Journal of ethnopharmacology最新文献

{"title":"Dantao formula alleviates hepatic fibrosis and portal hypertension via modulation of the cAMP/PKA/ROCK signaling pathway in hepatic stellate cells.","authors":"Rui Zeng, Yanan Guo, Jingshu Qi, Meng Li, Kai Huang, Yuan Peng, Zhengxin Li, Chenghai Liu","doi":"10.1016/j.jep.2025.120650","DOIUrl":"10.1016/j.jep.2025.120650","url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>The Dantao Formula (DTF) consists of Salvia miltiorrhiza Bunge (Danshen) and Prunus persica (L.) Batsch seeds (Taoren), which were the components of promoting circulation and removing stasis in the anti-fibrotic herbal--- Fuzheng Huayu Formula (FZHY). It has demonstrated efficacy in alleviating hepatic fibrosis and portal hypertension (PH); however, its pharmacological mechanisms remain unclear.</p><p><strong>Aim of the study: </strong>The aim is to investigate the effects and molecular mechanisms of DTF on liver fibrosis and PH.</p><p><strong>Materials and methods: </strong>In vivo experiments were evaluated using a CCl₄-induced mouse model with rivaroxaban (RIVA) as a drug control. PH was assessed by direct puncture method. Fibrosis was assessed by Sirius red staining and hydroxyproline. Network pharmacology analysis predicted the potential molecules or signal mediators. In vitro, an LX-2 cells was activated with ET-1, and Y-33075 used as a drug control. ELISA, Western blot, immunohistochemistry and immunofluorescence were conducted to assess the target expression of ET-1, ENDRA, ROCK, cAMP, PKA, MLC and p-MLC.</p><p><strong>Results: </strong>DTF or RIVA could alleviate liver fibrosis and PH compared to the model group. Network pharmacology analysis suggested that cAMP/PKA/ROCK signaling pathway acted as a key target in DTF. In vivo, DTF or RIVA suppressed ET-1, EDNRA and ROCK expression, enhanced cAMP and PKA expression. In vitro, DTF or Y-33075 attenuated the activation of LX-2 cells induced by ET-1, down-regulated ROCK and p-MLC expression, up-regulated cAMP and PKA expression.</p><p><strong>Conclusions: </strong>DTF alleviates liver fibrosis and PH by regulating the cAMP/PKA/ROCK signaling pathway in activated HSCs.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"120650"},"PeriodicalIF":5.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated activity-guided isolation and transcriptomic analysis reveal the therapeutic mechanism of Thonningianin A from Penthhorum chinense Pursh against colorectal cancer via p21 modulation.","authors":"Fanmuchen Zeng, Xuan Jiang, Fengmin Xiong, Siyu Yao, Wenying Lu, Yingli Chen, Huilin Yang, Xianlong Ye","doi":"10.1016/j.jep.2025.120655","DOIUrl":"10.1016/j.jep.2025.120655","url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>Pentrhothrum chinense Pursh (PCP) is a traditional Hmong dual-purpose medicinal plant that is known for its efficacy in activating blood circulation and removing blood stasis, protecting the liver, diuretic and anti-yellowing, and promoting digestion. It is commonly used for lowering blood glucose, protecting kidneys, antioxidant, anti-inflammatory, antibacterial, and has great potential in regulating the intestinal microenvironment and treating cancer. However, relatively few studies have been conducted on its material basis and mechanism of action in colorectal cancer (CRC) treatment.</p><p><strong>Aim of the study: </strong>Identification of the key therapeutic active ingredients in PCP for CRC through in vitro and in vivo experiments, and unraveling and validating their main mechanisms of action in CRC therapy.</p><p><strong>Materials and methods: </strong>Initially, key active compounds were isolated and identified from PCP using SPE, HPLC, and UPLC-MS. In vitro and in vivo experiments demonstrated that the compound inhibits proliferation, migration, and cell cycle progression in HCT116 and HT29 cells, and exhibited tumor-suppressive efficacy in an HT29 nude mouse xenograft model. Finally, the molecular mechanism of CRC treatment was elucidated by combining RNA-seq, TCGA database and siRNA knockdown assay.</p><p><strong>Results: </strong>The key active ingredient of CRC inhibition in PCP was identified as Thonningianin A (TA) by isolation and extraction techniques combined with cellular experiments, and then in vitro experiments showed that TA dose-dependently inhibited the proliferation, migration and clone formation of CRC cells and induced G1-phase blockage, and in vivo experiments showed that high doses of TA significantly inhibited the growth of tumors in nude mice, which further confirmed the therapeutic effect of TA in CRC treatment. Subsequently, in combination with RNA-seq and online pharmacology database, it was found that TA specifically activated oncogene p21/CDKN1A, and its knockdown reversed TA-induced cycle block and proliferation inhibition, and the low expression of p21 in CRC was further confirmed by TCGA data.</p><p><strong>Conclusion: </strong>It is clear that TA is the key active ingredient of PCP against CRC, and its up-regulation of p21 expression induces G1-phase blockade and inhibits tumor progression.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"120655"},"PeriodicalIF":5.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding Gujin Luyan Xuming decoction: How ancient wisdom meets modern science in promoting angiogenesis to ameliorate cerebral infarction.","authors":"Yuzhe Cai, Mengge Zhang, Qiuxing He, Huaguan Lu, Yulin Kuang, Yiheng Huang, Wenfei Liang, Jingling Zhu, Yihui Deng, Yuanqi Zhao, Weimin Ning","doi":"10.1016/j.jep.2025.120652","DOIUrl":"10.1016/j.jep.2025.120652","url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>Gujin Luyan Xuming decoction (XMD), a traditional chinese medicine formula documented in the \"Synopsis of the Golden Chamber\", is an effective prescription for treating cerebral infarction with notable clinical efficacy. However, its molecular mechanism remains to be fully elucidated.</p><p><strong>Aim of the study: </strong>This research seeks to clarify the molecular mechanisms by which XMD facilitates angiogenesis following cerebral infarction.</p><p><strong>Methods: </strong>The therapeutic levels of XMD on cerebral infarction were assessed in vivo, and the bioactive constituents of XMD were identified in systemic circulation. Afterward, the RNA-seq dataset GSE137482 and single-cell sequencing dataset GSE225948 were analyzed using R software, in conjunction with WGCNA, predicted drug targets derived from bioactive components, and angiogenesis-related gene sets, to identify key drug targets. We also performed molecular docking and molecular dynamics simulation. Finally, both in vivo and in vitro experiments were conducted for validation.</p><p><strong>Results: </strong>Our research showed that XMD-H yielded the most significant effect on improving ischemic brain injury. A total of 33 blood-entering components of XMD were identified using HPLC-MS/MS analysis. Network pharmacology, RNA sequencing, single-cell sequencing, and further investigations identified RAB11A as the primary target of XMD's effect in cerebral infarction. According to molecular docking and dynamics simulation, the bioactive components of XMD could partially bind with the RAB11A protein. Animal experiments demonstrated that XMD could enhance the expression of RAB11A, Wnt5a, β-catenin, VEGFA, VEGFR2, and other proteins. The outcomes of in vitro experiments indicated that XMD could further augment cell migration, lumen formation, and the expression of the aforementioned proteins. The silencing of RAB11A led to a partial reduction in XMD's efficacy in promoting cell migration, lumen formation, and the expression of proteins such as RAB11A, Wnt5a, and VEGFR2.</p><p><strong>Conclusions: </strong>XMD could affect the Wnt5a/β-catenin signaling pathway through RAB11A, thereby enhancing angiogenesis in cerebral infarction and mitigating cerebral ischemia injury.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"120652"},"PeriodicalIF":5.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-colitic effects of Centella asiatica (L.) Urb. juice via ERK/p38 and NF-κB signaling modulation and the characterization of a key marker compound.","authors":"Hyun Young Shin, Yun Young Jeong, Jong-Eun Kim, Kwang-Soon Shin, Kwang-Won Yu","doi":"10.1016/j.jep.2025.120657","DOIUrl":"https://doi.org/10.1016/j.jep.2025.120657","url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>Centella asiatica (L.) Urb. (CA), a member of the Apiaceae family encompassing around 50 species, has been traditionally used in Ayurvedic and other folk medicine systems to manage inflammatory disorders.</p><p><strong>Aim of study: </strong>This study explored the protective role of CA-Juice in a dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model. In addition, a validated method for its quality evaluation was established.</p><p><strong>Materials and methods: </strong>BALB/c mice were administered CA-Juice orally for two weeks prior to DSS induction of UC. An HPLC-UVD method was applied to quantify a marker compound for quality evaluation.</p><p><strong>Results: </strong>CA-Juice was well tolerated and significantly improved clinical symptoms of UC. It modulated inflammatory mediators and enhanced intestinal immunoglobulin A levels, while improving epithelial integrity. Histological analysis confirmed that CA-Juice reduced colonic tissue damage and improved mucin production, as demonstrated through the modulation of ERK/p38 MAPK and NF-κB signaling pathways. CA-Juice also elevated cecal concentrations of short-chain fatty acids, contributing to intestinal homeostasis. For standardization, an HPLC-UVD method was developed, showing high linearity, sensitivity, and specificity, and was applied to quantify miquelianin as a key marker compound in CA-Juice.</p><p><strong>Conclusion: </strong>These findings support the potential of CA-Juice as a functional dietary component for preventing intestinal inflammation and provide foundational data for its standardization and future applications.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"120657"},"PeriodicalIF":5.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chrysanthemum morifolium Extract Attenuates Pathological Angiogenesis of Age-Related Macular Degeneration via VEGF and Nrf2 Pathway Modulation.","authors":"Guan-Cheng Jiang, Hong-Ye Pan, Lei Gu, Tian-Tian Cheng, Bing-Xue Zhu, Xuan-Qi Wang, Jia-Yu Yu, Feng Zhu, Ming Lin, Jiang-Ning Hu, Xia-Wei Wang","doi":"10.1016/j.jep.2025.120660","DOIUrl":"https://doi.org/10.1016/j.jep.2025.120660","url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>Chrysanthemum morifolium has long been utilized in Traditional Chinese Medicine to improve visual acuity and alleviate ocular damage. Although recent pharmacological studies highlight its antioxidant and vasoprotective effects, its efficacy against neovascular processes in age-related macular degeneration (AMD) has not been established.</p><p><strong>Aim of the study: </strong>This study aimed to investigate the therapeutic potential and underlying mechanisms of Chrysanthemum morifolium extract (CME) in managing neovascular AMD, emphasizing its effects on vascular endothelial growth factor (VEGF)-mediated angiogenesis and oxidative stress regulation.</p><p><strong>Materials and methods: </strong>In vitro, ARPE-19 retinal pigment epithelial cells underwent hypoxic and oxidative stress assays to measure VEGF, hypoxia-inducible factor 1-alpha (HIF-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation. Human umbilical vein endothelial cells (HUVECs) were treated with a conditioned medium (CM) from CME-exposed ARPE-19 cells to assess migration, invasion, and tube formation. In vivo therapeutic efficacy was validated in cobalt chloride (CoCl₂)-induced zebrafish and laser-induced rat choroidal neovascularization (CNV) models.</p><p><strong>Results: </strong>CME significantly attenuated hypoxia- and CoCl₂-induced upregulation of VEGF and HIF-1α, enhanced Nrf2 signaling, and reduced reactive oxygen species (ROS) in ARPE-19 cells. CME-CM markedly suppressed HUVEC migration, invasion, and angiogenesis. In zebrafish and rat CNV models, CME treatment significantly reduced neovascular lesion area and preserved retinal architecture in a dose-dependent manner, without evident toxicity.</p><p><strong>Conclusions: </strong>CME exerts dual anti-angiogenic and antioxidant effects in AMD models by simultaneously targeting VEGF-driven angiogenesis and oxidative stress, supporting its therapeutic potential as a safe and effective herbal intervention for neovascular AMD.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"120660"},"PeriodicalIF":5.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicological evaluation of Shanzhu Tiqusan, a Garcinia mangostana pericarp-based preparation: Acute and chronic oral safety assessment in rats.","authors":"Shao-Feng Wu, Dan-Yang Ma, Si-Lu Hou, Qiao-Yue Hui, Ya-Rong Gong, Ji-Jun Kang, Chao Han, Zhi-Hui Hao","doi":"10.1016/j.jep.2025.120372","DOIUrl":"10.1016/j.jep.2025.120372","url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>Garcinia mangostana L. (Shanzhu), commonly known as mangosteen, is a tropical tree traditionally used in Southeast Asia and southern China to treat diarrhea, abdominal pain, skin infections, malaria, and septicemia. Its pericarp extract, Shanzhu Tiqusan (SZTQS), is prepared through reflux extraction, spray drying, and sucrose addition.</p><p><strong>Aim of the study: </strong>This study aimed to systematically evaluate the acute and long-term oral toxicity of SZTQS to verify its safety for potential long-term use.</p><p><strong>Materials and methods: </strong>The α-mangostin content in SZTQS was determined by high-performance liquid chromatography (HPLC). Acute oral toxicity was evaluated in rats using a limit dose of 15 g/kg body weight, with a 14-day observation period. For chronic toxicity assessment, SZTQS was incorporated into the feed at concentrations of 2.5, 5, and 15 g/kg feed and administered continuously for 180 days. Parameters monitored throughout the study included clinical signs, body weight, food consumption, hematological and biochemical profiles, and histopathological examination of major organs.</p><p><strong>Results: </strong>HPLC analysis revealed 34.3 mg/g α-mangostin in SZTQS. The acute study showed no mortality or toxicity at 15 g/kg BW, indicating a high safety margin. Chronic administration at 2.5 g/kg feed caused no adverse effects. At 5 g/kg feed, mild changes in blood parameters and occasional organ lesions were observed. At 15 g/kg feed, a significant reduction in body weight and feed/water intake was observed, particularly in male rats, indicating a dose-dependent toxicological effect.</p><p><strong>Conclusions: </strong>SZTQS is non-toxic at a single oral dose exceeding 15 g/kg BW in rats. Long-term intake at 2.5 g/kg feed for 180 days was well tolerated, with a calculated no-observed-effect level (NOEL) of 0.16 g/kg BW/day based on actual intake. This corresponds to a human equivalent dose (HED) of approximately 26 mg/kg BW/day. These findings support the safety of SZTQS for potential long-term oral use in humans.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"120372"},"PeriodicalIF":5.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deacylcynaropicrin from Cyclolepis genistoides attenuates iron-induced oxidative stress and inflammatory signaling in neuron and glial cells.","authors":"Natalia P Alza, Oriana N Benzi Juncos, Valeria Cavallaro, Eva-Maria Pferschy-Wenzig, Teresa Pirker, Rudolf Bauer, Ana Paula Murray, Gabriela A Salvador","doi":"10.1016/j.jep.2025.120348","DOIUrl":"10.1016/j.jep.2025.120348","url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>Cyclolepis genistoides has been traditionally used in Argentina, Chile and Paraguay in chronic diseases to intervene pain and inflammation-related conditions, suggesting a strong anti-inflammatory potential, which may also be useful to target neurodegenerative diseases (ND). However, the anti-(neuro)inflammatory and antioxidant effects of C. genistoides has not been assessed in neurodegeneration models.</p><p><strong>Aim of the study: </strong>To evaluate the antioxidant and anti-inflammatory potential of C. genistoides aqueous extract and its main constituent deacylcynaropicrin (DAC) using neuronal and glial cultures under iron-induced oxidative stress, a common condition in ND.</p><p><strong>Methods: </strong>The metabolite profile of C. genistoides extract was analyzed by UHPLC-DAD-HRMS, and DAC was isolated. The effects of C. genistoides and DAC on iron-induced oxidative stress were assessed using H2DCFDA, NBT, TBARS, and BODIPY^581/591 C11 assays, along with NRF2 status. DAC anti-inflammatory activity was evaluated by NO production, and the expression of NFκB, COX-2, IL-1β and GFAP in glial cells.</p><p><strong>Results: </strong>Pretreatment with C. genistoides extract (20 μg/mL) reduced reactive oxygen species and lipid peroxidation in iron-treated IMR-32 cells. The extract promoted NRF2 nuclear translocation and upregulated GCLc and catalase. DAC exhibited similar antioxidant effects. Furthermore, DAC (10 μM) demonstrated anti-inflammatory activity by inhibiting NO production, NFκB nuclear localization, and COX-2 and IL-1β expression in macrophages and glial cells, and it reduced reactivity and lipid peroxidation in astrocytes.</p><p><strong>Conclusions: </strong>Our work shows for the first time that C. genistoides and DAC display pronounced antioxidant and anti-inflammatory effects in cellular ND models, corroborating the scientific basis of the traditional use.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"120348"},"PeriodicalIF":5.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Dendrobium offfcinale Kimura et Migo polysaccharide ameliorated DNFB-induced atopic dermatitis in mice associated with suppressing MAPK/NF-κB/STAT3 signaling pathways\" [J. Ethnopharmacol. 335 (2024) 118677].","authors":"Jingru Liao, Wenjun Zhao, Yuwei Zhang, Zebin Zou, Qilin Zhang, Dongqiu Chen, Bing Du, Pan Li","doi":"10.1016/j.jep.2025.119827","DOIUrl":"10.1016/j.jep.2025.119827","url":null,"abstract":"","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"119827"},"PeriodicalIF":5.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Neuroprotection against cerebral ischemia/reperfusion by dietary phytochemical extracts from Tibetan turnip (Brassica rapa L.)\" [J. Ethnopharmacol. 265 (2021) 113410].","authors":"Hanyi Hua, Wenyi Zhang, Jiaying Li, Jiayi Li, Chang Liu, Yahui Guo, Yuliang Cheng, Fuwei Pi, Yunfei Xie, Weirong Yao, Yanqin Gao, He Qian","doi":"10.1016/j.jep.2025.119825","DOIUrl":"10.1016/j.jep.2025.119825","url":null,"abstract":"","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"119825"},"PeriodicalIF":5.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of potential disease-drug interactions when prescribed Fuzi for rheumatoid arthritis treatment, with focus on the pharmacokinetics of aconitine, mesaconitine, and hypaconitine.","authors":"Yating Lin, Xiaocui Li, Bingxuan Fu, Cong Xie, Ling Ye","doi":"10.1016/j.jep.2025.120350","DOIUrl":"10.1016/j.jep.2025.120350","url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>Fuzi is a toxic traditional Chinese medicine that is commonly prescribed for rheumatoid arthritis (RA), while CYP3A4 and P-gp are primarily responsible for the metabolism and efflux of its toxic alkaloids: aconitine (AC), mesaconitine (MA), and hypaconitine (HA). However, the RA condition may induce disease-drug interactions due to the elevated IL-6 and TNF-α levels, which significantly inhibit the function of CYPs and P-gp.</p><p><strong>Aim of the study: </strong>To investigate the existence of disease-drug interactions during Fuzi treatment for RA, focusing on the pharmacokinetics of AC, MA, and HA.</p><p><strong>Materials and methods: </strong>An RA model in DBA/1J mice was established using type II collagen, and the expression levels of Cyp3a11 and P-gp in mice were measured under RA conditions. Then, the pharmacokinetics and tissue distribution of AC, MA, and HA following the administration of HSP (the preparations of Fuzi) or pure alkaloids in both normal and RA model mice were investigated using UHPLC-MS/MS. At the same time, we measured the biomarkers indicative of Fuzi's cardiotoxicity in plasma after administering HSP or the individual monomers.</p><p><strong>Results: </strong>In the developed collagen-induced arthritis (CIA) mouse model, we observed significant IL-6 and TNF-α elevation accompanied by reduced hepatic Cyp3a11 (human CYP3A4 homolog) and P-gp expression. Pharmacokinetic analysis revealed remarkable increases in the C_max and AUC_0-t values of AC, MA, and HA following oral administration of Fuzi preparations or pure alkaloids in CIA mice compared with controls. The accumulation of these alkaloids in the heart (the primary target for Fuzi's toxicity), as well as in the intestine, liver, and kidneys of CIA mice, was also significantly elevated. Furthermore, CIA mice exhibited markedly elevated levels of cardiotoxic markers, creatine kinase, and lactate dehydrogenase, which strongly correlated with the AUC_0-t values of AC, MA, and HA.</p><p><strong>Conclusion: </strong>RA-induced cytokine dysregulation potentiates Fuzi's cardiotoxicity through CYP3A4/P-gp suppression-mediated pharmacokinetic alterations. Thus, caution should be exercised regarding the potential cardiotoxicity resulting from disease-drug interactions in RA patients undergoing treatment with Fuzi.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"120350"},"PeriodicalIF":5.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}