Phytomedicine最新文献

{"title":"HDCA alleviates Parkinson's disease symptoms by promoting autophagic degradation of α-synuclein in enteric neurons","authors":"Ren-Yu Kong ,&nbsp;Jin-Bao Zhang ,&nbsp;Xu Miao ,&nbsp;Xiao-yu Yao ,&nbsp;Mei-hua Pan ,&nbsp;Xin Yin ,&nbsp;Rui-qin Yao ,&nbsp;Chao Ren","doi":"10.1016/j.phymed.2025.156749","DOIUrl":"10.1016/j.phymed.2025.156749","url":null,"abstract":"<div><h3>Introduction</h3><div>Bile acids (BAs) are emerging as key modulators of Parkinson's disease (PD) through gut-brain interactions, yet their therapeutic potential remains underutilized. While BA imbalances contribute to PD pathogenesis, the specific subspecies regulating α-synuclein (α-syn) homeostasis and their mechanisms in enteric neurons—critical sites for PD initiation—require systematic investigation.</div></div><div><h3>Objective</h3><div>To investigate whether hyodeoxycholic acid (HDCA), a secondary BA with documented neuroprotective properties but unproven efficacy in synucleinopathy, modulates α-syn clearance through enteric neuronal autophagy to mitigate PD progression.</div></div><div><h3>Methods</h3><div>A53T transgenic mice underwent behavioral assessments for PD phenotyping. State-of-the-art UPLC/MS-based metabolomics quantified BA profiles. Pharmacological interventions using target-specific inhibitors (Gly-MCA, T0070907, VER-155,008) dissected the FXR-PPARγ-HSPA8 pathway. Multiscale analyses spanning immunofluorescence, western blotting, and LC3B autophagy flux reporter assays elucidated α-syn aggregation and autophagic dynamics in primary enteric neurons.</div></div><div><h3>Results</h3><div>HDCA decline correlated with PD severity, positioning it as a novel biomarker for gut-brain axis dysfunction in PD. HDCA supplementation not only alleviated motor/non-motor deficits but also conferred dual neuroprotection–reducing colonic α-syn oligomers and preserving nigral dopaminergic neurons. Mechanistic decoding revealed HDCA's unparalleled capacity to activate enteric neuronal autophagy via FXR-PPARγ-HSPA8 signaling, a pathway previously unrecognized in PD therapeutics.</div></div><div><h3>Conclusion</h3><div>Our study reveals a novel gut-brain axis where HDCA depletion drives PD pathogenesis via FXR-PPARγ-HSPA8-mediated autophagic dysfunction in enteric neurons. PD-associated HDCA deficiency directly impairs α-syn clearance, identifying HDCA as both a gut-derived synucleinopathy biomarker and a therapeutic target.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156749"},"PeriodicalIF":6.7,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844709","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":"Buyang Huanwu Decoction stabilizes atherosclerotic vulnerable plaques by regulating intestinal flora, TLR4-NF-κB-NLRP3 inflammatory pathway and mitophagy","authors":"Shi-yao Chang ,&nbsp;Yu-ting Li ,&nbsp;Hong-yang Zhu ,&nbsp;Zhi-xian He ,&nbsp;Yu You ,&nbsp;Yu-hui Liu","doi":"10.1016/j.phymed.2025.156751","DOIUrl":"10.1016/j.phymed.2025.156751","url":null,"abstract":"<div><h3>Objective</h3><div>This study explores the anti-atherosclerosis (AS) effects of Buyang Huanwu Decoction (BYHWD), focusing on its regulatory effects on the TLR4/NF-κB/NLRP3 inflammatory pathway, gut microbiota metabolites, and mitochondrial autophagy. Through the triple regulatory mechanisms of gut microbiota, the TLR4/NF-κB/NLRP3 inflammatory pathway, and mitochondrial autophagy, this study explores a novel strategy for stabilizing vulnerable AS plaques.</div></div><div><h3>Materials and methods</h3><div>The active components of Buyang Huanwu Decoction (BYHWD) were detected using LC-MS/MS. By feeding a high-fat diet (HFD) and adding 1.3 % choline chloride to the drinking water to induce ApoE^−/− mice gut microbiota dysbiosis, an AS mouse model with vulnerable plaques was established. The treatment groups were administered low, medium, and high doses of BYHWD, as well as broad-spectrum antibiotics. The effects of BYHWD on the vulnerable plaque area in the aorta, collagen content, macrophage and α-SMA protein expression, levels of inflammatory cytokines, reactive oxygen species (ROS), LC3 and NLRP3 expression, gut microbiota composition and abundance, serum trimethylamine-N-oxide (TMAO) levels, and the total bile acid content in the liver, serum, and gallbladder, as well as mitochondrial autophagy, were evaluated applying hematoxylin-eosin (HE) staining, Oil Red O staining, Sirius Red staining, immunohistochemistry, ELISA, immunofluorescence, 16S rRNA sequencing, biochemical analysis, and LC-MS detection. Western blot for TLR4, MyD88, ASC, pro-caspase-1, caspase-1, NLRP3, p-NF-κB/NF-κB, GPR41, GPR43, CYP7A1, CYP27A1, FMO3, FXR, TGR5, NIX, BNIP3, FUNDC1, PINK1, and Parkin proteins expression level.</div></div><div><h3>Results</h3><div>A total of 31 major active components were identified in Buyang Huanwu Decoction (BYHWD). BYHWD significantly reduced the vulnerable plaque area in the ApoE^−/− mouse model of AS, decreased the expression of inflammatory cytokines, inhibited the protein expression of TLR4, MyD88, p-NF-κB/NF-κB, ASC, pro-caspase-1, NLRP3, FMO3, NIX, BNIP3, FUNDC1, and PINK1/Parkin in aortic tissues, downregulated ROS levels and mitochondrial autophagy activity, regulated gut microbiota abundance, reduced serum TMAO levels, and up-regulated the expression of gut microbiota-related proteins, including GPR41, GPR43, CYP7A1, CYP27A1, FXR, and TGR5.</div></div><div><h3>Conclusion</h3><div>BYHWD exerts anti-AS effects through the inhibition of the TLR4/NF-κB/NLRP3 inflammatory pathway, modulating the gut microbiota, and stabilizing mitochondrial autophagy. The in-depth investigation of this mechanism effectively expands the therapeutic potential of BYHWD in the prevention and treatment of cardiovascular diseases and provides new theoretical insights and therapeutic targets for AS-related research.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156751"},"PeriodicalIF":6.7,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848694","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":"KAJF alleviated colorectal cancer liver metastasis by reshaping the gut microbiota and inhibiting M2-like macrophage polarization","authors":"Zongmei Zheng ,&nbsp;Yizhao Du ,&nbsp;Hua Jiang ,&nbsp;Zhenpeng Shi ,&nbsp;Hailun Zhou ,&nbsp;Lijing Jiao ,&nbsp;Peifeng Liu ,&nbsp;Yabin Gong","doi":"10.1016/j.phymed.2025.156766","DOIUrl":"10.1016/j.phymed.2025.156766","url":null,"abstract":"<div><h3>Background</h3><div>Colorectal cancer liver metastasis (CRLM) represents one of the most severe complications of colorectal cancer (CRC), often associated with unfavorable prognosis. The herbal formulation Kang-Ai-Jing-Fang (KAJF) has been employed clinically against CRC for several decades, although its precise mechanism of action remains elusive.</div></div><div><h3>Purpose</h3><div>This study investigates the anti-metastatic potential of KAJF in CRLM, focusing on its modulatory effects on gut microbiota and inhibition of M2-like macrophage activation.</div></div><div><h3>Methods</h3><div>KAJF was administered orally to CRLM model mice established through intrasplenic injection of murine CRC cells. To elucidate the role of gut microbiota reshaped by KAJF, fecal microbiota transplantation (FMT) was utilized to assess its impact on CRLM inhibition. Core targets and active compounds were identified through network pharmacology and molecular docking. To characterize microbiota composition, metabolite profiles, and gene expression variations, 16S rRNA sequencing, untargeted liquid chromatography-mass spectrometry (LC-MS/MS) metabolomics, and transcriptomics analyses were performed.</div></div><div><h3>Results</h3><div>KAJF demonstrated significant inhibitory effects on CRLM and ameliorated gut microbiota dysbiosis by enhancing the abundance of butyrate-producing bacteria (<em>Lactobacillus, Bacteroides, Bifidobacterium</em>). The therapeutic efficacy of KAJF-induced bacterial alterations in delaying CRLM and promoting butyrate-producing microbiota enrichment was further substantiated by FMT. Network pharmacology identified active ingredients in KAJF, including asperulosidic acid, polyphyllin II, ganoderenic acid B, calycosin, and ganoderic acid C, which exhibit substantial interactions with TLR4, PPARγ, SIRT1, PTGS2, and TNF. Molecular dynamics simulations and surface plasmon resonance (SPR) analysis demonstrated that ganoderic acid C2 exhibits a strong binding affinity for PPARγ. Moreover, KAJF administration led to a marked reduction in F4/80⁺ CD206⁺ macrophages and their associated cytokines (CCL17, CCL22, IL10, IL4, TGF), accompanied by a decrease in CD4⁺ T cells and myeloid-derived suppressor cells (MDSCs), while increasing CD8⁺ T cell populations.</div></div><div><h3>Conclusions</h3><div>This study demonstrates that KAJF mitigates CRLM, primarily through the regulation of gut microbiota and microbial metabolites, alongside inhibition of M2-like macrophage polarization. By integrating metabolomics, transcriptomics, and network pharmacology, this research elucidates the molecular mechanisms underpinning KAJF's therapeutic effects against CRLM, offering a promising approach for clinical intervention.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156766"},"PeriodicalIF":6.7,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868321","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":"Tongfu Xingshen capsule alleviates stroke-associated pneumonia-induced multiple organ injuries by modulating the gut microbiota and sphingolipid metabolism","authors":"Ruihua Wang ,&nbsp;Changlian Gan ,&nbsp;Baoying Gong ,&nbsp;Juan Huang ,&nbsp;Zhenzhen Lou ,&nbsp;Daxiu Wang ,&nbsp;Ru Yan ,&nbsp;Geng Li ,&nbsp;Tianqin Xiong ,&nbsp;Jianwen Guo","doi":"10.1016/j.phymed.2025.156756","DOIUrl":"10.1016/j.phymed.2025.156756","url":null,"abstract":"<div><h3>Background</h3><div>Stroke-associated pneumonia (SAP) represents a major complication and cause of death in patients suffering from intracerebral haemorrhage (ICH). It's urgent to develop more effective therapeutic strategies. Tongfu Xingshen capsule (TFXS) is a traditional Chinese medicine that has been utilised in clinical studies for the treatment of ICH and SAP, but the underlying mechanisms remain to be fully elucidated.</div></div><div><h3>Purpose</h3><div>This study aims to explore the therapeutic effects and mechanisms of TFXS on SAP using an aspiration-induced <em>Klebsiella pneumoniae</em> infection-complicating ICH rat model and an intratracheal injection of lipopolysaccharide (LPS)-induced acute lung injury-complicating ICH rat model.</div></div><div><h3>Methods</h3><div>The chemical components of TFXS are characterised using ULPLC-Q Exactive-Orbitrap-MS. The therapeutic effects of TFXS are evaluated through neurological scoring, histopathology analysis, magnetic resonance imaging, immunofluorescence, Alcian blue-nuclear fast red staining, myeloperoxidase activity assessment, leukocyte counting, and ELISA. To investigate the underlying mechanisms, faecal microbiota transplantation, 16S rRNA sequencing, untargeted metabolomics, and Spearman correlation analyses are performed.</div></div><div><h3>Results</h3><div>A total of 60 compounds are identified in TFXS. Pharmacological analysis reveals that TFXS significantly mitigates neurological deficits, enhances haematoma absorption, attenuates brain damage and neuroinflammation, and improves pneumonia and pulmonary injury by reducing the infiltration of leukocytes and lymphocytes, as well as suppressing the infiltration and overactivation of neutrophils. TFXS also alleviates intestinal lesions and barrier damage by increasing acidic mucins and the expression of the tight junction protein zonula occludens-1 (ZO-1). Mechanistically, TFXS ameliorates pneumonia and pulmonary injury in a gut microbiota-dependent manner. It reverses sphingolipid metabolism disorders and ceramide accumulation by modulating SAP-induced gut microbiota dysbiosis and enhancing the abundance of probiotics, including <em>Lactobacillus, Allobaculum</em> and <em>Enterococcus</em>.</div></div><div><h3>Conclusion</h3><div>TFXS exerts anti-inflammatory and protective effects on the brain, lung, and gut by alleviating gut microbiota dysbiosis and sphingolipid metabolism disorders. These findings highlight TFXS as a promising therapeutic candidate for the treatment of SAP.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156756"},"PeriodicalIF":6.7,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844374","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":"Integrated network pharmacology, metabolomics, and microbiome studies to reveal the therapeutic effects of Anacyclus pyrethrum in PD–MCI mice","authors":"Tayier Tuersong ,&nbsp;Qin Fen Wu ,&nbsp;Yan Chen ,&nbsp;Pei Shan Li ,&nbsp;Yu Xuan Yong ,&nbsp;Munire Shataer ,&nbsp;Samire Shataer ,&nbsp;Liang Ying Ma ,&nbsp;Xin Ling Yang","doi":"10.1016/j.phymed.2025.156729","DOIUrl":"10.1016/j.phymed.2025.156729","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;&lt;em&gt;Anacyclus pyrethrum&lt;/em&gt; (l.) DC has potential value in treating Parkinson's disease (PD)–mild cognitive impairment (MCI), manifesting as impaired memory, attention, executive function, and language. However, the specific targets and modes of action of &lt;em&gt;A. pyrethrum&lt;/em&gt; remain unclear.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;The aim of this study was to identify the active components of &lt;em&gt;A. pyrethrum&lt;/em&gt; and examine their effectiveness in treating a mouse model of PD–MCI.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We generated ethanol extracts of &lt;em&gt;A. pyrethrum&lt;/em&gt; root (EEAP) and identified its active components and related targets using UHPLC-MS/MS and network pharmacology.The PD–MCI model was induced via intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). After following continuous administration of EEAP,Altered learning or memory, as well as anxiety, were tested using the morris water maze, eight-arm radial arm maze (RAM), and open-field test,elevated plus-maze. Brain histopathology and ultrastructural changes were examined using brightfield microscopy, and electron microscopy, respectively. Furthermore, protein expression was assessed using western blotting.Stool samples were used for metabolomics analysis by UHPLC-MS/MS and for 16S rDNA sequencing to determine the compositional changes of the gut microbiota.We conducted a short-chain fatty acid targeted metabolomics experiment to study their role in the gut-brain axis in PD-MCI.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Using UPLC-MS-MS, 126 compounds were identified from &lt;em&gt;A. pyrethrum&lt;/em&gt; samples.After searching the databases and literature reports, 31 active components and 544 drug–disease targets were screened. Biological processes and molecular functions, such as energy channels, cell signaling, and metabolism, were discovered through GO analysis. The water maze experiment showed that the average swimming distance and escape latency of mice in EEAP groups decreased. The eight-arm maze experiment showed that model had a much higher number of errors related to working memory than the control mice. In the open field experiment, compared with the control group, the mice in the EEAP group exhibited an increase in the average movement speed and total movement distance, along with a decrease in the residence time.In the elevated plus maze, the control had less anxiety than the Model. Donepezil/Levodopa(D/l) mitigated anxiety-like behavior, and EEAP (100–400 mg/kg) showed a dose-dependent increase in open-arm metrics, suggesting it may ease anxiety in mice.Hippocampal tissue of mice treated with different doses of EEAP showed intact cellular layers and the hematoxylin-eosin-stained cones were slightly better;cells were arranged neatly; their morphology was normal, and were distributed uniformly. Electron microscopy revealed that the nuclear membrane, chromatin, and nucleoli were clearly demarcated in the hippocampus of mice tre","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156729"},"PeriodicalIF":6.7,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848682","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":"Gouqi-derived Nanovesicles (GqDNVs) Promoted MC3T3-E1 Cells Proliferation and Improve Fracture Healing","authors":"Shiyin Xu ,&nbsp;Zixuan Zhang ,&nbsp;Xiaolei Zhou ,&nbsp;Yuxiao Liao ,&nbsp;Zhao Peng ,&nbsp;Zitong Meng ,&nbsp;Andreas K. Nüssler ,&nbsp;Liang Ma ,&nbsp;Hui Xia ,&nbsp;Liegang Liu ,&nbsp;Wei Yang","doi":"10.1016/j.phymed.2025.156755","DOIUrl":"10.1016/j.phymed.2025.156755","url":null,"abstract":"<div><h3>Background</h3><div><em>Lycium barbarum</em> L., also known as Gouqi, a traditional Chinese herbal medicine, is widely utilized in health care products and clinical therapies. Its muscle and bone strengthening efficacy has been recorded in medical classics for a long time. In addition, plant exosome-like nanovesicles (PELNVs) have attracted more and more attention owing to their biological traits. Therefore, we intended to explore the functions, regulatory role, and underlying mechanism of Gouqi-derived Nanovesicles (GqDNVs) on fracture healing.</div></div><div><h3>Methods</h3><div>In this study, we employed the sucrose density gradient differential ultracentrifugation to isolate GqDNVs. The effects of GqDNVs on the proliferation and differentiation of MC3T3-E1 cells were evaluated using the CCK-8 assay, ALP activity measurement, and cell scratch assay. Additionally, leveraging a fracture mouse model, we utilized Micro-CT, immunological staining, and histologic analyses to comprehensively assess the impact of GqDNVs on fracture healing in mice.</div></div><div><h3>Results</h3><div>GqDNVs stimulated cell viability, increased ALP activity, and promoted cellular osteogenic protein expression (OPN, ALP, and RUNX2). Subsequently, in the mouse fracture model, trabecular thickness, and bone marrow density were increased in the GqDNVs treatment group after 28 days of injection. Meanwhile, the expressions of OPN and BGP were significantly elevated after both 14 and 28 days. Additionally, the expressions of p-PI3K/PI3K, p-Akt/Akt, p-mTOR/mTOR, p-4EBP1/4EBP1 and p-p70S6K/ p70S6K were also increased after14 days of treatment.</div></div><div><h3>Conclusions</h3><div>GqDNVs effectively promoted the proliferation and differentiation of MC3T3-E1 cells. Furthermore, GqDNVs could improve fracture healing, which is associated with PI3K/Akt/mTOR/p70S6K/4EBP1 signaling pathway.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156755"},"PeriodicalIF":6.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844375","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":"Ji-Ming-San enhances intestinal circadian rhythms and mitigates colitis in mice: The role of epithelial RORα","authors":"Zhixi Pan ,&nbsp;Jiahui Liu ,&nbsp;Shubin Lin ,&nbsp;Zhennan Li ,&nbsp;Shumin Qin ,&nbsp;Haomeng Wu ,&nbsp;Feng Li ,&nbsp;Baojian Wu ,&nbsp;Shuai Wang","doi":"10.1016/j.phymed.2025.156759","DOIUrl":"10.1016/j.phymed.2025.156759","url":null,"abstract":"<div><h3>Background</h3><div>Ji-Ming-San (JMS), a traditional Chinese medicine, exhibits time-dependent pharmacological effects, suggesting its potential as a circadian clock modulator. However, the precise mechanisms by which JMS regulates circadian rhythms remain unclear.</div></div><div><h3>Purpose</h3><div>This study aims to elucidate how JMS influences the local circadian clock machinery, and move beyond association to mechanistic discovery.</div></div><div><h3>Methods</h3><div>A jet lag model of circadian disruption was used to assess the regulatory effects of JMS on circadian behavior and clock gene expression. The impact of JMS on clock genes was examined in colon epithelial cells. Non-targeted metabolomics was utilized to identify key components and potential pathways. Network pharmacology, molecular docking, Gal4 co-transfection assays, and RNA sequencing were conducted to explore potential JMS targets. Chromatin immunoprecipitation assays were performed to investigate the transcriptional regulation mechanisms.</div></div><div><h3>Results</h3><div>JMS restored circadian rhythms in locomotor activity and intestinal clock gene expression in jet-lagged mice. Under colitis conditions, JMS reduced pathological severity and inflammation in mice with circadian disruption by upregulating BMAL1 and PER2. In mice with normal circadian rhythms, the protective effect of JMS was observed during the remission phase of colitis. At the cellular level, JMS activated RORα and enhanced the transcription and expression of BMAL1 and PER2 in colonic epithelial cells. Metabolomics and RNA sequencing revealed that JMS inhibited NF-κB signaling, contributing to its anti-inflammatory action. Mechanistically, JMS enhanced RORα/HDAC3 binding to NF-κB target genes in epithelial cells, leading to reduced H3K9Ac levels and repression of <em>Il-1β</em> and <em>Tnf-α</em>, while epithelial RORα knockdown abolished the anti-inflammatory effects.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that JMS activates epithelial RORα to restore circadian rhythm in the colon and suppresses NF-κB signaling, ultimately promoting colitis recovery These findings underscore the role of JMS in regulating intestinal circadian rhythm and highlight its potential as a chronotherapeutic strategy for colitis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156759"},"PeriodicalIF":6.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844384","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":"Didang decoction improves gut microbiota and cognitive function in TDACD rats: Combined proteomics and 16S rRNA sequencing","authors":"Zihan Li ,&nbsp;Caiyi Long ,&nbsp;Jiajing Tao ,&nbsp;Xi Peng ,&nbsp;Ya-yi Jiang ,&nbsp;Rensong Yue","doi":"10.1016/j.phymed.2025.156758","DOIUrl":"10.1016/j.phymed.2025.156758","url":null,"abstract":"<div><h3>Background</h3><div>Type 2 diabetes mellitus (T2DM) significantly elevates the risk of cognitive impairment. Didang Decoction (DDD), a classical Traditional Chinese Medicine (TCM) formula, has shown promise in alleviating diabetic symptoms and improving cognitive performance. Although historical TCM records suggest neuroprotective properties, ​the mechanistic basis for DDD's therapeutic effects on T2DM-associated cognitive dysfunction (TDACD) remains unexplored.</div></div><div><h3>Purpose</h3><div>This work sought to clarify the chemical composition and mechanisms of action of DDD by pursuing three primary objectives: (1) identification of the major active constituents of DDD; (2) validating of the hypothesis that DDD ameliorates TDACD via regulation of the gut microbiota; and (3) investigating DDD's regulatory effects on hippocampal lipid metabolism and autophagy pathways.</div></div><div><h3>Methods</h3><div>Ultra-high performance liquid chromatography-Q exactive mass spectrometry (UHPLC-QE-MS/MS) was employed to analyze the chemical composition of DDD. Cognitive function was assessed through behavioral tests. Histopathological examinations and western blotting (WB) were conducted to assess the effects of DDD on the hippocampus of TDACD rats. 16S ribosomal RNA (16S rRNA) sequencing was conducted to characterize gut microbiota, composition, and proteomics was used to evaluate hippocampal proteins expression.</div></div><div><h3>Results</h3><div>The major bioactive components of DDD were identified, including dihydrotanshinone I, aloe-emodin, chrysophanol, calycosin, sakuranetin, gallic acid, kaempferol, and rhein, emodin, etc. DDD increased neuronal density and synaptic function in the hippocampus of TDACD rats, hereby improving working memory and long-term memory. DDD boosted the relative abundance of beneficial bacteria, including <em>Roseburia, [Eubacterium] coprostanoligenes group, Christensenellaceae R-7 group</em>, and <em>Alistipes</em>, which were diminished in the TDACD group. Proteomics analysis indicated that DDD enhanced hippocampal energy metabolism and reduced neuronal damage in TDACD rats via pathways related to cholesterol and fatty acid metabolism, as well as autophagy.</div></div><div><h3>Conclusions</h3><div>DDD demonstrates potential as an adjuvant therapeutic agent for TDACD, with dual benefits in ameliorating glucose metabolism and cognitive impairments. Mechanistically, the neuroprotective effects of DDD are attributed to the regulation of hippocampal lipid energy metabolism and autophagic homeostasis, as well as the enhancement of beneficial gut microbes.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156758"},"PeriodicalIF":6.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848683","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":"Mechanism elucidation and biochemometric-based screening of substances in Schisandra chinensis leaves for alcoholic liver injury","authors":"Yifan Bing ,&nbsp;Xiang Zou ,&nbsp;Xiaolong Yang ,&nbsp;Xuejing Yang ,&nbsp;Jiejing Sheng ,&nbsp;Zhongyuan Qu","doi":"10.1016/j.phymed.2025.156757","DOIUrl":"10.1016/j.phymed.2025.156757","url":null,"abstract":"<div><h3>Background</h3><div>Alcoholic liver injury (ALI) represents a major international public health concern with no targeted pharmacological intervention and a dearth of clinical trial-approved medications for its management. The dried leaves of <em>Schisandra chinensis</em> (SCL) are rich in flavonoids, lignans, polysaccharides, and other active ingredients with anti-inflammatory, antioxidant, and antitumour activities and are commonly applied in the treatment of osteoarthritis, diabetes, and neurodegenerative diseases. The crude lignans of SCL have been reported to treat CCl₄-induced acute liver injury, and SCL tea has also been reported to have hepatoprotective effects. The components of SCL are currently the focus of investigation; however, conclusive pharmacological studies on SCL in the treatment of ethanol-induced ALI are rare.</div></div><div><h3>Purpose</h3><div>This study aimed to identify the bioactive components and elucidate the mechanism of action of SCL against ALI.</div></div><div><h3>Methods</h3><div>The optimal month for harvesting SCL was first determined using a cellular ALI model. Immediately afterwards, the efficacy of SCL was evaluated based on cellular ALI model and ALI mice model. The expression levels of NLRP3 inflammasome-associated proteins were examined via Western blotting. To identify the bioactive components of SCL, the common components in 10 batches of SCL were identified by UPLC‒Q-TOF‒MS/MS. Subsequent analysis via correlation identified common elements' pharmacological impacts, filtering for substances with notable contributions to effectiveness. Finally, potential bioactive components were further identified through molecular docking and verified in ALIcell models.</div></div><div><h3>Results</h3><div>SCL has the best efficacy in early August, and by improving hepatic aminotransferase activity, regulating lipid metabolism, alleviating oxidative stress, reducing the release of inflammatory mediators, and inhibiting the expression of NLRP3-related pyroptosis proteins, it plays a role in alleviating ALI. A total of 32 common components were identified in 10 batches of SCL. Through correlation analysis, 10 functional components, including Schisandrin B, Angeloylgomisin Q, Chlorogenic acid, Rutin, Schisandrin C, p-Hydroxycinnamic acid, Schisandrin A, Schisandrol A, Gomisin J, and Schisantherin B, were screened. Further screening using molecular docking identified 4 key functional components, Rutin, Chlorogenic acid, Schisandrin C, and Schisantherin B, which were verified to mitigate ethanol-induced liver damage.</div></div><div><h3>Conclusion</h3><div>The present study demonstrated that SCL prevented ALI, with the main contributing components being rutin, chlorogenic acid, pentosidine C and pentosidine B. Hence, our latest study offers significant experimental proof indicating SCL as a promising prospect for ALI prevention.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156757"},"PeriodicalIF":6.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844373","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 efficacy and toxicity equilibrium of emodin for liver injury: A bidirectional meta-analysis and machine learning","authors":"Sihan Hu ,&nbsp;Xiaochuan Guo ,&nbsp;Lang Tu ,&nbsp;Huiling Xiong ,&nbsp;Xiaohua Lu ,&nbsp;Xinyi Xu ,&nbsp;Yilai Li ,&nbsp;Yibing Yu ,&nbsp;Chenyang Zhou ,&nbsp;Kunpeng Hui ,&nbsp;Yeyu Li ,&nbsp;Jinhao Zeng ,&nbsp;Xiao Ma ,&nbsp;Thomas Efferth","doi":"10.1016/j.phymed.2025.156650","DOIUrl":"10.1016/j.phymed.2025.156650","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Emodin, a hepatoprotective agent derived from various herbs, exhibits dual effects on liver injury, necessitating further investigation into its therapeutic and toxic properties. Traditional meta-analyses lack predictive capability for dose- and duration-dependent effects. This study uniquely employs meta-analysis to confirm both hepatoprotective and hepatotoxic effects of emodin and uses machine learning to predict critical thresholds where these effects invert.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;We aimed to unravel the balance between emodin's hepatoprotective and hepatotoxic effects in rodent models, focusing on identifying dose- and duration-dependent responses. By dissecting emodin's efficacy and toxicity and elucidating the underlying mechanisms, our project contributes to developing a more rational dosing regimen and provides insights for the judicious and standardized use of traditional medicine in clinical pharmacology.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods and Materials&lt;/h3&gt;&lt;div&gt;A systematic review and meta-analysis, registered with INPLASY (202330123), were conducted to evaluate the bidirectional effects of emodin on liver injury. Relevant preclinical studies were searched in the Cochrane Library, PubMed, EMBASE, and Web of Science up until December 1, 2023. From an initial pool of 695 records, 28 pertinent rat and mouse studies were ultimately included. Data analysis for the meta-analysis was performed using STATA 17.0, while machine learning models were implemented in R 4.2.1 and Python 3.9 to assess the impact of intervention variables (dose and duration) on serum alanine aminotransferase (ALT) levels.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;This meta-analysis incorporated 28 studies with 537 rodents, confirming emodin's dual effects on liver injury. Controlled doses and durations of emodin significantly reduced aspartate aminotransferase (AST) (&lt;em&gt;SMD&lt;/em&gt; = -3.29, 95 % CI [-4.33, -2.25], &lt;em&gt;p&lt;/em&gt; &lt; 0.001), ALT (&lt;em&gt;SMD&lt;/em&gt; = -2.65, 95 % CI [-3.44, -1.86], &lt;em&gt;p&lt;/em&gt; &lt; 0.001), and alkaline phosphatase (ALP) (&lt;em&gt;SMD&lt;/em&gt; = -1.70, 95 % CI [-2.59, -0.80], &lt;em&gt;p&lt;/em&gt; &lt; 0.001) levels, primarily by inhibiting cytochrome P450 2E1 (CYP2E1) expression and activating the farnesoid X receptor/bile salt export pump (FXR/BSEP) pathway. Conversely, higher doses and prolonged durations were associated with increased hepatotoxicity, as indicated by a significant rise in AST (&lt;em&gt;SMD&lt;/em&gt; = 2.19, 95 % CI [0.91, 3.47], &lt;em&gt;p&lt;/em&gt; &lt; 0.001) in healthy animals, with ALT (&lt;em&gt;SMD&lt;/em&gt; = 0.59, 95 % CI [-0.18, 1.35], &lt;em&gt;p&lt;/em&gt; &gt; 0.05) and ALP (&lt;em&gt;SMD&lt;/em&gt; = -0.35, 95 % CI [-1.00, 0.30], &lt;em&gt;p&lt;/em&gt; &gt; 0.05) levels showing no significant changes. Furthermore, machine learning targeting serum ALT levels suggests that a dosage exceeding 45.74 mg/kg/day or a duration beyond 30.41 days may represent the critical thresholds at which emodin transitions from hepatoprotective to hepatotoxic. This provides a more objective r","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156650"},"PeriodicalIF":6.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913112","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}