Pub Date : 2025-03-07DOI: 10.1016/j.jep.2025.119583
Yun Li , Xiaofei Yu , Yezhi Liu , Shuxin Miao , Xiaoqian Liu , Zhimin Wang , Honglei Zhou
<div><h3>Ethnopharmacological relevance</h3><div>Rhizome of <em>Gastrodia elata</em> Blume (RGE) is a valuable traditional Chinese Medicine (TCM) in the clinical practice. <em>The Compendium of Materia Medica</em> records that RGE has the effect of flatting liver wind out. It has sedative, analgesic, hypnotic, anticonvulsant, anti-hypertensive, anti-myocardial ischemia, anti-arrhythmic and anti-platelet aggregation effects. RGE is often used to relieve and treat vertigo, headache, hypertension, convulsions, and epilepsy in TCM clinic for thousands of years. Accumulated evidences have suggested that hypertension disease is related to the renin-angiotensin-aldosterone system (RAAS) disturbance. However, the potential pharmacodynamic components and anti-hypertensive mechanisms of RGE are unclear now.</div></div><div><h3>Aim of the study</h3><div>The active component and mechanism of RGE in treating hypertension were elucidated to strengthen the quality control and development of anti-hypertensive drugs.</div></div><div><h3>Materials and methods</h3><div>The anti-hypertensive active components of RGE were analyzed by multi-dimensional qualitative analysis method including ethanol extract, <em>in-vitro</em> intestinal absorption, <em>in-vivo</em> plasma. The ultra high performance liquid chromatography-mass spectrometry (UPLC-Q-Exactive MS/MS) analysis technology was adopted to identify these components. Network pharmacology was applied to predicted anti-hypertensive active components, target proteins and pathways. Molecular docking was used to evaluate the potential molecular binding modes between 68 components and nine proteins. Spontaneously hypertensive rats (SHR) model was adopted to evaluate the activity of reducing systolic and diastolic blood pressure (SBP and DBP). Levels of renin, angiotcnsin II (Ang II) and aldosterone (ALD) in serum were determined by Elisa kit. Immunohistochemical were adopted to compare the changes of Ang II receptor 1 (AT1R) protein levels in SHR model and RGE groups.</div></div><div><h3>Results</h3><div>The multi-dimensional components qualitative analysis method of RGE was established. The results showed that 79, 70 and 30 components were identified in RGE ethanol extract, <em>in-vitro</em> intestinal absorption and <em>in-vivo</em> plasma, respectively. These components were mainly parishins, nucleosides, amino acids, phenolic acids, flavonoids, organic acids et al. Network pharmacology results showed that anti-hypertensive active components were nucleosides and organic acids. It was speculated that RGE could exert its anti-hypertensive effect by regulating aldosterone-regulated sodium reabsorption, renin-angiotensin system pathways and related target proteins. Molecular docking results showed that 21 components including parishins, nucleosides and phenolic acids were potential active components of anti-hypertensive. Taking together, parishin A, B, E, C, D, adenosine, N<sup>6</sup>-(4-hydroxybenzyl) adenosine, guanos
{"title":"Pharmacodynamic components and molecular mechanism of Gastrodia elata Blume in treating hypertension: Absorbed components, network pharmacology analysis, molecular docking and in vivo experimental verification","authors":"Yun Li , Xiaofei Yu , Yezhi Liu , Shuxin Miao , Xiaoqian Liu , Zhimin Wang , Honglei Zhou","doi":"10.1016/j.jep.2025.119583","DOIUrl":"10.1016/j.jep.2025.119583","url":null,"abstract":"<div><h3>Ethnopharmacological relevance</h3><div>Rhizome of <em>Gastrodia elata</em> Blume (RGE) is a valuable traditional Chinese Medicine (TCM) in the clinical practice. <em>The Compendium of Materia Medica</em> records that RGE has the effect of flatting liver wind out. It has sedative, analgesic, hypnotic, anticonvulsant, anti-hypertensive, anti-myocardial ischemia, anti-arrhythmic and anti-platelet aggregation effects. RGE is often used to relieve and treat vertigo, headache, hypertension, convulsions, and epilepsy in TCM clinic for thousands of years. Accumulated evidences have suggested that hypertension disease is related to the renin-angiotensin-aldosterone system (RAAS) disturbance. However, the potential pharmacodynamic components and anti-hypertensive mechanisms of RGE are unclear now.</div></div><div><h3>Aim of the study</h3><div>The active component and mechanism of RGE in treating hypertension were elucidated to strengthen the quality control and development of anti-hypertensive drugs.</div></div><div><h3>Materials and methods</h3><div>The anti-hypertensive active components of RGE were analyzed by multi-dimensional qualitative analysis method including ethanol extract, <em>in-vitro</em> intestinal absorption, <em>in-vivo</em> plasma. The ultra high performance liquid chromatography-mass spectrometry (UPLC-Q-Exactive MS/MS) analysis technology was adopted to identify these components. Network pharmacology was applied to predicted anti-hypertensive active components, target proteins and pathways. Molecular docking was used to evaluate the potential molecular binding modes between 68 components and nine proteins. Spontaneously hypertensive rats (SHR) model was adopted to evaluate the activity of reducing systolic and diastolic blood pressure (SBP and DBP). Levels of renin, angiotcnsin II (Ang II) and aldosterone (ALD) in serum were determined by Elisa kit. Immunohistochemical were adopted to compare the changes of Ang II receptor 1 (AT1R) protein levels in SHR model and RGE groups.</div></div><div><h3>Results</h3><div>The multi-dimensional components qualitative analysis method of RGE was established. The results showed that 79, 70 and 30 components were identified in RGE ethanol extract, <em>in-vitro</em> intestinal absorption and <em>in-vivo</em> plasma, respectively. These components were mainly parishins, nucleosides, amino acids, phenolic acids, flavonoids, organic acids et al. Network pharmacology results showed that anti-hypertensive active components were nucleosides and organic acids. It was speculated that RGE could exert its anti-hypertensive effect by regulating aldosterone-regulated sodium reabsorption, renin-angiotensin system pathways and related target proteins. Molecular docking results showed that 21 components including parishins, nucleosides and phenolic acids were potential active components of anti-hypertensive. Taking together, parishin A, B, E, C, D, adenosine, N<sup>6</sup>-(4-hydroxybenzyl) adenosine, guanos","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":"345 ","pages":"Article 119583"},"PeriodicalIF":4.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585892","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}
Pub Date : 2025-03-07DOI: 10.1016/j.jep.2025.119598
Zhe Zhu , Xiuxia Lian , Jicheng Hu , Zhe Wang , Yinghong Zhong , Yuan Zhao , Lu Lu , Yipeng Pan , Mingyan Zhou , Jian Xu
Ethnopharmacological relevance
Alpinia officinarum Hance (A. officinarum), a perennial herb used in the treatment of digestive system cancers, holds significant value for the Li people of Hainan as a traditional Chinese medicine. (R)-5-hydroxy-1,7-diphenyl-3-heptanone (DPHC), a diarylheptanoid component is derived from A. officinarum. Diarylheptanoids have demonstrated anti-proliferative effects on breast cancer cells, neuroblastoma cells, and other tumor cells. However, the pharmacological activity of DPHC in improving hepatocellular carcinoma (HCC) remains undefined.
Aim of the study
To elucidate the anti-HCC effects of DPHC derived from A. officinarum and explore its underlying mechanistic pathways both in vivo and in vitro.
Material and methods
The effects of DPHC on HCC cell lines were evaluated in vitro using cell counting kit-8, EdU cell proliferation assays, a wound healing assay, a three-dimensional tumor spheroid model, and flow cytometry. The ability of DPHC to ameliorate HCC was assessed in vivo via a nude mouse subcutaneous xenograft tumor model, serum biochemical marker detection, and hematoxylin-eosin staining. The molecular mechanism of DPHC in HCC was elucidated through a combination of transcriptome sequencing, cell transfection, immunohistochemistry assay, immunofluorescence staining, quantitative reverse transcription-PCR, and western blot analysis.
Results
DPHC induced significant G0/G1 phase arrest and apoptosis in HepG2 and HCCLM3 cells while also markedly inhibiting tumor growth in nude mice. Mechanically, DPHC directly interacted with centromere-associated protein U (CENPU) to suppress its expression. The reduced expression of CENPU results in decreased interaction with the transcription factor E2F6, thereby affecting the transcriptional activity of the transcription factor E2F1. This subsequently inhibits the expression of downstream cell cycle factors (CCND1, CDK4, and CDK1) and increases apoptosis factors (Caspase 3 and Caspase 9).
Conclusions
DPHC from A. officinarum specifically modulates the function of CENPU in the cell cycle and apoptosis to ameliorate HCC. Our study revealed the anti-HCC effect and underlying mechanism of DPHC, offering new insights and potential targets for HCC treatment.
{"title":"DPHC from Alpinia officinarum Hance specifically modulates the function of CENPU in the cell cycle and apoptosis to ameliorate hepatocellular carcinoma","authors":"Zhe Zhu , Xiuxia Lian , Jicheng Hu , Zhe Wang , Yinghong Zhong , Yuan Zhao , Lu Lu , Yipeng Pan , Mingyan Zhou , Jian Xu","doi":"10.1016/j.jep.2025.119598","DOIUrl":"10.1016/j.jep.2025.119598","url":null,"abstract":"<div><h3>Ethnopharmacological relevance</h3><div><em>Alpinia officinarum</em> Hance (<em>A</em>. <em>officinarum</em>), a perennial herb used in the treatment of digestive system cancers, holds significant value for the Li people of Hainan as a traditional Chinese medicine. (R)-5-hydroxy-1,7-diphenyl-3-heptanone (DPHC), a diarylheptanoid component is derived from <em>A</em>. <em>officinarum</em>. Diarylheptanoids have demonstrated anti-proliferative effects on breast cancer cells, neuroblastoma cells, and other tumor cells. However, the pharmacological activity of DPHC in improving hepatocellular carcinoma (HCC) remains undefined.</div></div><div><h3>Aim of the study</h3><div>To elucidate the anti-HCC effects of DPHC derived from <em>A</em>. <em>officinarum</em> and explore its underlying mechanistic pathways both in vivo and in vitro.</div></div><div><h3>Material and methods</h3><div>The effects of DPHC on HCC cell lines were evaluated in vitro using cell counting kit-8, EdU cell proliferation assays, a wound healing assay, a three-dimensional tumor spheroid model, and flow cytometry. The ability of DPHC to ameliorate HCC was assessed in vivo via a nude mouse subcutaneous xenograft tumor model, serum biochemical marker detection, and hematoxylin<em>-</em>eosin staining. The molecular mechanism of DPHC in HCC was elucidated through a combination of transcriptome sequencing, cell transfection, immunohistochemistry assay, immunofluorescence staining, quantitative reverse transcription-PCR, and western blot analysis.</div></div><div><h3>Results</h3><div>DPHC induced significant G0/G1 phase arrest and apoptosis in HepG2 and HCCLM3 cells while also markedly inhibiting tumor growth in nude mice. Mechanically, DPHC directly interacted with centromere-associated protein U (CENPU) to suppress its expression. The reduced expression of CENPU results in decreased interaction with the transcription factor E2F6, thereby affecting the transcriptional activity of the transcription factor E2F1. This subsequently inhibits the expression of downstream cell cycle factors (CCND1, CDK4, and CDK1) and increases apoptosis factors (Caspase 3 and Caspase 9).</div></div><div><h3>Conclusions</h3><div>DPHC from <em>A</em>. <em>officinarum</em> specifically modulates the function of CENPU in the cell cycle and apoptosis to ameliorate HCC. Our study revealed the anti-HCC effect and underlying mechanism of DPHC, offering new insights and potential targets for HCC treatment.</div></div>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":"345 ","pages":"Article 119598"},"PeriodicalIF":4.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585815","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}
Pub Date : 2025-03-07DOI: 10.1016/j.jep.2025.119576
Wenjie Bi , Yougang Zhang , Zixu Lu , Huanxin Zhao , Haiyang Wang , Songsong Wang , Rajiv Kumar Malhotra , Xiaojing Wang , Liwen Han
Ethnopharmacological relevance
As a traditional health beverage in China, Dark Tea (DT) have been proved to effectively mitigate vascular lesions induced by hyperlipidemia. However, key active ingredient of DT and the potential pharmacological mechanism protecting vascular endothelium is still unclear.
Aim of the study: This study aimed to investigate the key active ingredient in DT and reveal underlying mechanism responsible for its protective effect on vascular endothelium.
Materials and methods
The protective effect of DT on vascular endothelium was evaluated using a high-fat diet-induced zebrafish model. The chemical ingredients of DT were analyzed by ultra-high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-Q/TOF-MS), and the active ingredients were identified using a multidimensional molecular data mining approach. Molecular biology experiments were used to explore the underlying mechanisms of DT and its active components.
Results
The results showed that DT could significantly prevent the deposition of circulatory lipids on the vascular wall, inhibit inflammatory cell aggregation, and reduce microvascular hyperplasia in zebrafish models. An integrated multi-dimensional data mining technique was successfully employed to identify a key active lignan in DT, matairesinol. Furthermore, DT and matairesinol significantly protected endothelial cells by activating AMPK phosphorylation, thereby inhibiting downstream HMGCR protein expression and promoting PPARγ phosphorylation.
Conclusions
Matairesinol has been characterized as a key active ingredient in DT. It protects against high-fat-induced vascular endothelial damage by activating AMPK and downstream signaling pathways. These findings offer new insights into the therapeutic potential of DT as a daily dietary supplement for maintaining vascular health.
{"title":"Matairesinol discovered as a key active ingredient in Chinese dark tea protects against high-fat induced endothelial injury via activating AMPK phosphorylation","authors":"Wenjie Bi , Yougang Zhang , Zixu Lu , Huanxin Zhao , Haiyang Wang , Songsong Wang , Rajiv Kumar Malhotra , Xiaojing Wang , Liwen Han","doi":"10.1016/j.jep.2025.119576","DOIUrl":"10.1016/j.jep.2025.119576","url":null,"abstract":"<div><h3>Ethnopharmacological relevance</h3><div>As a traditional health beverage in China, Dark Tea (DT) have been proved to effectively mitigate vascular lesions induced by hyperlipidemia. However, key active ingredient of DT and the potential pharmacological mechanism protecting vascular endothelium is still unclear.</div><div><em>Aim of the study</em>: This study aimed to investigate the key active ingredient in DT and reveal underlying mechanism responsible for its protective effect on vascular endothelium.</div></div><div><h3>Materials and methods</h3><div>The protective effect of DT on vascular endothelium was evaluated using a high-fat diet-induced zebrafish model. The chemical ingredients of DT were analyzed by ultra-high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-Q/TOF-MS), and the active ingredients were identified using a multidimensional molecular data mining approach. Molecular biology experiments were used to explore the underlying mechanisms of DT and its active components.</div></div><div><h3>Results</h3><div>The results showed that DT could significantly prevent the deposition of circulatory lipids on the vascular wall, inhibit inflammatory cell aggregation, and reduce microvascular hyperplasia in zebrafish models. An integrated multi-dimensional data mining technique was successfully employed to identify a key active lignan in DT, matairesinol. Furthermore, DT and matairesinol significantly protected endothelial cells by activating AMPK phosphorylation, thereby inhibiting downstream HMGCR protein expression and promoting PPARγ phosphorylation.</div></div><div><h3>Conclusions</h3><div>Matairesinol has been characterized as a key active ingredient in DT. It protects against high-fat-induced vascular endothelial damage by activating AMPK and downstream signaling pathways. These findings offer new insights into the therapeutic potential of DT as a daily dietary supplement for maintaining vascular health.</div></div>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":"345 ","pages":"Article 119576"},"PeriodicalIF":4.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585885","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}
Pub Date : 2025-03-07DOI: 10.1016/j.jep.2025.119597
Xiaojing Liu , Jiamin Zhao , Jia Liu , Yan Huang , Wei Deng , Luwen Yan , Ming Cui , Xinhua Pan , Huiwen Xiao , Xingzhong Liu
Ethnopharmacological relevance
Aging is a complex, universal process characterized by structural and functional decline across multiple organs. Ganoderma lucidum (G. lucidum), a renowned traditional Chinese medicinal fungus, has long been recognized for its anti-aging properties. However, the underlying mechanisms remain incompletely understood.
Aim of the study
This study aimed to investigate the anti-aging effects of G. lucidum and its underlying mechanisms.
Materials and methods
We investigated the anti-aging effects of G. lucidum sporoderm-broken spore powder (Gl-SBSP) on Caenorhabditis elegans (C. elegans) lifespan and aging across multiple organs using natural aging, D-galactose (D-gal)-induced aging, and radiation-induced premature senescence mouse models. In C. elegans, we assessed lifespan, reproductive capacity, body length, pharyngeal pumping, body bends, fat and lipofuscin levels, as well as reactive oxygen species (ROS) accumulation. In mice, histopathological staining, complete blood counts, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate tissue damage, while quantitative real-time PCR (RT-qPCR) was employed to access small intestine barrier integrity. Western blot (WB) and immunohistochemistry (IHC) were utilized to analyze the distribution of alpha Klotho (α-Klotho) in the kidney, blood, and urine.
Results
Gl-SBSP significantly extended C. elegans lifespan, improved reproductive capacity and mobility, and reduced lipofuscin and ROS levels. In naturally aged mice, Gl-SBSP enhanced physical appearance and performance. Additionally, Gl-SBSP alleviated aging-related structural and functional decline in multiple organs, including the colon, spleen, kidneys, liver, and small intestine, across all aging models. Biochemical analyses revealed that Gl-SBSP increased transmembrane α-Klotho (mα-Klotho) and soluble α-Klotho (sα-Klotho) levels in kidney tissue and elevated sα-Klotho levels in serum and urine.
Conclusion
This study is the first to demonstrate that G. lucidum exerts α-Klotho-associated anti-aging effects in animal models, highlighting its potential as an anti-aging intervention.
{"title":"Association of α-Klotho with anti-aging effects of Ganoderma lucidum in animal models","authors":"Xiaojing Liu , Jiamin Zhao , Jia Liu , Yan Huang , Wei Deng , Luwen Yan , Ming Cui , Xinhua Pan , Huiwen Xiao , Xingzhong Liu","doi":"10.1016/j.jep.2025.119597","DOIUrl":"10.1016/j.jep.2025.119597","url":null,"abstract":"<div><h3>Ethnopharmacological relevance</h3><div>Aging is a complex, universal process characterized by structural and functional decline across multiple organs. <em>Ganoderma lucidum</em> (<em>G. lucidum</em>), a renowned traditional Chinese medicinal fungus, has long been recognized for its anti-aging properties. However, the underlying mechanisms remain incompletely understood.</div></div><div><h3>Aim of the study</h3><div>This study aimed to investigate the anti-aging effects of <em>G. lucidum</em> and its underlying mechanisms.</div></div><div><h3>Materials and methods</h3><div>We investigated the anti-aging effects of <em>G. lucidum</em> sporoderm-broken spore powder (<em>Gl</em>-SBSP) on <em>Caenorhabditis elegans</em> (<em>C. elegans</em>) lifespan and aging across multiple organs using natural aging, D-galactose (D-gal)-induced aging, and radiation-induced premature senescence mouse models. In <em>C. elegans</em>, we assessed lifespan, reproductive capacity, body length, pharyngeal pumping, body bends, fat and lipofuscin levels, as well as reactive oxygen species (ROS) accumulation. In mice, histopathological staining, complete blood counts, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate tissue damage, while quantitative real-time PCR (RT-qPCR) was employed to access small intestine barrier integrity. Western blot (WB) and immunohistochemistry (IHC) were utilized to analyze the distribution of alpha Klotho (α-Klotho) in the kidney, blood, and urine.</div></div><div><h3>Results</h3><div><em>Gl</em>-SBSP significantly extended <em>C. elegans</em> lifespan, improved reproductive capacity and mobility, and reduced lipofuscin and ROS levels. In naturally aged mice, <em>Gl</em>-SBSP enhanced physical appearance and performance. Additionally, <em>Gl</em>-SBSP alleviated aging-related structural and functional decline in multiple organs, including the colon, spleen, kidneys, liver, and small intestine, across all aging models. Biochemical analyses revealed that <em>Gl</em>-SBSP increased transmembrane α-Klotho (mα-Klotho) and soluble α-Klotho (sα-Klotho) levels in kidney tissue and elevated sα-Klotho levels in serum and urine.</div></div><div><h3>Conclusion</h3><div>This study is the first to demonstrate that <em>G. lucidum</em> exerts α-Klotho-associated anti-aging effects in animal models, highlighting its potential as an anti-aging intervention.</div></div>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":"345 ","pages":"Article 119597"},"PeriodicalIF":4.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585811","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}
Pub Date : 2025-03-07DOI: 10.1016/j.jep.2025.119607
Hai-Xin Liu , Yu-Chang Li , Ru-Bin Su , Cai-Xia Liu , Shi-Yuan Wen
<div><h3>Ethnopharmacological relevance</h3><div><em>Astragalus membranaceus</em>, commonly known as Huangqi in China, is a traditional herbal medicine that has attracted significant attention for its immunomodulatory effects. It has been widely studied in various clinical contexts, including cancer treatment. <em>Astragalus</em> injection (HQI) is clinically used for treating myocarditis and cardiac insufficiency. However, its potential therapeutic effects on osteosarcoma, a highly aggressive bone tumor, remain largely unexplored.</div></div><div><h3>Aim of the study</h3><div>The aim of this study was to investigate the potential therapeutic effects of HQI on osteosarcoma and to elucidate its underlying mechanisms of action. Specifically, we aimed to determine whether HQI could inhibit osteosarcoma growth <em>in vivo</em>, identify its key active components and molecular targets, and explore its immunomodulatory effects on the tumor microenvironment.</div></div><div><h3>Materials and methods</h3><div>Mice with osteosarcoma were treated with HQI, and tumor growth was monitored. The number of CD8<sup>+</sup> T cells in spleen was assessed using flow cytometry. High-performance liquid chromatography coupled with electrospray ionization time-of-flight mass spectrometry (HPLC-ESI-TOF-MS/MS) was used to identify the active ingredients of HQI that entered the peripheral blood of treated mice. Network pharmacology and weighted gene co-expression network analysis (WGCNA) were employed to identify key molecular targets of HQI in osteosarcoma inhibition. In vitro cell assays were conducted to evaluate the effects of HQI and its active components on osteosarcoma cell viability. Molecular docking studies were performed to identify the binding affinity of key active components to the identified molecular targets. The expression of Cathepsin L (CTSL) and the activation of cytotoxic T lymphocytes were assessed <em>in vivo</em> and in vitro to elucidate the primary mechanism of action of HQI and its active component calycosin 7-O-β-D-glucoside (CG).</div></div><div><h3>Results</h3><div>Our study found that HQI significantly suppresses osteosarcoma growth <em>in vivo</em> by increasing the number of CD8<sup>+</sup> T cells, without causing significant toxic side effects. Eight active ingredients entered the peripheral blood of mice through HPLC-ESI-TOF-MS/MS detection. The network pharmacology and WGCNA revealed that CTSL was a key target of HQI in osteosarcoma inhibition. Cell assays and molecular docking identified CG as the key active component of HQI to inhibit the activity of osteosarcoma cells, capable of binding to CTSL. <em>In vivo</em>, CG activates cytotoxic T lymphocytes and inhibits CTSL expression, thereby exerting its anti-osteosarcoma effects.</div></div><div><h3>Conclusion</h3><div>Our study demonstrated that HQI, particularly its active component CG, holds potential as a therapeutic agent for osteosarcoma. The primary mechanism underlying its ant
{"title":"Astragalus injection inhibits the growth of osteosarcoma by activating cytotoxic T lymphocyte and targeting CTSL","authors":"Hai-Xin Liu , Yu-Chang Li , Ru-Bin Su , Cai-Xia Liu , Shi-Yuan Wen","doi":"10.1016/j.jep.2025.119607","DOIUrl":"10.1016/j.jep.2025.119607","url":null,"abstract":"<div><h3>Ethnopharmacological relevance</h3><div><em>Astragalus membranaceus</em>, commonly known as Huangqi in China, is a traditional herbal medicine that has attracted significant attention for its immunomodulatory effects. It has been widely studied in various clinical contexts, including cancer treatment. <em>Astragalus</em> injection (HQI) is clinically used for treating myocarditis and cardiac insufficiency. However, its potential therapeutic effects on osteosarcoma, a highly aggressive bone tumor, remain largely unexplored.</div></div><div><h3>Aim of the study</h3><div>The aim of this study was to investigate the potential therapeutic effects of HQI on osteosarcoma and to elucidate its underlying mechanisms of action. Specifically, we aimed to determine whether HQI could inhibit osteosarcoma growth <em>in vivo</em>, identify its key active components and molecular targets, and explore its immunomodulatory effects on the tumor microenvironment.</div></div><div><h3>Materials and methods</h3><div>Mice with osteosarcoma were treated with HQI, and tumor growth was monitored. The number of CD8<sup>+</sup> T cells in spleen was assessed using flow cytometry. High-performance liquid chromatography coupled with electrospray ionization time-of-flight mass spectrometry (HPLC-ESI-TOF-MS/MS) was used to identify the active ingredients of HQI that entered the peripheral blood of treated mice. Network pharmacology and weighted gene co-expression network analysis (WGCNA) were employed to identify key molecular targets of HQI in osteosarcoma inhibition. In vitro cell assays were conducted to evaluate the effects of HQI and its active components on osteosarcoma cell viability. Molecular docking studies were performed to identify the binding affinity of key active components to the identified molecular targets. The expression of Cathepsin L (CTSL) and the activation of cytotoxic T lymphocytes were assessed <em>in vivo</em> and in vitro to elucidate the primary mechanism of action of HQI and its active component calycosin 7-O-β-D-glucoside (CG).</div></div><div><h3>Results</h3><div>Our study found that HQI significantly suppresses osteosarcoma growth <em>in vivo</em> by increasing the number of CD8<sup>+</sup> T cells, without causing significant toxic side effects. Eight active ingredients entered the peripheral blood of mice through HPLC-ESI-TOF-MS/MS detection. The network pharmacology and WGCNA revealed that CTSL was a key target of HQI in osteosarcoma inhibition. Cell assays and molecular docking identified CG as the key active component of HQI to inhibit the activity of osteosarcoma cells, capable of binding to CTSL. <em>In vivo</em>, CG activates cytotoxic T lymphocytes and inhibits CTSL expression, thereby exerting its anti-osteosarcoma effects.</div></div><div><h3>Conclusion</h3><div>Our study demonstrated that HQI, particularly its active component CG, holds potential as a therapeutic agent for osteosarcoma. The primary mechanism underlying its ant","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":"345 ","pages":"Article 119607"},"PeriodicalIF":4.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585813","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}
<div><h3>Ethnopharmacological relevance</h3><div><em>Gentiana</em> is the largest genus within the <em>Gentianaceae</em> family, comprising around 400 species that are widely distributed in temperate alpine regions worldwide, including the Mongolian Plateau. Despite their broad distribution, no comprehensive review on the distribution, ethnobotany, traditional uses, phytochemistry, pharmacology, and toxicology of <em>Gentiana</em> species in the Mongolian plateau.</div></div><div><h3>Aim</h3><div>This paper aims to provide the first detailed summary of <em>Gentiana</em> species distributed in the Mongolian Plateau, including those in Mongolia. It comprehensively addresses their botanical characteristics, traditional applications, phytochemistry, pharmacology, and toxicity, of <em>Gentiana</em>, providing a scientific basis for further research and identifying gaps in knowledge.</div></div><div><h3>Materials and methods</h3><div>Data were collected through a comprehensive survey of journal articles, books, and dissertations from databases such as Web of Science, ScienceDirect, Google Scholar, PubMed, Springer Link, CNKI, VIP, and Wan Fang Data. Additionally, online resources like Flora of China and Plants of the World Online were consulted for species distribution and scientific name verification. Phytochemical compounds were visualized using Chem Draw 14.0 software.</div></div><div><h3>Results</h3><div>This review identifies twenty-nine <em>Gentiana</em> species distributed in the Mongolian Plateau, with nine species having documented folkloric uses for the treating digestive, skin, joint diseases, and sore throat, etc. Phytochemical studies have led to the isolation and identification of 602 compounds, including iridoids, triterpenoids, flavonoids, lignans, coumarins, xanthones, alkaloids, fatty acids, amino acids, organic acids, and polysaccharides. Notably, gentiopicroside (75) and swertiamarin (118) are the most studied monomeric compounds. Crude extracts of <em>Gentiana</em> show a broad spectrum of pharmacological activities, such as anti-inflammatory, analgesic, anti-bacterial, antioxidant, anti-tumor, anti-cancer, anti-diabetic, immunomodulatory, hepatoprotective, gastroprotective, neuroprotective, and joint and bone protective activities, etc. These extracts exhibit no apparent toxicity <em>in vivo</em> and <em>in vitro</em> studies. However, clinical research on the therapeutic applications of <em>Gentiana</em> remains limited.</div></div><div><h3>Conclusions</h3><div>This review provides the first comprehensive summary of <em>Gentiana</em> species from the Mongolian Plateau, covering their distribution, morphology, phytochemistry, traditional uses, and pharmacological activities. Compared to existing literature, it offers a more thorough taxa, emphasizing key bioactive compounds such as gentiopicroside and swertiamarin, which are recognized for their anti-inflammatory and hepatoprotective effects. The review also reveals the correlatio
{"title":"A comprehensive and systemic review of the Gentiana: Ethnobotany, traditional applications, phytochemistry, pharmacology, and toxicology in the Mongolian Plateau","authors":"Hongzhen Yu , Batzaya Gachmaa , Jiaoneng Yu , Tian-Liang , Xorgan Uranghai , Guangying Guo , Weiwei Xu , Ping Wang , Jinxin Liu , Azzaya Jukov , Urtnasan Mandakh , Danzanchadav Ganbat , Tsambaa Battseren , Almaz Borjigidai","doi":"10.1016/j.jep.2025.119573","DOIUrl":"10.1016/j.jep.2025.119573","url":null,"abstract":"<div><h3>Ethnopharmacological relevance</h3><div><em>Gentiana</em> is the largest genus within the <em>Gentianaceae</em> family, comprising around 400 species that are widely distributed in temperate alpine regions worldwide, including the Mongolian Plateau. Despite their broad distribution, no comprehensive review on the distribution, ethnobotany, traditional uses, phytochemistry, pharmacology, and toxicology of <em>Gentiana</em> species in the Mongolian plateau.</div></div><div><h3>Aim</h3><div>This paper aims to provide the first detailed summary of <em>Gentiana</em> species distributed in the Mongolian Plateau, including those in Mongolia. It comprehensively addresses their botanical characteristics, traditional applications, phytochemistry, pharmacology, and toxicity, of <em>Gentiana</em>, providing a scientific basis for further research and identifying gaps in knowledge.</div></div><div><h3>Materials and methods</h3><div>Data were collected through a comprehensive survey of journal articles, books, and dissertations from databases such as Web of Science, ScienceDirect, Google Scholar, PubMed, Springer Link, CNKI, VIP, and Wan Fang Data. Additionally, online resources like Flora of China and Plants of the World Online were consulted for species distribution and scientific name verification. Phytochemical compounds were visualized using Chem Draw 14.0 software.</div></div><div><h3>Results</h3><div>This review identifies twenty-nine <em>Gentiana</em> species distributed in the Mongolian Plateau, with nine species having documented folkloric uses for the treating digestive, skin, joint diseases, and sore throat, etc. Phytochemical studies have led to the isolation and identification of 602 compounds, including iridoids, triterpenoids, flavonoids, lignans, coumarins, xanthones, alkaloids, fatty acids, amino acids, organic acids, and polysaccharides. Notably, gentiopicroside (75) and swertiamarin (118) are the most studied monomeric compounds. Crude extracts of <em>Gentiana</em> show a broad spectrum of pharmacological activities, such as anti-inflammatory, analgesic, anti-bacterial, antioxidant, anti-tumor, anti-cancer, anti-diabetic, immunomodulatory, hepatoprotective, gastroprotective, neuroprotective, and joint and bone protective activities, etc. These extracts exhibit no apparent toxicity <em>in vivo</em> and <em>in vitro</em> studies. However, clinical research on the therapeutic applications of <em>Gentiana</em> remains limited.</div></div><div><h3>Conclusions</h3><div>This review provides the first comprehensive summary of <em>Gentiana</em> species from the Mongolian Plateau, covering their distribution, morphology, phytochemistry, traditional uses, and pharmacological activities. Compared to existing literature, it offers a more thorough taxa, emphasizing key bioactive compounds such as gentiopicroside and swertiamarin, which are recognized for their anti-inflammatory and hepatoprotective effects. The review also reveals the correlatio","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":"345 ","pages":"Article 119573"},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585881","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}
Pub Date : 2025-03-06DOI: 10.1016/j.jep.2025.119588
Yanze Yang , Felix Boahen Owusu , Han Wu , Xinyue Zhang , Ruiqiao Li , Zhanbiao Liu , Shaozhuo Zhang , Ling Leng , Qilong Wang
<div><h3>Ethnopharmacological relevance</h3><div>Natural products represent a unique medical approach to treating disease and have been used in clinical practice for thousands of years in cardiovascular disease (CVDs). In recent years, natural products have received increasing attention for their high efficiency, safety, and low toxicity, and their targeted regulation of mitochondria offers promising strategies for the treatment of CVDs. However, the potential mechanisms by which natural products target mitochondria for cardiovascular treatment have not been fully elucidated.</div></div><div><h3>Aim of the study</h3><div>Literature from the past decade is reviewed to emphasize the therapeutic efficacy and potential mechanisms of natural products targeting mitochondria in the treatment of CVDs.</div></div><div><h3>Materials and methods</h3><div>In the NCBI PubMed database, relevant literature was searched using ‘natural products’, ‘mitochondria’ and ‘cardiovascular disease’ as search terms, and review papers were excluded. The remaining articles were screened for relevance. Priority was given to articles using rat models, in vivo, <em>ex vivo</em> or in vitro assays. The resulting articles were categorized into natural product categories, including saponins, alkaloids, plant extracts and preparations. This article reviews the research progress on mitochondria as potential therapeutic targets for CVDs and summarizes the application of mitochondria-targeted natural products in the treatment of CVDs.</div></div><div><h3>Results</h3><div>Mitochondrial damage may be attributed to impairment of biogenesis (mitochondrial number and mitochondrial DNA damage), dynamics disruption (mitophagy inhibition and overpromotion, fusion and fission),disruption of optimal function including Adenosine triphosphate generation, Reactive oxygen species (ROS) production, fatty acid β oxidation, mitochondrial membrane permeability, calcium homeostasis imbalance, and membrane potential depolarization. Mitochondrial dysfunction or damage leads to cardiomyocyte dysfunction, ion disorders, cell death, and ultimately CVDs, such as myocardial infarction, heart failure, ischemia reperfusion, and diabetic heart disease. Natural products, which include flavonoids, saponins, phenolic acids, alkaloids, polysaccharides, extracts, and formulations, are seen to have significant clinical efficacy in the treatment of CVDs. Mechanistically, natural products regulate mitophagy, mitochondrial fusion and fission, while improving mitochondrial respiratory function, reducing ROS production, and inhibiting mitochondria-dependent apoptosis in cardiomyocytes, thereby protecting myocardial cells and heart function.</div></div><div><h3>Conclusions</h3><div>This paper reviews the potential and mechanism of natural products to regulate mitochondria for the treatment of CVDs, creating more opportunities for understanding their therapeutic targets and derivatization of lead compounds, and providing a sc
{"title":"Mitochondria as therapeutic targets for Natural Products in the treatment of Cardiovascular Diseases","authors":"Yanze Yang , Felix Boahen Owusu , Han Wu , Xinyue Zhang , Ruiqiao Li , Zhanbiao Liu , Shaozhuo Zhang , Ling Leng , Qilong Wang","doi":"10.1016/j.jep.2025.119588","DOIUrl":"10.1016/j.jep.2025.119588","url":null,"abstract":"<div><h3>Ethnopharmacological relevance</h3><div>Natural products represent a unique medical approach to treating disease and have been used in clinical practice for thousands of years in cardiovascular disease (CVDs). In recent years, natural products have received increasing attention for their high efficiency, safety, and low toxicity, and their targeted regulation of mitochondria offers promising strategies for the treatment of CVDs. However, the potential mechanisms by which natural products target mitochondria for cardiovascular treatment have not been fully elucidated.</div></div><div><h3>Aim of the study</h3><div>Literature from the past decade is reviewed to emphasize the therapeutic efficacy and potential mechanisms of natural products targeting mitochondria in the treatment of CVDs.</div></div><div><h3>Materials and methods</h3><div>In the NCBI PubMed database, relevant literature was searched using ‘natural products’, ‘mitochondria’ and ‘cardiovascular disease’ as search terms, and review papers were excluded. The remaining articles were screened for relevance. Priority was given to articles using rat models, in vivo, <em>ex vivo</em> or in vitro assays. The resulting articles were categorized into natural product categories, including saponins, alkaloids, plant extracts and preparations. This article reviews the research progress on mitochondria as potential therapeutic targets for CVDs and summarizes the application of mitochondria-targeted natural products in the treatment of CVDs.</div></div><div><h3>Results</h3><div>Mitochondrial damage may be attributed to impairment of biogenesis (mitochondrial number and mitochondrial DNA damage), dynamics disruption (mitophagy inhibition and overpromotion, fusion and fission),disruption of optimal function including Adenosine triphosphate generation, Reactive oxygen species (ROS) production, fatty acid β oxidation, mitochondrial membrane permeability, calcium homeostasis imbalance, and membrane potential depolarization. Mitochondrial dysfunction or damage leads to cardiomyocyte dysfunction, ion disorders, cell death, and ultimately CVDs, such as myocardial infarction, heart failure, ischemia reperfusion, and diabetic heart disease. Natural products, which include flavonoids, saponins, phenolic acids, alkaloids, polysaccharides, extracts, and formulations, are seen to have significant clinical efficacy in the treatment of CVDs. Mechanistically, natural products regulate mitophagy, mitochondrial fusion and fission, while improving mitochondrial respiratory function, reducing ROS production, and inhibiting mitochondria-dependent apoptosis in cardiomyocytes, thereby protecting myocardial cells and heart function.</div></div><div><h3>Conclusions</h3><div>This paper reviews the potential and mechanism of natural products to regulate mitochondria for the treatment of CVDs, creating more opportunities for understanding their therapeutic targets and derivatization of lead compounds, and providing a sc","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":"345 ","pages":"Article 119588"},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585888","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}
Pub Date : 2025-03-06DOI: 10.1016/j.jep.2025.119586
Min Zhan , Xiaoyu Zheng , Jiaming Gao , Shengnan Shi , Wenting Song , Mingjiang Yao , Linjuan Sun , Xiaodi Fan , Yehao Zhang , Jianxun Liu
Ethnopharmacological relevance
Multiple cerebral infarctions (MCIs) represent a common type of ischaemic stroke that affects or even endangers a patient's life. Qilong capsule (QLC), a Chinese patent medicine made from Buyang Huanwu Decoction (BYHWD) is suitable for treating the sequelae of ischaemic stroke, such as multi-infarct dementia (MID). However, its biological mechanism has not been fully explored.
Ami of the study
The aim of this study was to explore the mechanism of QLC in treating MCI and its sequelae.
Methods
Male SD rats aged 7–8 weeks and weighing 210–230 g were used as an MCI model, and QLC was used as interventions. The neurobehavioural effects of QLC on MCI model rats were evaluated by observing body weight, neurological function score, and forelimb grip and water maze test results. The effects of QLC on neurons and microglia were observed via haematoxylin‒eosin (HE) staining, silver staining, transmission electron microscopy and positron emission tomography/computed tomography (PET/CT). The effects of QLC on platelets were observed via the platelet aggregation rate and flow cytometry (FCM). Finally, the mechanism of QLC was verified via ELISA, immunofluorescence staining and Western blotting.
Results
These experiments showed that QLC improves neurobehavioural measures, forelimb grip strength, and spatial memory after MCI by ameliorating brain tissue and neuronal damage. QLC also effectively inhibited the inflammatory response after MCI. We also found that QLC can decrease microglia activation and reduce the expression of translocator protein 18 kDa (TSPO). QLC can improve platelet aggregation and reduce the expression of CD62p and CD61, indicating that QLC has a significant anti-platelet aggregation effect. At the molecular level, we found that QLC affects the content of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), reduces the expression of recombinant purinergic receptor P2Y, G protein coupled 12 (P2Y12) in microglia, and regulates the P2Y12/adenylate cyclase (AC)/cAMP signalling pathway.
Conclusions
QLC can ameliorate neuronal necrosis and MID induced by MCI and has an antiplatelet aggregation effect in rats. QLC may treat MID by regulating P2Y12/AC/cAMP.
{"title":"Qilong capsule regulates microglial function and inhibits platelet activation after multiple cerebral infarctions by regulating the P2Y12/AC/cAMP signalling pathway","authors":"Min Zhan , Xiaoyu Zheng , Jiaming Gao , Shengnan Shi , Wenting Song , Mingjiang Yao , Linjuan Sun , Xiaodi Fan , Yehao Zhang , Jianxun Liu","doi":"10.1016/j.jep.2025.119586","DOIUrl":"10.1016/j.jep.2025.119586","url":null,"abstract":"<div><h3>Ethnopharmacological relevance</h3><div>Multiple cerebral infarctions (MCIs) represent a common type of ischaemic stroke that affects or even endangers a patient's life. Qilong capsule (QLC), a Chinese patent medicine made from Buyang Huanwu Decoction (BYHWD) is suitable for treating the sequelae of ischaemic stroke, such as multi-infarct dementia (MID). However, its biological mechanism has not been fully explored.</div></div><div><h3>Ami of the study</h3><div>The aim of this study was to explore the mechanism of QLC in treating MCI and its sequelae.</div></div><div><h3>Methods</h3><div>Male SD rats aged 7–8 weeks and weighing 210–230 g were used as an MCI model, and QLC was used as interventions. The neurobehavioural effects of QLC on MCI model rats were evaluated by observing body weight, neurological function score, and forelimb grip and water maze test results. The effects of QLC on neurons and microglia were observed via haematoxylin‒eosin (HE) staining, silver staining, transmission electron microscopy and positron emission tomography/computed tomography (PET/CT). The effects of QLC on platelets were observed via the platelet aggregation rate and flow cytometry (FCM). Finally, the mechanism of QLC was verified via ELISA, immunofluorescence staining and Western blotting.</div></div><div><h3>Results</h3><div>These experiments showed that QLC improves neurobehavioural measures, forelimb grip strength, and spatial memory after MCI by ameliorating brain tissue and neuronal damage. QLC also effectively inhibited the inflammatory response after MCI. We also found that QLC can decrease microglia activation and reduce the expression of translocator protein 18 kDa (TSPO). QLC can improve platelet aggregation and reduce the expression of CD62p and CD61, indicating that QLC has a significant anti-platelet aggregation effect. At the molecular level, we found that QLC affects the content of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), reduces the expression of recombinant purinergic receptor P2Y, G protein coupled 12 (P2Y<sub>12</sub>) in microglia, and regulates the P2Y<sub>12</sub>/adenylate cyclase (AC)/cAMP signalling pathway.</div></div><div><h3>Conclusions</h3><div>QLC can ameliorate neuronal necrosis and MID induced by MCI and has an antiplatelet aggregation effect in rats. QLC may treat MID by regulating P2Y<sub>12</sub>/AC/cAMP.</div></div>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":"345 ","pages":"Article 119586"},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578006","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}
Pub Date : 2025-03-06DOI: 10.1016/j.jep.2025.119589
Yuanchao Li , Lingwei Zhou , Kang Sun , Ran Guo , Zehua Li , Qingqing Wen , Guifeng Fu , Shuohui Yang
Ethnopharmacological relevance
Bufalin is a potent bioactive compound extracted from the venom of toads such as Bufo gargarizans. It has rich pharmacological effects, and its traditional applications mainly include anti-cancer, anti-inflammatory and analgesic, especially in cancer treatment, which has been a hot topic of research. Prior research has suggested that bufalin may have anti-tumor angiogenic effects. However, the efficacy and mechanism of bufalin inhibiting hepatocellular carcinoma (HCC) angiogenesis have yet to be further investigated.
Aim of the study
An extensive detailed strategy via network pharmacology, proteomics, histopathological analysis, molecular docking, in vitro experiments, and in vivo magnetic resonance imaging (MRI) examinations were adopted to investigate the efficacy and mechanisms of bufalin against HCC angiogenesis.
Materials and methods
Micro-vessel density (MVD) and intravoxel incoherent motion (IVIM) perfusion-related parameters based on magnetic resonance diffusion-weighted imaging were used to identify the effect of bufalin against HCC angiogenesis. Potential bufalin and HCC targets were gathered from appropriate databases. The STRING database was used to construct the target protein interaction networks. The "clusterprofiler" package (version 4.2.2) in R was applied to conduct the target-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) analysis. Network pharmacology and proteomics were integrated to identify key targets and pathways related to bufalin against HCC angiogenesis. Molecular docking and Western Blot were utilized to validate the findings.
Results
Analysis through IVIM and MVD showed that bufalin could inhibit HCC angiogenesis in nude mice models. A total of 159 common targets of bufalin and HCC were identified by network pharmacology. GO analysis revealed that these targets focused on multiple angiogenesis-related biological processes, including endothelial cell proliferation and migration, sprouting angiogenesis, and regulation of angiogenesis. The KEGG enrichment results suggested that bufalin could regulate multiple signaling pathways to inhibit HCC angiogenesis, including VEGF, MAPK, PI3K-Akt, mTOR, and HIF-1 signaling pathways. MAPK1, MAPK14, PRKCA, EIF4E, and APEX1 might be critical targets in regulating the above pathways. The molecular docking and Western blot analysis verified the effects of bufalin on target proteins.
Conclusion
This study demonstrated that bufalin might inhibit HCC angiogenesis by regulating multiple targets and pathways. These findings offer theoretical insights and experimental foundations for the clinical application and commercial development of bufalin in the treatment of HCC.
{"title":"Integrated network pharmacology, proteomics, molecular docking, and experiments in vivo and in vitro to explore the efficacy and potential mechanism of bufalin against hepatocellular carcinoma angiogenesis","authors":"Yuanchao Li , Lingwei Zhou , Kang Sun , Ran Guo , Zehua Li , Qingqing Wen , Guifeng Fu , Shuohui Yang","doi":"10.1016/j.jep.2025.119589","DOIUrl":"10.1016/j.jep.2025.119589","url":null,"abstract":"<div><h3>Ethnopharmacological relevance</h3><div>Bufalin is a potent bioactive compound extracted from the venom of toads such as Bufo gargarizans. It has rich pharmacological effects, and its traditional applications mainly include anti-cancer, anti-inflammatory and analgesic, especially in cancer treatment, which has been a hot topic of research. Prior research has suggested that bufalin may have anti-tumor angiogenic effects. However, the efficacy and mechanism of bufalin inhibiting hepatocellular carcinoma (HCC) angiogenesis have yet to be further investigated.</div></div><div><h3>Aim of the study</h3><div>An extensive detailed strategy via network pharmacology, proteomics, histopathological analysis, molecular docking, in vitro experiments, and in vivo magnetic resonance imaging (MRI) examinations were adopted to investigate the efficacy and mechanisms of bufalin against HCC angiogenesis.</div></div><div><h3>Materials and methods</h3><div>Micro-vessel density (MVD) and intravoxel incoherent motion (IVIM) perfusion-related parameters based on magnetic resonance diffusion-weighted imaging were used to identify the effect of bufalin against HCC angiogenesis. Potential bufalin and HCC targets were gathered from appropriate databases. The STRING database was used to construct the target protein interaction networks. The \"clusterprofiler\" package (version 4.2.2) in R was applied to conduct the target-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) analysis. Network pharmacology and proteomics were integrated to identify key targets and pathways related to bufalin against HCC angiogenesis. Molecular docking and Western Blot were utilized to validate the findings.</div></div><div><h3>Results</h3><div>Analysis through IVIM and MVD showed that bufalin could inhibit HCC angiogenesis in nude mice models. A total of 159 common targets of bufalin and HCC were identified by network pharmacology. GO analysis revealed that these targets focused on multiple angiogenesis-related biological processes, including endothelial cell proliferation and migration, sprouting angiogenesis, and regulation of angiogenesis. The KEGG enrichment results suggested that bufalin could regulate multiple signaling pathways to inhibit HCC angiogenesis, including VEGF, MAPK, PI3K-Akt, mTOR, and HIF-1 signaling pathways. MAPK1, MAPK14, PRKCA, EIF4E, and APEX1 might be critical targets in regulating the above pathways. The molecular docking and Western blot analysis verified the effects of bufalin on target proteins.</div></div><div><h3>Conclusion</h3><div>This study demonstrated that bufalin might inhibit HCC angiogenesis by regulating multiple targets and pathways. These findings offer theoretical insights and experimental foundations for the clinical application and commercial development of bufalin in the treatment of HCC.</div></div>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":"345 ","pages":"Article 119589"},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578007","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}
Pub Date : 2025-03-05DOI: 10.1016/j.jep.2025.119569
Yuanjing Zou , Bingyun Lu , Zhong Feng , Haobo Chen , Chuqiu Zhang , Chang Peng , Ling Ou , Ruixia Wei , Meicun Yao , Qingchang Chen , Ye Chen
Ethnopharmacological relevance
Terminalia bellirica (Gaertn.) Roxb. (Combretaceae) (T. bellirica) is a longstanding medicinal plant traditionally referenced in both Indian and Tibetan medical practices. Currently, approximately 50% of the global population is infected with Helicobacter pylori (H. pylori). To curb antibiotic overuse, asymptomatic patients might require alternative therapy to mitigate the intestinal side effects commonly associated with excessive antibiotic usage.
Aim of the study
Preliminary screening conducted by our team revealed that T. bellirica had excellent anti-H. pylori action in vitro. However, further research elucidating the mechanism behind T. bellirica's impact on H. pylori infection and its protective effects against related gastrointestinal diseases is yet to be explored.
Materials and methods
To assess the specific effect and underlying mechanism, we employed a comprehensive range of methodologies, including UPLC-MS/MS, in vitro and in vivo antibacterial assays, 5R 16S, molecular dynamics simulation and RT-qPCR.
Results
Phytochemical analysis revealed abundant phenolic contents in T. bellirica, including chebulagic acid, chebulinic acid, corilagin, gallic acid, and ellagic acid. In vitro antibacterial evaluations demonstrated significant efficacy of T. bellirica against H. pylori, with a minimum inhibitory concentration (MIC) of 160 μg/mL, effectively inhibiting critical bacterial defense such as urease, adhesion and gene vacA. In vivo animal experiments showed that in addition to its anti-H. pylori effect, T. bellirica exhibited mild influence on gastric microbiota, with the composition restoring to normal levels after administration.
Conclusions
T. bellirica exerts potent anti-H. pylori activity both in vitro and in vivo, indicating its potential as an alternative therapeutic strategy for managing H. pylori infections while exerting minimal impact on gastric microbial balance. Further studies are warranted to elucidate additional pathways involved and to validate its clinical applications.
{"title":"Anti Helicobacter pylori activity and gastrointestinal protective effects of Terminalia bellirica: Mechanistic insights from in vitro and in vivo studies","authors":"Yuanjing Zou , Bingyun Lu , Zhong Feng , Haobo Chen , Chuqiu Zhang , Chang Peng , Ling Ou , Ruixia Wei , Meicun Yao , Qingchang Chen , Ye Chen","doi":"10.1016/j.jep.2025.119569","DOIUrl":"10.1016/j.jep.2025.119569","url":null,"abstract":"<div><h3>Ethnopharmacological relevance</h3><div><em>Terminalia bellirica</em> (Gaertn.) Roxb. (<em>Combretaceae</em>) (<em>T. bellirica</em>) is a longstanding medicinal plant traditionally referenced in both Indian and Tibetan medical practices. Currently, approximately 50% of the global population is infected with <em>Helicobacter pylori</em> (<em>H. pylori</em>). To curb antibiotic overuse, asymptomatic patients might require alternative therapy to mitigate the intestinal side effects commonly associated with excessive antibiotic usage.</div></div><div><h3>Aim of the study</h3><div>Preliminary screening conducted by our team revealed that <em>T. bellirica</em> had excellent anti-<em>H. pylori</em> action <em>in vitro</em>. However, further research elucidating the mechanism behind <em>T. bellirica</em>'s impact on <em>H. pylori</em> infection and its protective effects against related gastrointestinal diseases is yet to be explored.</div></div><div><h3>Materials and methods</h3><div>To assess the specific effect and underlying mechanism, we employed a comprehensive range of methodologies, including UPLC-MS/MS, <em>in vitro</em> and <em>in vivo</em> antibacterial assays, 5R 16S, molecular dynamics simulation and RT-qPCR.</div></div><div><h3>Results</h3><div>Phytochemical analysis revealed abundant phenolic contents in <em>T. bellirica</em>, including chebulagic acid, chebulinic acid, corilagin, gallic acid, and ellagic acid. <em>In vitro</em> antibacterial evaluations demonstrated significant efficacy of <em>T. bellirica</em> against <em>H. pylori</em>, with a minimum inhibitory concentration (MIC) of 160 μg/mL, effectively inhibiting critical bacterial defense such as urease, adhesion and gene <em>vacA</em>. <em>In vivo</em> animal experiments showed that in addition to its anti-<em>H. pylori</em> effect, <em>T. bellirica</em> exhibited mild influence on gastric microbiota, with the composition restoring to normal levels after administration.</div></div><div><h3>Conclusions</h3><div><em>T. bellirica</em> exerts potent anti-<em>H. pylori</em> activity both <em>in vitro</em> and <em>in vivo</em>, indicating its potential as an alternative therapeutic strategy for managing <em>H. pylori</em> infections while exerting minimal impact on gastric microbial balance. Further studies are warranted to elucidate additional pathways involved and to validate its clinical applications.</div></div>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":"345 ","pages":"Article 119569"},"PeriodicalIF":4.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585883","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}
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