Phytomedicine最新文献

{"title":"Lycium barbarum extract improves brain and visual functions in mice models of Alzheimer's disease through activating WNT pathway","authors":"Xiu Han ,&nbsp;Mengrong Zhang ,&nbsp;Yajing Liu ,&nbsp;Yongxia Huang ,&nbsp;Xifei Yang ,&nbsp;Rong Wang ,&nbsp;Wan-Yang Sun ,&nbsp;Kwok-Fai So ,&nbsp;Kin Chiu ,&nbsp;Rong-Rong He ,&nbsp;Ying Xu","doi":"10.1016/j.phymed.2025.156523","DOIUrl":"10.1016/j.phymed.2025.156523","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by visual deficits and cognitive impairment. However, current therapies have limited efficacy.</div></div><div><h3>Purpose</h3><div>This study aims to investigate whether <em>Lycium barbarum</em> extract (LBE) can mitigate the decline in brain and visual function in mouse models of AD during the middle and late stages.</div></div><div><h3>Methods</h3><div>The chemical constituents of LBE were identified using Liquid Chromatography-Mass Spectrometry. LBE was administered daily to 5xFAD mice for one month and to 3xTG mice for two months, via the intragastric route, until the middle and late stages of AD. Visual and brain functions were assessed through behavioral tests and electrophysiological recordings. The structure of the hippocampal region and retina was evaluated using immunostaining. RNA sequencing and western blotting were performed to explore potential mechanisms.</div></div><div><h3>Results</h3><div>Sixteen compounds were identified in LBE, with lycibarbarspermidines and rutin being the major components. Functionally, LBE significantly improved memory and light responses of retinal ganglion cells in both 5xFAD and 3xTG mice. It also enhanced long-term potentiation in the hippocampus of 5xFAD mice and cortical visual function in 3xTG mice. Structurally, LBE reduced hippocampal Aβ deposits in 5xFAD mice and Tau phosphorylation in 3xTG mice. In the retinas of 3xTG mice, LBE increased ganglion cell survival and inhibited inflammation and oxidative stress. Mechanistically, LBE restored the expression of WNT5a/b and KRAS, and inhibited GSK3β activation in the retinas of 3xTG mice.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that LBE can alleviate visual and brain function deterioration in various AD mouse models, even at the middle or late stages, possibly through the activation of the WNT pathway leading to the inhibition of Tau phosphorylation. This study reveals a novel mechanism of LBE action and proposes a promising strategy for treating AD patients using natural plant extracts, even at advanced stages.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156523"},"PeriodicalIF":6.7,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143474512","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":"Linggui Zhugan decoction ameliorating mitochondrial damage of doxorubicin-induced cardiotoxicity by modulating the AMPK-FOXO3a pathway targeting BTG2","authors":"Liang Kong ,&nbsp;Yang Liu ,&nbsp;Jia-hua Wang ,&nbsp;Mei-jun Lv ,&nbsp;Ya-zhu Wang ,&nbsp;Wan-ping Sun ,&nbsp;Hui-min Cao ,&nbsp;Rui-bo Guo ,&nbsp;Lu Zhang ,&nbsp;Yang Yu ,&nbsp;Juan Zang ,&nbsp;Lian-qun Jia ,&nbsp;Xue-tao Li","doi":"10.1016/j.phymed.2025.156529","DOIUrl":"10.1016/j.phymed.2025.156529","url":null,"abstract":"<div><h3>Background</h3><div>Doxorubicin (DOX), a widely used anthracycline chemotherapy agent, is effective against various malignant tumors. However, its clinical application is significantly limited due to dose-dependent cardiotoxicity. Linggui Zhugan Decoction (LGZGD), a traditional Chinese medicine formulation, has demonstrated notable cardioprotective effects. However, its potential to mitigate DOX-induced cardiotoxicity (DIC) remains unexplored.</div></div><div><h3>Objective</h3><div>This study investigated the protective effects of LGZGD against DIC and explores its ability to enhance mitochondrial function by modulating the AMPK-FOXO3a pathway via targeting BTG2.</div></div><div><h3>Methods</h3><div>A zebrafish DIC model was established to evaluate the cardioprotective effects of LGZGD on embryos and adults. Further investigations included <em>in vitro</em> studies with H9c2 cells and <em>in vivo</em> experiments using mouse models to assess LGZGD's pharmacological actions and their impact on mitochondrial function. Network pharmacology and transcriptomic analyses were performed to predict the potential mechanism of LGZGD in regulating the AMPK-FOXO3a pathway via BTG2. Verification was conducted through molecular docking, molecular dynamics (MD) simulations, and immunofluorescence co-localization.</div></div><div><h3>Results</h3><div>LGZGD enhanced survival rates and alleviated heart tissue damage in zebrafish. <em>In vitro</em>, LGZGD reduced DOX-induced reactive oxygen species (ROS) production in H9c2 cells, decreased apoptosis, improved mitochondrial membrane potential, and preserved mitochondrial function. <em>In vivo</em>, LGZGD improved cardiac function and prevented myocardial structural damage in mice. Additionally, it mitigated oxidative stress, inflammation, and apoptosis while reversing DOX-induced mitochondrial structural damage. Network pharmacology and transcriptomic analyses suggested that LGZGD regulates the BTG2 gene and AMPK-FOXO3a pathway activity. Molecular docking, MDs, and immunofluorescence co-localization supported the hypothesis that LGZGD modulates the AMPK-FOXO3a pathway by targeting BTG2.</div></div><div><h3>Conclusion</h3><div>LGZGD exerts significant cardioprotective effects against DIC by reducing oxidative stress, inflammation, and apoptosis preserving while mitochondrial structure and function. These findings offer a novel insight into LGZGD's clinical relevance in DIC management. Targeting BTG2 to regulate the AMPK-FOXO3a pathway highlights LGZGD as a promising therapeutic strategy for preventing and treating DIC.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156529"},"PeriodicalIF":6.7,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453137","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":"Shenfuyixin Granules enhance mitochondrial autophagy after myocardial infarction by regulating protein deacetylation via the SIRT3/FOXO1 signaling axis","authors":"Lanxin Li ,&nbsp;Shanshan Nie ,&nbsp;Bin Wang ,&nbsp;Qifei Zhao ,&nbsp;Jingjing Wei ,&nbsp;Wenjie Han ,&nbsp;Ruipeng Wu ,&nbsp;Yanze Liu ,&nbsp;Jiale Yun ,&nbsp;Yongxia Wang ,&nbsp;Mingjun Zhu ,&nbsp;Xinlu Wang","doi":"10.1016/j.phymed.2025.156503","DOIUrl":"10.1016/j.phymed.2025.156503","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Heart failure (HF) represents the terminal stage of various cardiovascular diseases, with current treatment options remaining limited. Shenfuyixin Granules (SFYX) have been integrated into clinical practice, demonstrating significant therapeutic efficacy. However, the underlying mechanisms of action are still not fully understood.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This study aims to investigate whether SFYX promotes mitochondrial autophagy and enhances cardiac function in HF following myocardial infarction via the SIRT3/FOXO1 signaling axis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The rat model of HF was established by ligation of the left anterior descending artery, while in vitro experiments were conducted using H9C2 cells. The blood-entry components of SFYX were identified using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Network analysis, integrating proteomics and transcriptomics, was conducted to determine the active components of SFYX and elucidate the key regulatory mechanisms involved in its treatment of HF. After a 4-week intervention with SFYX, cardiac function was assessed via echocardiography. Myocardial infarct size was measured using triphenyl tetrazolium chloride (TTC) staining, while H&amp;E and Masson staining were employed to evaluate myocardial tissue fibrosis and hypertrophy. Mitochondrial function was assessed using transmission electron microscopy and JC-1 dye. Cell apoptosis was detected via TUNEL assay. Additionally, molecular docking was performed to assess the binding affinity between key components of SFYX and autophagy-related proteins. Mechanistically, the expression levels of SIRT3, FOXO1, P62, and BNIP3 were determined using quantitative PCR and Western blotting.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;UPLC-MS/MS analysis revealed 21 blood-entry components in SFYX. Integrated analyses of network pharmacology, proteomics, and transcriptomics indicated that SFYX may ameliorate HF by stimulating mitochondrial autophagy through activation of the SIRT3/FOXO1 pathway. Compared with the model group, SFYX significantly attenuated myocardial hypertrophy, apoptosis, and fibrosis while enhancing autophagy, which may be partially attributed to the recovery of mitochondrial function. We propose that SFYX enhances mitochondrial function by reducing membrane potential and reactive oxygen species (ROS) production. Further results demonstrated that SFYX treatment upregulated SIRT3 and FOXO1 levels while inhibiting FOXO1 acetylation. Furthermore, the levels of mitophagy-associated proteins (ATG5, ATG7, BNIP3, and LC3B-II), which are downstream mediators of FOXO1, were enhanced by SFYX. Activation of SIRT3 or overexpression of FOXO1 enhanced the cardioprotective efficacy of SFYX, whereas inhibition of SIRT3 or silencing of FOXO1 partially reversed SFYX-induced favorable activities. Molecular docking analysis revealed that Glyceryl linolenate, a blood-entry","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156503"},"PeriodicalIF":6.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463538","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":"Dihydromyricetin regulates the miR-155-5p/SIRT1/VDAC1 pathway to promote liver regeneration and improve alcohol-induced liver injury","authors":"Qing Ma ,&nbsp;Shuo Huang ,&nbsp;Mei-ya Li ,&nbsp;Qi-han Luo ,&nbsp;Fang-ming Chen ,&nbsp;Chun-lan Hong ,&nbsp;Hong-hao Yan ,&nbsp;Jiang Qiu ,&nbsp;Kang-lu Zhao ,&nbsp;Yu Du ,&nbsp;Jin-kai Zhao ,&nbsp;Li-qin Zhou ,&nbsp;Da-yong Lou ,&nbsp;Thomas Efferth ,&nbsp;Chang-yu Li ,&nbsp;Ping Qiu","doi":"10.1016/j.phymed.2025.156522","DOIUrl":"10.1016/j.phymed.2025.156522","url":null,"abstract":"<div><h3>Background</h3><div>Alcohol-related liver disease (ALD) has become an increasingly serious global health issue. In recent years, growing evidence has highlighted the restoration of liver regenerative capacity as an effective therapeutic strategy for improving ALD. Previous studies have demonstrated the protective effect of dihydromyricetin (DMY) in alcohol-induced liver injury, but its pharmacological role in ALD-related liver regeneration impairment remains poorly understood.</div></div><div><h3>Objective</h3><div>This study aims to explore the therapeutic potential and molecular mechanisms of DMY in the context of liver regeneration impairment in ALD.</div></div><div><h3>Methods</h3><div>The classic Lieber-DeCarli alcohol liquid diet was used to establish an ALD model <em>in vivo</em>. DMY (75 and 150 mg/kg/day) and silybin (200 mg/kg) were administered for 7 weeks to assess the hepatoprotective effects of DMY. First, biochemical markers and liver histopathology were used to evaluate liver inflammation and steatosis in ALD mice. Second, we explored the potential molecular mechanisms by which DMY improves ALD through serum untargeted metabolomics, hepatic transcriptomics, and single-cell sequencing data. Furthermore, <em>in vivo</em> and <em>in vitro</em> experiments, combined with Western blotting, dual-luciferase reporter assays, and immunofluorescence, were conducted to elucidate the protective mechanisms underlying DMY's effects on ALD.</div></div><div><h3>Results</h3><div><em>In vivo</em> studies showed that DMY significantly ameliorated ALT/AST abnormalities, liver inflammation, and steatosis in ALD mice. Multi-omics and bioinformatics analyses revealed that DMY may exert its anti-ALD effects by regulating the miR-155–5p/SIRT1/VDAC1 pathway, thereby mitigating cellular senescence. Notably, knockdown of miR-155 provided partial protection against ethanol-induced liver damage. Additionally, clinical ALD samples and <em>in vivo</em> and <em>in vitro</em> experiments further confirmed that excessive alcohol exposure induces the production of miR-155–5p in liver Kupffer cells. miR-155–5p targets and inhibits SIRT1, promoting the expression of mitochondrial VDAC1, leading to mitochondrial DNA leakage, thereby accelerating hepatocyte senescence and inflammation. However, DMY improved the disruption of the miR-155–5p/SIRT1/VDAC1 pathway and hepatocyte senescence, thereby restoring liver regenerative function and exerting anti-ALD effects.</div></div><div><h3>Conclusion</h3><div>In this study, we provide the first evidence that DMY improves liver inflammation and cellular senescence by regulating the miR-155–5p/SIRT1/VDAC1 positive feedback loop, promoting liver regeneration to improve ALD. In summary, our work provides important research evidence and theoretical support for DMY as a promising candidate drug for the prevention and treatment of ALD.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156522"},"PeriodicalIF":6.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453136","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":"Isoforskolin, adenylate cyclase agonist, inhibits endothelial-to-mesenchymal transition in atherosclerosis","authors":"Yiming Ma ,&nbsp;Yunke Shi ,&nbsp;Jinping Lun ,&nbsp;Mingqiang Wang ,&nbsp;Chaoyue Zhang ,&nbsp;Xianbin Li ,&nbsp;Qian Yi ,&nbsp;Xingyu Cao ,&nbsp;Zhao Hu ,&nbsp;Weimin Yang ,&nbsp;Hongyan Cai","doi":"10.1016/j.phymed.2025.156520","DOIUrl":"10.1016/j.phymed.2025.156520","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Atherosclerosis is a common chronic disease characterized by the formation of atheromatous plaques and endothelial dysfunction. Endothelial-to-mesenchymal transition (EndMT) has been identified as a crucial driver of atherosclerosis, with TGF-β serving as a pivotal mediator of EndMT. Isoforskolin (ISOF), derived from the plant &lt;em&gt;Coleus forskohlii&lt;/em&gt;, is an effective activator of adenylyl cyclase (AC). AC can catalyze the production of cyclic adenosine monophosphate (cAMP), mediating various biological functions. Several phosphodiesterase (PDE) inhibitors that degrade cAMP have been clinically utilized in the treatment of atherosclerosis. However, the evidence regarding the efficacy and mechanisms of AC agonists in the treatment of atherosclerosis remains inadequate.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;In this study, our primary objective was to examine the therapeutic impact of ISOF on atherosclerosis and elucidate its potential mechanisms.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Male ApoE&lt;sup&gt;−/−&lt;/sup&gt; rats were fed a high-fat diet for 18 weeks and then administered ISOF by gavage continuously for 12 weeks. A cell model was established by injuring mouse aortic endothelial cells (MAECs) with ox-LDL. Oil Red O staining and Masson staining were used to assess the plaque area and content of collagen. Aortic vasodilatory function was analyzed using the DMT Myograph system. Immunofluorescence was used to determine the localization of CD31 and α-SMA. Proteomics analysis was utilized to identify potential pharmacological mechanisms of ISOF. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the mRNA expression levels of AC (1–10) in aortic tissue. AC activity and cAMP concentration were detected using specific kits. The CCK-8 assay, wound-healing, and transwell assays were used to measure cell viability and proliferation. Mechanistically, western blot analysis was used to detect candidate protein expression levels. Finally, the pharmacological knockdown of AC5 was employed to clarify the potential mechanism of ISOF.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;ISOF effectively inhibited atherosclerotic plaque progression and improved aortic vasodilatory function in ApoE&lt;sup&gt;−/−&lt;/sup&gt; rats fed a high-fat diet. At the cellular level, ISOF enhanced cell viability and proliferation of MAECs compromised by ox-LDL. These phenotypic improvements were attributed to the inhibitory effect of ISOF on endothelial-to-mesenchymal transition (EndMT); ISOF increased the expression of endothelial markers such as CD31 and E-cadherin while decreasing the expression of mesenchymal markers, including N-cadherin and α-SMA. Mechanistically, and consistent with the results of proteomic analysis, ISOF markedly inhibited the TGF-β/Smad3 signaling pathway both in vivo and in vitro. Furthermore, the expression levels of adenylyl cyclase 5 (AC5) were significantly higher than those of other AC isoforms in rat aorta. ISOF might ","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156520"},"PeriodicalIF":6.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463898","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":"Yinzhihuang formula modulates the microbe‒gut‒liver axis and bile acid excretion to attenuate cholestatic liver injury","authors":"Xin Luo ,&nbsp;Peng Cheng ,&nbsp;Yuan Fang ,&nbsp;Feihui Wang ,&nbsp;Ting Mao ,&nbsp;Yunlong Shan ,&nbsp;Yin Lu ,&nbsp;Zhonghong Wei","doi":"10.1016/j.phymed.2025.156495","DOIUrl":"10.1016/j.phymed.2025.156495","url":null,"abstract":"<div><div><em>Background:</em> Cholestatic liver injury is a hepatobiliary disorder primarily characterized by cholestasis, which significantly contributes to liver damage. The Yinzhihuang (YZH) oral preparation is an effective clinical treatment for cholestatic liver injury; however, the specific mechanism of action has not been clarified.</div><div><em>Purpose:</em> This study investigated YZH's pharmacological mechanisms associated with the microbe‒gut‒liver axis in cholestatic mice, offering new perspectives for the treatment of cholestasis.</div><div><em>Methods:</em> YZH's protective effects were evaluated by evaluating serum liver injury indices and liver staining in an alpha-nephthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis mouse model. Colon hematoxylin‒eosin (H&amp;E) and alcian blue staining and FITC‒dextran leakage assays were performed to assess intestinal barrier integrity. Fluorescence in situ hybridization was employed to analyze bacterial translocation. Additionally, 16S rRNA sequencing, fecal microbiota transplantation, and bile acid metabolomics analysis were conducted to examine the relationships among the microbiome, bile acid metabolism, and YZH formula.</div><div><em>Results:</em> We found that YZH administration alleviated symptoms of ANIT-induced hepatic pathological injury and fibrosis. In addition, YZH reduced the transfer of gut bacteria to liver tissue by maintaining an intact intestinal barrier. Notably, YZH influenced the intestinal microbiota composition, upregulated the abundance of bile acid metabolism-associated probiotic bacteria, including <em>Clostridiales, Lachnospiraceae</em> and <em>Bifidobacterium pseudolongum</em>; and downregulated the abundance of <em>Escherichia-Shigella</em> and <em>Serratia</em>, thereby promoting bile acid excretion.</div><div><em>Conclusion:</em> YZH protects against cholestatic liver damage by promoting bile excretion and maintaining intestinal mucosal barrier integrity. Furthermore, YZH alleviates cholestasis in a gut microbiota-dependent manner, and upregulation of probiotics may be crucial for YZH's influence on bile acid metabolism.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156495"},"PeriodicalIF":6.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436584","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":"A topical Chinese herbal inhibits pruritus and skin inflammation via neural TRPM8 in atopic dermatitis","authors":"Yao Chen ,&nbsp;Ziyuan Tang ,&nbsp;Zhiyao Han ,&nbsp;Mingyang Wang ,&nbsp;Xinran Li ,&nbsp;Luying Lai ,&nbsp;Pingzheng Zhou ,&nbsp;Fang Wang ,&nbsp;Fengxian Li","doi":"10.1016/j.phymed.2025.156524","DOIUrl":"10.1016/j.phymed.2025.156524","url":null,"abstract":"<div><h3>Background</h3><div>Atopic dermatitis (AD) is a chronic, itchy, and inflammatory skin disease. The neuroimmune concept of itch involves aberrant immune responses and neural activities. Chinese herbal medicine has been demonstrated to alleviate AD symptoms, but the underlying mechanisms remain not fully understand.</div></div><div><h3>Purpose</h3><div>Chushizhiyang (CS) ointment is a topical treatment consisting of Chinese herbal ingredients. We aimed to study the underlying mechanism of CS on treating AD.</div></div><div><h3>Method</h3><div>To investigate the therapeutic efficacy of CS, we utilized a well-established atopic dermatitis mouse model, administering CS ointment topically to the ears. To unravel the underlying mechanisms, we employed a multifaceted approach, including behavioral assay, network pharmacology analysis, RNA-sequencing analysis, neural tracing, and calcium imaging. Additionally, transient receptor potential (TRP) M8-deficient mice were employed to validate the specific targets of CS.</div></div><div><h3>Results</h3><div>By employing a murine model of AD-like disease, we found that CS ointment can reduce skin inflammation and inhibit scratching behavior. Importantly, its capacity to alleviate itch-induced scratching surpasses that of topical steroid, a positive control treatment. The RNA-sequencing analysis of the affected skin revealed that the differentially expressed genes were enriched in neuroactive pathways that include ion channels particularly TRPM8. Calcium imaging demonstrated that CS ointment is capable of activating TRPM8-positive sensory neurons. Using transgenic animals, we found that CS ointment exhibited its anti-inflammatory or anti-pruritic effects only when TRPM8 is functional intact. Additionally, CS treatment reduced neuronal activities in wild-type, rather than TRPM8-compromised animals.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that topical Chinese herbals participate in neuroimmune mechanisms for AD-like disease via TRPM8.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156524"},"PeriodicalIF":6.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463536","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":"Integrating serum pharmacochemistry, network pharmacology, metabolomics and 16S rRNA sequencing to explore the mechanism of total flavonoids from Flemingia philippinensis in treating collagen induced arthritis rats","authors":"Jingwen Qiu ,&nbsp;Yingyin Zhang ,&nbsp;Kairan Chen ,&nbsp;Junya Xu ,&nbsp;Yingnan Chen ,&nbsp;Minjing Li ,&nbsp;Chenchen Zhu ,&nbsp;Song Wang ,&nbsp;Lei Zhang","doi":"10.1016/j.phymed.2025.156531","DOIUrl":"10.1016/j.phymed.2025.156531","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Backgroud&lt;/h3&gt;&lt;div&gt;Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disease characterized by symmetric polyarthritis, resulting in pain and swelling in the synovial joints. &lt;em&gt;Flemingia philippinensis&lt;/em&gt;, a traditional Chinese medicine, has been shown to be an effective treatment approach for anti-rheumatoid arthritis (RA), which still needs further research in its active ingredient and regulatory mechanisms.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This study aimed at investigate the pharmacodynamic basis and intricate mechanism of action of &lt;em&gt;Flemingia philippinensis&lt;/em&gt; (FPTF) in the treatment of RA based on integrated omics technologies.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;UPLC-Q-Orbitrap HRMS was first established to identify the active components of FPTF in blood and network pharmacology was then used to predict the key therapeutic targets and corresponding pathways of FPTF in treatment of RA. To substantiate the pharmacodynamic effects, a collagen-induced arthritis (CIA) animal model was employed to observe the anti-RA effects of FPTF through a series of indicators, including rat body weight, arthritis scoring, paw swelling, histopathological analysis of synovial tissue, and serum inflammatory factors. Subsequently, the potential mechanisms underlying the anti-RA efficacy of FPTF was elucidated by integrating metabolomics analysis with 16S rRNA gene sequencing. Specifically, the RT-qPCR experiment was further conducted to validate the pathways predicted by serum pharmacochemistry, network pharmacology, metabolomics and 16S rRNA gene sequencing.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;A total of 10 compounds derived from FPTF were identified by serum sample analysis. Utilizing network pharmacology, we identified 117 common targets for FPTF in the treatment of RA. Notably, KEGG analysis highlighted the PI3K/AKT signaling pathway and the IL17 signaling pathway as key pathways associated with the anti-RA effects of FPTF. Pharmacodynamic studies showed that FPTF can significantly alleviate CIA-induced arthritis. Compared with the CIA model group, FPTF treatment significantly improved the expression of mRNA in the PI3K/AKT and IL-17 signaling pathways. Further investigation unveiled a total of 28 differential metabolites in serum samples, among which 21 metabolites were observed to be reversed following FPTF administration. Metabolomic profiling revealed pronounced perturbations in amino acid metabolism, fatty acid metabolism, and glycerophospholipid metabolism pathways in CIA rats, which were partially rectified by FPTF treatment. Additionally, 16S rRNA gene sequencing analysis indicated that FPTF could restore the gut microbiota balance disrupted by RA. RT-qPCR further confirmed that FPTF can modulate key enzymes in metabolic pathway analysis and gut microbiota metabolic pathways.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;This study pioneeringly elucidates the potential pharmacodynamic material basis of FPTF for treatment of ","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156531"},"PeriodicalIF":6.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463633","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":"Celastrol-loaded ginsenoside Rg3 liposomes enhance anti-programmed death ligand 1 immunotherapy by inducing immunogenic cell death in triple-negative breast cancer","authors":"Jingyi Huang ,&nbsp;Jingbin Shi ,&nbsp;Ninghui Ma ,&nbsp;Yujie Li ,&nbsp;Wanyu Jin ,&nbsp;Hongyan Zhang ,&nbsp;Xin Zhang ,&nbsp;Ningchao Luo ,&nbsp;Ye Ding ,&nbsp;Qiong Xie ,&nbsp;Qiushuang Li ,&nbsp;Yang Xiong","doi":"10.1016/j.phymed.2025.156514","DOIUrl":"10.1016/j.phymed.2025.156514","url":null,"abstract":"<div><h3>Background</h3><div>Triple-negative breast cancer (TNBC), characterized by high heterogeneity and invasiveness. Currently, inducing immunogenic cell death (ICD) of tumor cells through approaches such as radiotherapy and chemotherapy is an effective strategy to enhance the response to anti-programmed death-ligand 1 antibody (aPD-L1) therapy in TNBC. However, radiotherapy and chemotherapy treatments often upregulate PD-L1 expression in tumor cells, thereby weakening the tumor cells' response to aPD-L1. Celastrol exhibits broad-spectrum and potent anti-tumor activity, efficiently inducing ICD without increasing PD-L1 levels in tumor cells.</div></div><div><h3>Purpose</h3><div>This study aims to elucidate the tumor-targeting effects of celastrol-loaded liposomes and its synergistic efficacy and mechanism of action in combination with aPD-L1 against TNBC.</div></div><div><h3>Methods</h3><div>The Rg3 liposomes loaded with celastrol (Cel-Rg3-Lp) were prepared using the thin-film hydration method. BALB/c mice were utilized to establish an <em>in situ</em> breast cancer model. Mice were intravenously injected with Cel-Rg3-Lp at a dosage of celastrol 1 mg/kg once every two days for a total of 7 injections. Flow cytometry, western blot, and immunofluorescence techniques were employed to investigate the synergistic effects and mechanisms of Cel-Rg3-Lp combined with aPD-L1 in the treatment of TNBC.</div></div><div><h3>Results</h3><div>The findings of this study demonstrate that after 7 administrations of Cel-Rg3-Lp (1 mg/kg celastrol, intravenously), significant anti-tumor effects are observed, including the recruitment of CD8⁺ <em>T</em> cells and dendritic cells (DCs), while reducing the infiltration of immunosuppressive cells. The therapeutic efficacy was further enhanced when combined with aPD-L1. Additionally, Cel-Rg3-Lp markedly downregulated glucose-regulated protein 78 (GRP78) expression, thereby inducing ICD in tumor cells.</div></div><div><h3>Conclusion</h3><div>This study successfully constructed a multifunctional liposome and proposed a mechanism for inducing ICD through the GRP78-endoplasmic reticulum stress pathway. The liposome downregulates GRP78, triggering endoplasmic reticulum stress in tumor cells, inducing ICD, activating DCs, and enhancing antigen presentation to T cells. This improves the tumor immune microenvironment and provides a theoretical foundation for combining Cel-Rg3-Lp with aPD-L1 in the treatment of TNBC. This mechanism opens unique prospects for using celastrol in TNBC therapy and enhancing the effectiveness of immunotherapy.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156514"},"PeriodicalIF":6.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463535","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":"Uncovering the potential mechanism and bioactive compounds of Salviae Miltiorrhizae Radix et Rhizoma in attenuating diabetic retinopathy","authors":"Shiyuan Dong ,&nbsp;Yue Zhang ,&nbsp;Yumin Xie ,&nbsp;Hao Ouyang ,&nbsp;Siyan Zhou ,&nbsp;Jionghua Shi ,&nbsp;Bin Lu ,&nbsp;Xiyu Mei ,&nbsp;Lili Ji","doi":"10.1016/j.phymed.2025.156461","DOIUrl":"10.1016/j.phymed.2025.156461","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic retinopathy (DR) is a serious microangiopathy resulting from diabetes. Salviae Miltiorrhizae Radix et Rhizoma (Danshen) is commonly used to treat cardiovascular diseases in clinics in China. However, whether it can also be used for DR treatment, along with its primary active compounds and underlying mechanisms of action, remains unclear.</div></div><div><h3>Purpose</h3><div>To evaluate the alleviation of water extract of Salvia miltiorrhiza Radix et Rhizoma (SWE) on DR, elucidate the underlying mechanisms, and identify the primary active compounds.</div></div><div><h3>Methods</h3><div>Mice were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. Blood-retina barrier (BRB) breakdown was detected. The potential underlying mechanisms were predicted by network pharmacology and further validated by Western blot, leukostasis assay and real-time polymerase chain reaction (PCR). The primary active compounds in SWE were identified by integrating <em>in vitro</em> activity analysis and molecular docking.</div></div><div><h3>Results</h3><div>SWE attenuated BRB breakdown in STZ-induced DR mice. Results of network pharmacology and further experimental validation implied that inhibiting retinal inflammation and angiogenesis, and reversing endothelial barrier dysfunction were involved in the SWE-provided alleviation of DR, and the key involved signaling pathways were PI3K-AKT, VEGF, TNF, and NFκB pathways. Further results <em>in vitro</em> demonstrated that salvianolic acid A (SalA), salvianolic acid B (SalB), salvianolic acid C (SalC), and Tanshinone IIA (TanIIA) not only reduced the expression of pro-inflammatory cytokines but also inhibited the adhesion of inflammatory cells. However, danshensu (DSS), cryptotanshinone (CTS), and tanshinone I (TanI) only downregulated the expression of pro-inflammatory cytokines. SalA, SalB, and CTS reversed endothelial barrier dysfunction <em>in vitro</em>. SalA, SalB, SalC, CTS, DSS, and TanIIA decreased VEGF mRNA expression, and TanIIA also inhibited VEGF-induced angiogenesis <em>in vitro</em>. Molecular docking predicted potential interactions between these active compounds and several key molecules involved in regulating inflammation, angiogenesis, and cell-cell junctions. These compounds abrogated hyperglycemia-induced phosphorylation of AKT1 and PI3 K <em>in vitro</em>. Furthermore, the interactions of SalA, SalB, SalC, and TanIIA with TNFR1 were further validated using cellular thermal shift assay (CETSA).</div></div><div><h3>Conclusion</h3><div>SWE alleviated DR via reversing BRB breakdown and suppressing retinal inflammation and angiogenesis. SalA, SalB, SalC, TanIIA, and CTS might be primary active compounds in SWE, and they contributed greatly to the improvement of SWE against DR via reversing endothelial barrier injury, inhibiting inflammation and angiogenesis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156461"},"PeriodicalIF":6.7,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463634","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}