Can Cao, Jiena Li, Yu Zhang, Shixing Wu, Qi Liu, Yu Xi, Can Chen, Ming He
{"title":"补肾调精汤通过调节klf4介导的线粒体功能和转录活性，促进子宫内膜血管生成，改善子宫内膜容受性。","authors":"Can Cao, Jiena Li, Yu Zhang, Shixing Wu, Qi Liu, Yu Xi, Can Chen, Ming He","doi":"10.1016/j.jep.2025.120658","DOIUrl":null,"url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>Traditional Chinese medicine has numerous advantages in the treatment of infertility. The traditional Chinese herbal formula Bushen Tiaojing Decoction (BSTJD) is widely used for treating infertility, which can effectively promote embryo implantation rate for infertility patients in in vitro fertilization and embryo transfer (IVF-ET) by improving endometrial receptivity. However, the exact mechanism underlying BSTJD-improved endometrial receptivity has not yet been elucidated.</p><p><strong>Aim of the study: </strong>Krüppel-like factor 4 (KLF4) is an essential transcription factor that regulates endometrial angiogenesis. This study investigates the effect and mechanism of BSTJD on promoting endometrial angiogenesis involved in KLF4.</p><p><strong>Methods: </strong>The controlled ovarian hyperstimulation (COH) mouse model was established and treated with BSTJD. Embryo implantation numbers and the changes in uterine morphology were evaluated. Human endometrial microvascular endothelial cells (HEMECs) were treated with BSTJD medicated serum, or adenovirus overexpressing KLF4. Tube formation assay was performed to observe HEMEC tubulogenesis. Mitochondrial function of HEMECs was evaluated. The levels of MMP-9, PCNA, Caspase 3, VEGFA, KLF4, GCN5, and succinylated H3K79 in HEMECs were measured. The KLF4 combined with GCN5 and its succinylation were detected by immunoprecipitation, and their localization was performed for immunofluorescence staining. Chromatin immunoprecipitation assay was performed for KLF4 and succinylated H3K79 enrichments on the VEGFA promoter.</p><p><strong>Results: </strong>BSTJD promoted endometrial angiogenesis to improve endometrial receptivity, so as to increase the embryo implantation numbers in the COH mice model. BSTJD could coordinate with VEGFA to upregulate KLF4 level, which increased HEMECs proliferation and migration and decreased cell apoptosis via improving mitochondrial function. BSTJD promoted KLF4-GCN5 complex formation via activating the ERK pathway. This complex was recruited to the KLF4-binding site of the VEGFA promoter in HEMECs and transactivated VEGFA expression, leading to endometrial angiogenesis.</p><p><strong>Conclusions: </strong>BSTJD contributes to endometrial receptivity to increasing embryo implantation by activating the KLF4 to promote angiogenesis through improving mitochondrial function and increased the KLF4-GCN5 interaction to activate VEGFA transcription.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"120658"},"PeriodicalIF":5.4000,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Bushen Tiaojing Decoction promotes endometrial angiogenesis to improve endometrial receptivity by regulating KLF4-mediated mitochondrial function and transcription activity.\",\"authors\":\"Can Cao, Jiena Li, Yu Zhang, Shixing Wu, Qi Liu, Yu Xi, Can Chen, Ming He\",\"doi\":\"10.1016/j.jep.2025.120658\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Ethnopharmacological relevance: </strong>Traditional Chinese medicine has numerous advantages in the treatment of infertility. The traditional Chinese herbal formula Bushen Tiaojing Decoction (BSTJD) is widely used for treating infertility, which can effectively promote embryo implantation rate for infertility patients in in vitro fertilization and embryo transfer (IVF-ET) by improving endometrial receptivity. However, the exact mechanism underlying BSTJD-improved endometrial receptivity has not yet been elucidated.</p><p><strong>Aim of the study: </strong>Krüppel-like factor 4 (KLF4) is an essential transcription factor that regulates endometrial angiogenesis. This study investigates the effect and mechanism of BSTJD on promoting endometrial angiogenesis involved in KLF4.</p><p><strong>Methods: </strong>The controlled ovarian hyperstimulation (COH) mouse model was established and treated with BSTJD. Embryo implantation numbers and the changes in uterine morphology were evaluated. Human endometrial microvascular endothelial cells (HEMECs) were treated with BSTJD medicated serum, or adenovirus overexpressing KLF4. Tube formation assay was performed to observe HEMEC tubulogenesis. Mitochondrial function of HEMECs was evaluated. The levels of MMP-9, PCNA, Caspase 3, VEGFA, KLF4, GCN5, and succinylated H3K79 in HEMECs were measured. The KLF4 combined with GCN5 and its succinylation were detected by immunoprecipitation, and their localization was performed for immunofluorescence staining. Chromatin immunoprecipitation assay was performed for KLF4 and succinylated H3K79 enrichments on the VEGFA promoter.</p><p><strong>Results: </strong>BSTJD promoted endometrial angiogenesis to improve endometrial receptivity, so as to increase the embryo implantation numbers in the COH mice model. BSTJD could coordinate with VEGFA to upregulate KLF4 level, which increased HEMECs proliferation and migration and decreased cell apoptosis via improving mitochondrial function. BSTJD promoted KLF4-GCN5 complex formation via activating the ERK pathway. This complex was recruited to the KLF4-binding site of the VEGFA promoter in HEMECs and transactivated VEGFA expression, leading to endometrial angiogenesis.</p><p><strong>Conclusions: </strong>BSTJD contributes to endometrial receptivity to increasing embryo implantation by activating the KLF4 to promote angiogenesis through improving mitochondrial function and increased the KLF4-GCN5 interaction to activate VEGFA transcription.</p>\",\"PeriodicalId\":15761,\"journal\":{\"name\":\"Journal of ethnopharmacology\",\"volume\":\" \",\"pages\":\"120658\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-09-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of ethnopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jep.2025.120658\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of ethnopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jep.2025.120658","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Bushen Tiaojing Decoction promotes endometrial angiogenesis to improve endometrial receptivity by regulating KLF4-mediated mitochondrial function and transcription activity.
Ethnopharmacological relevance: Traditional Chinese medicine has numerous advantages in the treatment of infertility. The traditional Chinese herbal formula Bushen Tiaojing Decoction (BSTJD) is widely used for treating infertility, which can effectively promote embryo implantation rate for infertility patients in in vitro fertilization and embryo transfer (IVF-ET) by improving endometrial receptivity. However, the exact mechanism underlying BSTJD-improved endometrial receptivity has not yet been elucidated.
Aim of the study: Krüppel-like factor 4 (KLF4) is an essential transcription factor that regulates endometrial angiogenesis. This study investigates the effect and mechanism of BSTJD on promoting endometrial angiogenesis involved in KLF4.
Methods: The controlled ovarian hyperstimulation (COH) mouse model was established and treated with BSTJD. Embryo implantation numbers and the changes in uterine morphology were evaluated. Human endometrial microvascular endothelial cells (HEMECs) were treated with BSTJD medicated serum, or adenovirus overexpressing KLF4. Tube formation assay was performed to observe HEMEC tubulogenesis. Mitochondrial function of HEMECs was evaluated. The levels of MMP-9, PCNA, Caspase 3, VEGFA, KLF4, GCN5, and succinylated H3K79 in HEMECs were measured. The KLF4 combined with GCN5 and its succinylation were detected by immunoprecipitation, and their localization was performed for immunofluorescence staining. Chromatin immunoprecipitation assay was performed for KLF4 and succinylated H3K79 enrichments on the VEGFA promoter.
Results: BSTJD promoted endometrial angiogenesis to improve endometrial receptivity, so as to increase the embryo implantation numbers in the COH mice model. BSTJD could coordinate with VEGFA to upregulate KLF4 level, which increased HEMECs proliferation and migration and decreased cell apoptosis via improving mitochondrial function. BSTJD promoted KLF4-GCN5 complex formation via activating the ERK pathway. This complex was recruited to the KLF4-binding site of the VEGFA promoter in HEMECs and transactivated VEGFA expression, leading to endometrial angiogenesis.
Conclusions: BSTJD contributes to endometrial receptivity to increasing embryo implantation by activating the KLF4 to promote angiogenesis through improving mitochondrial function and increased the KLF4-GCN5 interaction to activate VEGFA transcription.
期刊介绍：
The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
