Hui He ,&nbsp;Yangyan Ge ,&nbsp;Yan Fu ,&nbsp;Tao Zhou ,&nbsp;Zili You ,&nbsp;Jinqiang Zhang","doi":"10.1016/j.phymed.2025.156761","DOIUrl":"10.1016/j.phymed.2025.156761","url":null,"abstract":"<div><h3>Background</h3><div>Gastrodiae Rhizoma (GR) and its extract have been widely used in the treatment of depression, but the underlying mechanism of its antidepressant effects is unclear due to its numerous components.</div></div><div><h3>Purpose</h3><div>Revealing the cellular and molecular mechanisms underlying the antidepressant effects of GR through a comprehensive pharmacology-based in vivo and in vitro investigation.</div></div><div><h3>Methods</h3><div>A mouse model of depression was established using chronic mild stress (CMS) procedure, and the antidepressant effects of GR were evaluated using systematic behavior. Metabolites in GR decoction and in mouse brain were identified by UPLC-QTOF-MS technology. Core components and targets of GR against MDD were screened based on network pharmacology analysis and molecular docking. The mechanism through which GR mitigated MDD was explored using transcriptome analysis, immunohistochemistry and western blotting in vitro and in vivo.</div></div><div><h3>Results</h3><div>A total of 273 components were identified in the GR decoction, out of which 15 were detected in the brain of depressed mice treated with the GR decoction. We further identified nine key active ingredients, six essential targets, and fifth signaling pathways associated with the therapeutic effects of GR against MDD. We confirmed that the active ingredients of GR can target the neural stem/precursor cells (NSPCs) in the hippocampus of depressed mice to promote neurogenesis, as evidenced by a significant increase in the numbers of DCX⁺ cells, BrdU⁺ cells, BrdU⁺-DCX⁺ cells, and BrdU⁺-NeuN⁺ cells within the hippocampus of GR-treated mice compared to salinetreated mice under CMS exposure. Moreover, we have identified that the key active constituents of GR, namely gastrodin and parishin C, exert a targeted effect on EGFR to activate PI3K-Akt signaling in NSPCs, thereby facilitating proliferation and differentiation of NSPCs.</div></div><div><h3>Conclusion</h3><div>The antidepressant effect of GR involves the facilitation of PI3K/Akt-mediated neurogenesis through gastrodin and parishin C targeting EGFR in NSPCs.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156761"},"PeriodicalIF":6.7,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868395","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 mitochondrial DNA-STING-NF-κB Axis-mediated microglia activation by cryptotanshinone alleviates ischemic retinopathy","authors":"Wanlu Qiu ,&nbsp;Zhihua Zheng ,&nbsp;Jiaojiao Wang ,&nbsp;Youran Cai ,&nbsp;Jiami Zou ,&nbsp;Ziqing Huang ,&nbsp;Pinglian Yang ,&nbsp;Weile Ye ,&nbsp;Mei Jin ,&nbsp;Dongmei Zhang ,&nbsp;Peter J Little ,&nbsp;Qing Zhou ,&nbsp;Zhiping Liu","doi":"10.1016/j.phymed.2025.156779","DOIUrl":"10.1016/j.phymed.2025.156779","url":null,"abstract":"<div><h3>Background</h3><div>Ischemic retinopathy, a leading cause of vision impairment, involves oxidative stress and dysregulated inflammation, with microglia playing a key role. Cryptotanshinone (CTS), a bioactive compound from <em>Salvia miltiorrhiza</em>, exhibits anti-inflammatory and antioxidant properties and thus has the potential for development as a therapeutic agent. However, the actual mechanism of action of CTS in ischemic retinopathy is not known. Overactivation of the STING pathway in microglia is critical in ischemic retinopathy pathogenesis and a potential target of CTS.</div></div><div><h3>Purpose</h3><div>This study aimed to explore whether CTS alleviates ischemic retinopathy by modulating microglial STING signaling.</div></div><div><h3>Methods</h3><div>Oxygen-induced retinopathy (OIR) mice and hypoxia-induced microglial cells were used. CTS efficacy in ischemic retinopathy was evaluated at multiple stages using fluorescein fundus angiography, electroretinogram, H&amp;E staining, and Western blotting of relevant proteins. Network pharmacology and RNA sequencing identified STING as a key target. Furthermore, surface plasmon resonance (SPR), molecular docking, and site-directed mutagenesis were systematically employed to elucidate the precise binding interface between CTS and the STING protein. STING activation and knockout models were employed to further investigate the mechanisms of action of CTS.</div></div><div><h3>Results</h3><div>CTS treatment reduced microglial activation and pathological retinal angiogenesis, and protected both retinal function and structure in OIR mice. Network pharmacology, RNA sequencing, and experimental validation demonstrated a significant link between the protective effect of CTS and the inhibition of STING signaling. Mechanistically, CTS suppressed cytosolic mtDNA release, blocked STING translocation from the ER to the Golgi, and enhanced lysosomal STING degradation. These CTS-mediated effects were abolished by STING activation and absent in <em>Sting</em>-deficient OIR mice. Notably, CTS combined with anti-VEGF therapy showed synergistic efficacy in suppressing pathological retinal neovascularization.</div></div><div><h3>Conclusion</h3><div>CTS, a natural inhibitor of STING, alleviated ischemic retinopathy by inhibiting the mtDNA-STING-NF-κB signaling pathway via multifaceted mechanisms in microglia.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156779"},"PeriodicalIF":6.7,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868323","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}