中药药理与临床2025，Vol.41Issue(6)：6-12,7.
左归丸调控AGS/RAGE/JAK2/STAT3信号通路促卵巢血管生成的机制
Mechanism of Zuogui(左归)Pills in Promoting Ovarian Angiogenesis via the AGES/RAGE/JAK2/STAT3 Signaling Pathway
摘要
Abstract
Objective:To explore the relationship of Zuogui(左归)Pills with ovarian angiogenesis and advanced glycation end products(AGEs)/receptor for advanced glycation end product(RAGE)/Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)signaling pathway in the early-aging rats based on network pharmacology and molecular docking,and explore the mechanism of Zuogui Pills in ameliorating ovarian hypofunction in early-aging rats.Methods:Network pharmacology was employed to study the active components and target effect of Zuogui Pills and predict the targets and signaling pathways.The mechanisms of Zuogui Pills in ameliorating ovarian hypofunction dis-eases such as ovarian dysfunction on early age,ovarian atrophy,diminished ovarian reserve,and peri-menopausal period syndrome were ana-lyzed.Autodock-vina was used for dynamic molecular docking.Animal experiments were carried out to examine the prediction results.Specific-ally,40 SD female rats of 14 months old and with estrous cycle disorder were randomized into model,conjugated estrogen(65 μg/kg),and Zuogui Pills(11 g/kg and 33 g/kg)groups.Ten SD female rats of 4 months old were selected as the youth control group.Rats were adminis-trated with corresponding drugs once per day for 15 consecutive days.They were sacrificed 24 h after the last administration,and the ovarian tissue was collected to calculate the organ index.Hematoxylin-eosin staining was performed to observe changes in the number of ovarian folli-cles,corpus lutea,and blood vessels.Immunohistochemistry was employed to detect the expression of JAK2,p-JAK2,STAT3,p-STAT3,and nuclear factor of activated T cells 1(NFATc1)in the ovarian tissue.Western blotting was employed to determine the protein levels of RAGE,p-JAK2,p-STAT3,and NFATc1 in the ovarian tissue.Results:The main active components of Zuogui Pills included betalain,rubrosterone,α1-sitosterol,cycloartenol,and piperlonguminine.A total of 229 targets were predicted,including IL-6,TNF,VEGFA,AKT1,TP53,and ESR1.The top 5 KEGG signaling pathways were AGEs-RAGE signaling pathway,cancer pathway,NF-kappa B signaling pathway,Apelin signaling pathway,and proteoglycans in cancer.The binding energy between the active components of Zuogui Pills and the targets was in the range of-7.6 to-2.9 kcal/mol.Compared with the youth control group,the model group showed down-regulated protein levels of RAGE,p-JAK2,p-STAT3,and NFATc1(P<0.05).After treatment,the number of growing follicles,corpus lutea,and blood vessels increased(P<0.05),while that of atretic follicles decreased(P<0.05).In addition,the protein levels of RAGE,p-JAK2,p-STAT3,and NFATc1 in the ovarian tissue were up-regulated after treatment(P<0.05).Conclusion:Overall,Zuogui Pills can promote ovarian angiogenesis and improve the ovarian function of early-aging rats by activating the AGES/RAGE/JAK2/STAT3 signaling pathway.关键词
左归丸/卵巢血管生成/卵巢功能低下性病证/糖基化终末产物受体/酪氨酸蛋白激酶2/信号转导和转录激活因子3/网络药理学/分子对接Key words
Zuogui(左归)Pills/Ovarian angiogenesis/Ovarian hypofunction diseases/Receptor of advanced glycation end product/Janus kinase 2/Signal transducer and activator of transcription 3/Network pharmacology/Molecular docking引用本文复制引用
彭万春,宋谦谦,段恒..左归丸调控AGS/RAGE/JAK2/STAT3信号通路促卵巢血管生成的机制[J].中药药理与临床,2025,41(6):6-12,7.基金项目
重庆市科卫联合项目(编号:2021ZY023852). （编号:2021ZY023852）
