Phytomedicine最新文献

{"title":"Tanshinone IIA modulates Sirt5 and Metll3 interaction to govern mitochondria-endoplasmic reticulum unfolded protein response in coronary microvascular injury","authors":"Xiangyi Pu ,&nbsp;Qiaomin Wu ,&nbsp;Zhaoqi Yan ,&nbsp;Siyuan Zhou,&nbsp;Qin Zhang,&nbsp;Xinai Zhang,&nbsp;Yongyuan Cai,&nbsp;Zhiming Liu,&nbsp;Ruxiu Liu,&nbsp;Xing Chang","doi":"10.1016/j.phymed.2025.156982","DOIUrl":"10.1016/j.phymed.2025.156982","url":null,"abstract":"<div><h3>Background</h3><div>Traditional Chinese medicine (TCM) has demonstrated significant advantages in the treatment of coronary microvascular injury, offering novel therapeutic strategies for cardiovascular diseases. Among its active compounds, Tanshinone IIA (TS) has been shown to regulate mitochondrial and endoplasmic reticulum (ER) function. However, the precise mechanisms through which TS exerts its effects, particularly via METTL3- and SIRT5-mediated unfolded protein response (UPR) pathways in microvascular endothelial cells (MECs), remain poorly understood.</div></div><div><h3>Purpose</h3><div>This study aims to elucidate the role of SIRT5 and METTL3 in mediating the protective effects of TS on mitochondrial and ER function in MECs, focusing on the UPR pathways.</div></div><div><h3>Study design</h3><div>Cardiomyocyte-specific knockout and transgenic mice were utilized to investigate the role of SIRT5 and METTL3. MECs from experimental groups were treated with TS, and various cellular functions were analyzed.</div></div><div><h3>Methods</h3><div>The study employed confocal microscopy, electron microscopy, JC-1 assay, MTT assay, and molecular docking techniques to assess mitochondrial and ER functions. Key markers, including mitochondrial membrane potential, protein expression (PINK1, Parkin, PERK, CHOP, and Nrf-1), and transcription levels (PGC1-α, TFAM, and ATF5), were quantified. Calcium ion levels and mitochondrial respiratory functions were also evaluated.</div></div><div><h3>Results</h3><div>TS treatment enhanced mitochondrial stability, restored mitochondrial membrane potential, and regulated calcium overload through METTL3- and SIRT5-mediated UPR pathways. It upregulated protective proteins (PGC1-α, TFAM, and Nrf-1) while reducing oxidative stress and ER stress markers (CHOP, PERK, and ATF5). Molecular docking confirmed a direct interaction between SIRT5 and METTL3. These changes collectively mitigated microvascular endothelial damage and normalized mitochondrial biogenesis.</div></div><div><h3>Conclusion</h3><div>TS exerts protective effects on MECs by stabilizing mitochondrial function, alleviating calcium overload, and modulating UPR signaling via METTL3 and SIRT5.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 156982"},"PeriodicalIF":6.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329675","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":"Jiangu formula modulates the gut microbiota structure and the NF-κB/NLRP3 signaling pathway to alleviate synovitis","authors":"Shuying Li ,&nbsp;Aoyu Zhang ,&nbsp;Jie Qiao ,&nbsp;Jingjing Yang ,&nbsp;Haozhu Chen ,&nbsp;Shiyan Shang ,&nbsp;Tingshuai Fu ,&nbsp;Beier Zhang ,&nbsp;Kemin Xu ,&nbsp;Gongxu Yang ,&nbsp;Qing Zhang","doi":"10.1016/j.phymed.2025.156995","DOIUrl":"10.1016/j.phymed.2025.156995","url":null,"abstract":"<div><h3>Background</h3><div>Synovitis is a pivotal pathological hallmark of arthritis, and timely intervention is essential for mitigating joint degeneration. Jiangu formula (JGF) can reduce inflammation in joint synovial fluid. However, its mechanism in treating synovial inflammation remains unclear.</div></div><div><h3>Method</h3><div>Chemical characterization of JGF's principal constituents was achieved through liquid chromatography-tandem mass spectrometry analysis. This study established a CFA -induced adjuvant arthritis model and investigated both the joint synovium and gut ecology. Through methodologies including 16S rRNA gene sequencing, it elucidated the mechanism by which JGF influences joint inflammation by modulating the NF-κB/NLRP3 signaling pathway and regulating gut microbiota structure.</div></div><div><h3>Results</h3><div>JGF significantly improved behavioral and histopathological alterations in the CFA-induced mouse, enhanced locomotor function, reduced serum inflammatory factor levels, downregulated NF-κB/NLRP3 pathway in joint and gut tissues, and modulated the structure of gut microbiota. It may reduce inflammation by promoting arginine and proline metabolism, inhibiting amino sugar and nucleotide sugar metabolism, aiding in the repair of the intestinal mucosa.</div></div><div><h3>Conclusion</h3><div>JGF ameliorates synovial inflammatory response in mice model through modulation of gut microbiota structure and intervention in the NF-κB/NLRP3 signaling pathway, with the beneficial effects demonstrating gut microbiota dependency.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 156995"},"PeriodicalIF":6.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144489549","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":"Tanshinone I alleviates post-ischemic myocardial injury by targeting TGFBR1 and modulating the TGF-β signaling pathway","authors":"Liyuan Ke ,&nbsp;Ziyao Zheng ,&nbsp;Shumin Ye ,&nbsp;Chenhui Zhong ,&nbsp;Qingyun Lin ,&nbsp;Yan Hu ,&nbsp;Peiying Shi ,&nbsp;Lei Wen ,&nbsp;Hong Yao","doi":"10.1016/j.phymed.2025.156994","DOIUrl":"10.1016/j.phymed.2025.156994","url":null,"abstract":"<div><h3>Background</h3><div>Tanshinone I (Tan I) is an essential active ingredient of the traditional cardiovascular medicine <em>Salvia miltiorrhiza</em> Bunge (<em>S. miltiorrhiza</em>). Although the protection of Tan I on cardiomyocyte has been reported, its anti-myocardial ischemia effects and mechanisms remain unknown.</div></div><div><h3>Purpose</h3><div>Systematic evaluation of the role of Tan I in reducing myocardial ischemia (MI) injury and elucidation of the underlying molecular mechanisms by which Tan I improves myocardial fibrosis and ventricular function in mouse MI models.</div></div><div><h3>Methods</h3><div><em>In vivo</em> and <em>in vitro</em> MI models were constructed to substantiate the anti-MI effects of Tan I. Through target fishing, molecular docking, and network pharmacology investigation, the effect mechanisms and potential target proteins of Tan I against MI were predicted further. Tandem mass tags (TMT)-based quantitative proteomics, transforming growth factor beta receptor I (TGFBR1)-overexpressing lentiviral vectors, molecular dynamics (MD) simulations, biolayer interferometry (BLI), cellular thermal shift assay (CETSA), TGFBR1 kinase activity, and drug affinity responsive target stability (DARTS) assay were subsequently used to validate the anti-MI-effect mechanisms and targets of Tan I.</div></div><div><h3>Results</h3><div>Tan I can markedly increase the survival of oxidative stress cell models, improve intracellular environment, and inhibit the release of intracellular reactive oxygen species. Moreover, it can restore abnormal electrocardiograms, decrease myocardial infarction area, inhibit cardiac fibrosis, and reduce serum levels of key cardiac injury biomarkers in the MI mouse model. Mechanistically, Tan I considerably inhibited the phosphorylation modification levels of TGFBR1 and Smad2 and the aberrant expressions of Collagen I/III, α-smooth muscle actin, Bcl-2, and Bax proteins in MI mice. These findings were further verified in NIH-3T3 cells overexpressing TGFBR1 or activated by TGF-β1. MD simulations, CETSA, and DARTS showed that TGFBR1 binding to Tan I was relatively stable. In addition, BLI indicated that the equilibrium dissociation constant of Tan I binding TGFBR1 was 1.5 × 10⁻⁶ M. Based on the kinase activity assay, Tan I restrained TGFBR1 with a half-maximal inhibitory concentration of 739.6 nM.</div></div><div><h3>Conclusion</h3><div>This work reveals for the first time that Tan I can reduce MI injury and fibrosis by modulating the TGF-β signaling pathway via targeting of TGFBR1.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 156994"},"PeriodicalIF":6.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144501914","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":"Gegen Qinlian Tablets attenuate immune-related adverse events in NSCLC patients: A multi-center randomized controlled trial in China","authors":"Xingyu Lu ,&nbsp;Aolin Wang ,&nbsp;Dongna Chen ,&nbsp;Meng Yang ,&nbsp;Yongming Zhang ,&nbsp;Meng Liu ,&nbsp;Xiaoyan Zhang ,&nbsp;Yuan Li ,&nbsp;Daiwei Liu ,&nbsp;Yunliang Wang ,&nbsp;Zhiqiang Cheng ,&nbsp;Liya Li ,&nbsp;Huijuan Cui","doi":"10.1016/j.phymed.2025.156968","DOIUrl":"10.1016/j.phymed.2025.156968","url":null,"abstract":"<div><h3>Background</h3><div>Immune related adverse events (irAEs) significantly compromise patients’ quality of life and limit the application of immunotherapy. Gegen Qinlian Tablets (GQT), a classical Chinese herbal formula, have shown potential in mitigating irAEs. However, clinical evidence supporting the use of GQT as a synergy therapy for immune checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (NSCLC) remains insufficient.</div></div><div><h3>Purpose</h3><div>To evaluate the efficacy and safety of GQT in reducing the incidence of irAEs in NSCLC with ICI treatment.</div></div><div><h3>Study design</h3><div>A multi-center, open-label, randomized controlled trial.</div></div><div><h3>Methods</h3><div>Eligible patients were randomly assigned (1:1) to receive ICI plus chemotherapy plus GQT (GQT group) or ICI plus chemotherapy alone (control group). The primary outcome was the incidence and severity of irAEs. Secondary outcomes included objective response rate (ORR) and disease control rate (DCR). Serum levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) were assessed at baseline and after treatment.</div></div><div><h3>Results</h3><div>From October 2022 to August 2024, 94 participants were randomized to the GQT group (<em>n</em> = 47) or the control group (<em>n</em> = 47) at four hospitals in China. The incidence of irAEs was significantly lower in the GQT group than in the control group [31.91 % (15/47) vs. 59.57 % (28/47), <em>p</em> = 0.007, 95 % CI: 0.137–0.741]. No patient in the GQT group experienced multi-systemic toxicity, whereas 3 patients in the control group did (3/28, 10.7 %). The median onset time of irAEs in the GQT group was 14.9 weeks, and was 8.7 weeks in the control group (<em>p</em> = 0.807). Among response-evaluable patients, the ORR was 48.9 % (0 CR, 23 PR) in the GQT group (<em>n</em> = 45), and 36.2 % (1 CR, 16 PR) in the control group (<em>n</em> = 43) (<em>p</em> = 0.211, 95 % CI: 0.686–3.725). IL-6 level significantly decreased after 3 treatment cycles in the GQT group (<em>p</em> &lt; 0.001), potentially contributing to the reduced incidence of irAEs.</div></div><div><h3>Conclusion</h3><div>GQT significantly reduced the incidence of irAEs and prolonged the median onset time of irAEs in patients with advanced NSCLC receiving ICI therapy. The observed effects may be associated with the downregulation of IL-6. GQT showed promise as a synergistic treatment that mitigated irAEs and might enhance the therapeutic efficacy of ICIs.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 156968"},"PeriodicalIF":6.7,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366721","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":"Shen-Ying-Yang-Zhen formula promotes angiogenesis around hair follicles, alleviates oxidative stress, and inhibits hair follicle apoptosis through the VEGF/Akt/Caspase-9 signaling axis","authors":"Huixing Zhang ,&nbsp;Lin Su ,&nbsp;Yan Qiang ,&nbsp;Junnan Chen ,&nbsp;Shiyu Hang ,&nbsp;Mingxi Liu ,&nbsp;Han Ding ,&nbsp;Qianxi Ouyang ,&nbsp;Yangzhuangzhuang Zhu ,&nbsp;Xiaoyu Wang ,&nbsp;Xiaowen Zhu ,&nbsp;Qiuyue Wang ,&nbsp;Wuqing Wang ,&nbsp;Zihang Xu ,&nbsp;Chunpu Zou","doi":"10.1016/j.phymed.2025.156963","DOIUrl":"10.1016/j.phymed.2025.156963","url":null,"abstract":"<div><h3>Background</h3><div>Androgenic alopecia (AGA) represents the most predominant form of hair loss in clinical practice, yet currently approved pharmacological options (e.g., finasteride and minoxidil) face limitations in safety and long-term efficacy. Shen-Ying-Yang-Zhen formula (SYF) is a classical prescription in traditional Chinese medicine to AGA; nevertheless, its specific mechanisms of action in addressing AGA remain to be further explored and elucidated. In our study, we for the first time propose that SYF uniquely reshapes the perifollicular microenvironment through dual regulation of oxidative stress and angiogenesis, thus providing a potential medication for AGA.</div></div><div><h3>Methods</h3><div>In this study, the chemical constituents of SYF were identified using UPLC-MS. An AGA mouse model was established by induction with testosterone propionate (TP), and a human dermal papilla cell (HDPC) model was induced by dihydrotestosterone (DHT). The mechanism underlying SYF treatment for AGA was examined by merging network pharmacology with RNA sequencing, and the findings were corroborated through flow cytometry, multiple immunofluorescences, Western blotting, RT-qPCR, and ELISA techniques.</div></div><div><h3>Results</h3><div>In the AGA mouse model, histological analysis revealed that oral administration of SYF significantly increased skin thickness and hair follicle density (2.8-fold vs. TP group, <em>p</em> &lt; 0.001). Immunofluorescence staining further confirmed that SYF treatment promoted a 2.9-fold increase in p-S6-positive hair follicles—indicative of anagen-phase induction (<em>p</em> &lt; 0.001). Network pharmacology and RNA-seq analyses showed that SYF treatment was associated with cellular oxidative stress and the angiogenic microenvironment around AGA hair follicles, which may be related to targets such as VEGF and Akt Additionally, expression of Ki67, SRY-box transcription factor 9, phospho-S6 ribosomal protein (p-S6), and Nrf2 was enhanced in the skin of the SYF-treated mice, whereas reactive oxygen species expression was decreased. RT-qPCR analysis revealed downregulation of follicle degradation-related factors DKK1, IL-6, and TGFβ1, along with decreased Caspase-9 expression and upregulated key targets VEGF and Akt in the VEGF/Akt/Caspase-9 signaling axis. In the DHT-HDPC model, SYF promoted the proliferation of HDPCs and elevated the Bcl-2/Bax ratio, which in turn suppressed apoptosis of HDPCs in vitro.</div></div><div><h3>Conclusion</h3><div>SYF shows promise as a therapeutic agent for prevention of hair loss by improving oxidative stress and angiogenesis in the area surrounding hair follicles in AGA. It reduces apoptosis in DHT-treated HDPCs by regulating the VEGF/Akt/Caspase-9 signaling axis. This multi-target, systems-level approach highlights SYF’s potential as a novel therapeutic agent for AGA.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 156963"},"PeriodicalIF":6.7,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329754","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":"Raspberry ketone alleviates radiation-induced lung injury through the STAT2-P2X7r/NLRP3 signaling pathway","authors":"Yu-Chen Jiang ,&nbsp;Bin Zhao ,&nbsp;Peng Jiang ,&nbsp;Si-Ying Wang ,&nbsp;Lin Ma ,&nbsp;Guo-Li Wu ,&nbsp;Man-Li Wang ,&nbsp;Hai-Ming Sun","doi":"10.1016/j.phymed.2025.156984","DOIUrl":"10.1016/j.phymed.2025.156984","url":null,"abstract":"<div><h3>Background</h3><div>Radiation-induced lung injury (RILI) is a frequent side effect in patients with breast cancer receiving radiotherapy. Currently, there is no optimal radioprotective agent that is widely utilized for RILI treatment. Raspberry ketone (RK) is a natural aromatic compound found in raspberries (Rubus idaeus L.). A recent study by our research revealed that RK has strong anti-inflammatory and anti-fibrosis effects. However, its actual mechanism of action in inflammation-related lung injury remains elusive.</div></div><div><h3>Purpose</h3><div>This study aimed to clarify whether RK can alleviate RILI and determine the possible underlying mechanisms. C57BL/6 mice were exposed to Coγ-rays to establish a lung injury model. RK was orally administered to the mice daily for 14 days, followed by STAT2 gene silencing. Lung tissue, serum, and bronchoalveolar lavage fluid were collected to detect lung injury-related biomarkers. Tissue morphological changes and biomarker expression related to the ECM, inflammation, EMT, and pyroptosis in the lung tissue were detected.</div></div><div><h3>Methods</h3><div>C57BL/6 mice were exposed to Coγ-rays to establish a lung injury model. RK was orally administered to the mice daily for 14 days, followed by STAT2 gene silencing. Primary lung fibroblasts were activated with TGF-β or supernatant under inflammatory conditions and incubated with RK or Nifuroxazide, respectively. BMDMs were also treated with LPS and RK to form a conditioned medium. Primary lung fibroblasts and BMDMs were injected with siRNA-STAT2.</div></div><div><h3>Results</h3><div>RK could improve the levels of biochemical indicators in the lung tissue, suppress the expression of ECM markers, and downregulate the levels of inflammatory factors, such as IL-1β, in RILI. RK could also regulate radiation-induced histopathological damage and EMT progression and inhibit the upregulation of pyroptosis-related proteins. Furthermore, RK inhibited the expression of the downstream signals of STAT2 and P2 × 7r. In addition, STAT2 deletion inhibited the occurrence of ECM, inflammation, EMT, and pyroptosis. Notably, silencing the STAT2 gene led to a low expression of P2 × 7r and the NLRP3 inflammasome in the lung tissue of RILI mice, primary lung fibroblasts, and BMDMs. Primary lung fibroblasts were activated with conditioned medium from LPS-primed BMDMs, which resulted in significant enhance of EMT markers and inflammatory cytokines.</div></div><div><h3>Conclusion</h3><div>This study indicated that RK improved RILI through STAT2-P2 × 7r/NLRP3 signaling. RK might be a prospective therapeutic candidate, and its mechanism would be a novel approach for RILI treatment.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 156984"},"PeriodicalIF":6.7,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329751","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":"Integration of heart-on-a-chip and metabolomics for understanding the toxicity-attenuating effect of ethnomedicinal processing","authors":"Xinmei Xu ,&nbsp;Yue Liu ,&nbsp;Shufu Yu ,&nbsp;Suet Cheung ,&nbsp;Mengyang Cui ,&nbsp;Yongjian Ai ,&nbsp;Yi Zhang ,&nbsp;Qionglin Liang","doi":"10.1016/j.phymed.2025.156985","DOIUrl":"10.1016/j.phymed.2025.156985","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Tiebangchui (TBC), is a well-known traditional Tibetan medicine that coexists with toxicity and effects. Highland barley wine is an effective and unique processing method to reduce TBC’s toxic side effects. However, the toxicity reduction mechanism is ambiguous and needs to be explored urgently. Meanwhile, the limitations of traditional animal models and two-dimensional (2D) cell culture models urgently require the development of more reliable analytical platforms for drug detection.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Study design&lt;/h3&gt;&lt;div&gt;The integrated metabolomics and biomimetic 3D anisotropic heart-on-a-chip were utilized to reveal the toxicity-attenuating effect of highland barley wine-processed TBC from the dual perspectives of &lt;em&gt;in vitro&lt;/em&gt; compositional changes and &lt;em&gt;in vivo&lt;/em&gt; toxicity mechanisms. The combination of organ-on-a-chip and metabolomics provides a powerful tool for achieving spatiotemporal control of cell growth and biochemistry, as well as rapid detection of small molecule metabolites.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) coupled with global natural products social molecular networking (GNPS) was utilized for the expeditious identification of chemical constituents in both raw and processed TBC products. Multivariate statistical analysis was applied to screen for differential constituents before and after processing, followed by quantification of these constituents using ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry (UPLC-QqQ-MS/MS). After constructing a 3D heart-on-a-chip model, the structure and function of the chip model were validated via COMSOL finite element analysis, immunofluorescence, and qPCR. Leveraging this chip model, integrating molecular biology and metabolomics was employed to further elucidate the detoxification mechanism by highland barley wine-processed TBC.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The comprehensive analytical strategies demonstrated that the loss of the toxic constituents of TBC through leaching during steeping and the esterification of diterpene alkaloids with long-chain fatty acids in highland barley wine to produce less toxic lipid alkaloids were the main mechanisms of toxicity reduction. Furthermore, a biomimetic 3D anisotropic heart-on-a-chip was fabricated to evaluate differences in cardiotoxicity before and after processing. The results illustrated that the raw TBC and aconitine caused a significant increase in the extracellular LDH level, resulting in intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; overload, substantial ROS production, and metabolite disorders primarily associated with the tricarboxylic acid cycle. This cascade of reactions ultimately led to apoptosis; however, highland barley wine processing of TBC mitigated these cardiotoxic effects.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;This work not only revealed the toxicity-reducing mechan","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 156985"},"PeriodicalIF":6.7,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329826","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":"Chaihu Shugan San formula alleviates psychological stress-induced ovarian cancer susceptibility by inhibiting ubiquitin degradation of TLR2 in macrophages","authors":"Fang Wu ,&nbsp;Yang Liu ,&nbsp;Gan-Qing Luo ,&nbsp;Dan-Hong Huang ,&nbsp;Wan-Li Liang ,&nbsp;Shu-Xin Cao ,&nbsp;Jie Niu ,&nbsp;Hiroshi Kurihara ,&nbsp;Xu-Hui Zhang ,&nbsp;Yi-Fang Li ,&nbsp;Wen Jin ,&nbsp;Xiang Luo ,&nbsp;Yan-Ping Wu ,&nbsp;Rong-Rong He ,&nbsp;Lei Liang","doi":"10.1016/j.phymed.2025.156967","DOIUrl":"10.1016/j.phymed.2025.156967","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Psychological stress is increasingly recognized for its potential to expedite tumor growth and enhance cancer susceptibility, yet the specific mechanisms at play remain largely unclear. Traditional Chinese Medicine (TCM) formulation, Chaihu Shugan San formula (CHSGS), known for its efficacy in alleviating liver Qi stagnation syndrome, has exhibited therapeutic benefits in cancer management. Macrophages are key immune cells in the tumor microenvironment, and their phagocytic and clearance functions for tumor cells play a crucial role in the occurrence and progression of tumors. In previous studies, we have found that macrophage phagocytosis is closely related to psychological stress-induced tumor susceptibility. However, the detailed comprehension of CHSGS’s pharmacological mechanism and bioactive ingredients that are pertinent to its clinical use in treating ovarian cancer exacerbated by stress remains an open question in the field.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This study aimed to elucidate the impact and mechanism of CHSGS in modulating psychosocial stress-associated ovarian cancer susceptibility, while also pinpointing its primary bioactive constituents responsible for mediating antitumor effects in ovarian cancer.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Initially, the relationship between the macrophage phagocytosis impaired by psychological stress and the ubiquitin degradation of Toll-like receptor 2 (TLR2) using flow cytometry and co-immunoprecipitation (CO-IP). The therapeutic efficacy and mechanism of CHSGS on ovarian cancer were evaluated by the tumor volume, tumor weight, macrophage phagocytosis and CO-IP analysis. Then, the impact of the key active ingredients in CHSGS on the of TLR2/MARCH6 interaction was further elucidated through molecular docking analysis, assessment of cell viability, phagocytosis of macrophage, CO-IP analysis and microscale thermophoresis (MST) assays. Finally, the therapeutic efficacy and mechanisms of baicalin in ovarian cancer were evaluated based on the results of tumor volume, tumor weight, and macrophage phagocytosis in vivo.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Our findings indicate that psychosocial stress promotes lipid peroxidation in macrophages, which in turn recruits the E3 ubiquitin ligase MARCH6 and triggers the proteasome-dependent degradation of TLR2, thereby impairing macrophage phagocytic function and increasing ovarian cancer susceptibility. CHSGS intervention effectively disrupted the binding relationship between TLR2 and MARCH6, markedly diminishing TLR2 degradation and consequently restoring the macrophage's phagocytic capability. Baicalin is a promising active ingredient of CHSGS that can alleviate stress-induced impairment of macrophage phagocytosis by inhibiting the binding of TLR2/MARCH6.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Our results reveal that stress enhances susceptibility to ovarian cancer via ubiquitin degradation of TLR2 in macrophages, and i","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 156967"},"PeriodicalIF":6.7,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144471220","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":"Ovatodiolide alleviates renal fibrosis through regulating metabolic reprogramming via targeting glucose-6-phosphate dehydrogenase","authors":"Xiaoyang He ,&nbsp;Xiaowen Chen ,&nbsp;Wenting Wu ,&nbsp;Ruiling Tang ,&nbsp;Huiting Wu ,&nbsp;Yunyi Liang ,&nbsp;Lingyu Shen ,&nbsp;Xiaohong Zheng ,&nbsp;Zerong Zheng ,&nbsp;Ping Yang ,&nbsp;Yihao Long ,&nbsp;Jinzhu Yang ,&nbsp;Liyuan Zhao ,&nbsp;Zhe Zhang ,&nbsp;Huizhen Wang ,&nbsp;Congwei Luo ,&nbsp;Fenfen Peng ,&nbsp;Haibo Long","doi":"10.1016/j.phymed.2025.156983","DOIUrl":"10.1016/j.phymed.2025.156983","url":null,"abstract":"<div><h3>Background</h3><div>Ovatodiolide (Ova) is a bioactive compound from <em>Anisomeles indica</em> (l.) Kuntze, which has been traditionally utilized to tonify the kidney function. There is limited targeted therapies available for renal fibrosis (RF) in chronic kidney disease (CKD).</div></div><div><h3>Purpose</h3><div>This study aims to investigate the effect of Ova on RF and its underlying mechanism.</div></div><div><h3>Methods</h3><div>Unilateral ischemia-reperfusion injury (UIRI) and unilateral ureteral obstruction (UUO) were intragastrically administrated by solvent (vehicle group) or Ova at two concentations (25 and 50 mg kg⁻¹ day⁻¹) as treatment groups and telmisartan (Tel) as a positive control group. Mass spectrometry (MS), HuProt^TM proteome microarray, surface plasmon resonance (SPR) assays and molecular docking were utilized to explore the molecular mechanism by which Ova regulated metabolic reprogramming in renal tubular epithelial cells (RTECs). In vitro, RTECs were subjected to small interfering RNA (siRNA) and mutant plasmids to evaluate the role of glucose-6-phosphate dehydrogenase (G6PD) in metabolic reprogramming.</div></div><div><h3>Results</h3><div>Ova treatment markedly attenuated RF in UIRI and UUO mice by suppressing pentose phosphate pathway (PPP) overactivation. Ova bound specifically to G6PD’s Lys403 site, promoted its acetylation and thereby inhibited dimer formation and enzymatic activity without affecting overall protein expression. Notably, Ova effectively inhibited but did not completely abolish G6PD activity, thereby preserving basal PPP levels crucial for cellular survival and physiological functions.</div></div><div><h3>Conclusion</h3><div>For the first time, we identify Ova as a potential therapeutic agent for RF through selective modulation of G6PD. These findings advance the development of metabolism-targeted therapies for RF, offering scientific and translational value.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 156983"},"PeriodicalIF":6.7,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144489548","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":"Study on the effects of the atractylodes macrocephala koidz-raphanus sativus l herb pair in alleviating senile constipation via the gut microbiota-SCFAs-5-HT axis","authors":"Fan Gao ,&nbsp;Jie Su ,&nbsp;Jin Li ,&nbsp;Changsheng Gan ,&nbsp;Xiaohu Jin,&nbsp;Hengpu Zhou,&nbsp;Xingyu Liu,&nbsp;Jingjing Yu,&nbsp;Meiqiu Yan,&nbsp;Suhong Chen,&nbsp;Guiyuan Lv","doi":"10.1016/j.phymed.2025.156977","DOIUrl":"10.1016/j.phymed.2025.156977","url":null,"abstract":"<div><h3>Background</h3><div>Senile constipation is a common functional gastrointestinal disorder that severely affects the quality of life in elderly populations. Chronic constipation can lead to colonic dysfunction and related complications. <em>Atractylodes macrocephala</em> Koidz. and <em>Raphanus sativus</em> L. are traditional Chinese medicinal herbs known for their \"Qi-replenishing and spleen-strengthening\" and \"digestion-promoting and stagnation-relieving\" properties, respectively. The herb pair (BZLF) is effective in treating senile constipation. However, the underlying mechanisms by which BZLF alleviating senile constipation remain unclear and require further investigation.</div></div><div><h3>Purpose</h3><div>This study aims to explore how BZLF alleviates senile constipation by promoting intestinal motility via the gut microbiota-short-chain fatty acids (SCFAs)-(5-hydroxytryptamine) 5-HT axis.</div></div><div><h3>Methods</h3><div>A mouse model of senile constipation was established by feeding aged mice a low-fiber diet. The therapeutic effects of BZLF were evaluated by assessing defecation frequency, fecal water content, time to first black stool, small intestine transit rate, and gastric emptying rate. Histological changes in the colon were observed using HE staining and AB-PAS staining. Immunohistochemistry and immunofluorescence were used to detect intestinal barrier-related protein expression in colonic tissues. Serum and colonic hormone levels were measured by ELISA. Western blotting and RT-qPCR were employed to analyze the expression of 5-HT signaling pathway-related proteins and mRNA. Gut microbiota composition was analyzed using 16S rDNA sequencing, and SCFAs levels were detected via GC/MS.</div></div><div><h3>Results</h3><div>BZLF improved defecation function and promoted intestinal motility in the mouse model of senile constipation. BZLF repaired intestinal barrier damage and increased serum levels of motilin (MTL), gastrin (GAS), endothelin (ET), and acetylcholine (ACH), thereby regulating gastrointestinal hormone imbalances. BZLF modulated gut microbiota dysbiosis in senile constipated mice by significantly increasing the abundance of beneficial bacteria (<em>Lactobacillus</em> and <em>Ruminococcus</em>) and suppressing the overgrowth of harmful bacteria (<em>Escherichia-Shigella</em>). Additionally, BZLF elevated SCFAs levels, particularly butyrate, in feces, which activated the 5-HT signaling pathway to alleviate constipation.</div></div><div><h3>Conclusion</h3><div>BZLF significantly alleviates senile constipation. Its mechanism of action is likely related to the modulation of gut microbiota composition, promotion of SCFAs production, and subsequent activation of the 5-HT signaling pathway. This study provides strong theoretical support for the development of BZLF as a potential anti-constipation herbal medicine and offers new therapeutic strategies for the treatment of senile constipation.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 156977"},"PeriodicalIF":6.7,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144338557","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}