{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:28:09Z","timestamp":1783427289978,"version":"3.54.6"},"reference-count":33,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Dysregulated migration and invasion of endometrial stromal cells is implicated in the pathogenesis of endometriosis. Hypoxia functions as critical microenvironmental factor that results in promotion of endometrial stromal cells migration and invasion through up-regulation of autophagy. Paeonol functioned as a tumor suppressor in human ovarian cancer and promoted cytoprotective autophagy. However, the role of paeonol in hypoxia-induced autophagy in endometriosis remains unknown. Methods: Stromal cells were isolated from endometriotic patients by enzymatic digestion of ectopic endometrial tissues, and then characterized by immunohistochemical analysis of cytoskeleton 19 (CK19) and vimentin. Cellular morphology was evaluated under microscope. Cell viability, proliferation and apoptosis of stromal cells were assessed by Cell Counting Kit-8, EdU labeling and flow cytometry, respectively. Wound healing and transwell assays were performed to detect metastasis of the stromal cells. Hypoxia-induced autophagy was evaluated through immunohistochemistry and western blot. Results: Paeonol treatment dosage dependently decreased cell proliferation and metastasis of the ectopic endometrial stromal cells (ecESCs), while promoted the cell apoptosis. Hypoxia-induced autophagy in the ecESCs was repressed by paeonol through down-regulation of LC3-II\/LC3-I and Beclin-1, while up-regulation of p62. Hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) was reduced post paeonol treatment, and paeonol-induced increase of p62 and decrease of LC3-II\/LC3-I and Beclin-1 were reversed by over-expression of HIF-1\u03b1. Over-expression of HIF-1\u03b1 also attenuated the suppressive effect of paeonol on cell growth of ecESCs. Conclusions: Paeonol attenuated HIF-1\u03b1-induced promotion of ecESCs migration and invasion through reducing autophagy, and reduced HIF-1\u03b1-induced endometriotic lesion in rats, providing potential therapeutic strategy for the treatment of endometriosis.<\/jats:p>","DOI":"10.52586\/4961","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T08:48:01Z","timestamp":1632905281000},"source":"Crossref","is-referenced-by-count":22,"title":["Paeonol alleviates migration and invasion of endometrial stromal cells by reducing HIF-1\u03b1-regulated autophagy in endometriosis"],"prefix":"10.31083","volume":"26","author":[{"given":"Conghui","family":"Pang","sequence":"first","affiliation":[{"name":"Center of Reproduction and Genetics Integrated Traditional Chinese and Western Medicine, The Hospital Affiliated to Shandong University of Traditional Chinese Medicine, 250014 Jinan, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijuan","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Gynecology of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, 250014 Jinan, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Xu","sequence":"first","affiliation":[{"name":"Center of Reproduction and Genetics Integrated Traditional Chinese and Western Medicine, The Hospital Affiliated to Shandong University of Traditional Chinese Medicine, 250014 Jinan, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxiu","family":"Yang","sequence":"first","affiliation":[{"name":"Center of Reproduction and Genetics Integrated Traditional Chinese and Western Medicine, The Hospital Affiliated to Shandong University of Traditional Chinese Medicine, 250014 Jinan, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxuan","family":"Wang","sequence":"first","affiliation":[{"name":"Center of Reproduction and Genetics Integrated Traditional Chinese and Western Medicine, The Hospital Affiliated to Shandong University of Traditional Chinese Medicine, 250014 Jinan, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghua","family":"Qi","sequence":"first","affiliation":[{"name":"Center of Reproduction and Genetics Integrated Traditional Chinese and Western Medicine, The Hospital Affiliated to Shandong University of Traditional Chinese Medicine, 250014 Jinan, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Chantalat E, Valera M-C, Vaysse C, Noirrit E, Rusidze M, Weyl A, et al. Estrogen Receptors and Endometriosis. International Journal of Molecular Sciences. 2020; 21: 2815.","DOI":"10.3390\/ijms21082815"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"Vercellini P, Vigan\u00f2 P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nature Reviews Endocrinology. 2014; 10: 261\u2013275.","DOI":"10.1038\/nrendo.2013.255"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Hirsch M, Begum MR, Paniz \u00c9, Barker C, Davis CJ, Duffy JMN. Diagnosis and management of endometriosis: a systematic review of international and national guidelines. BJOG: An International Journal of Obstetrics & Gynaecology. 2018; 125: 556\u2013564.","DOI":"10.1111\/1471-0528.14838"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"Kajiyama H, Suzuki S, Yoshihara M, Tamauchi S, Yoshikawa N, Niimi K, et al. Endometriosis and cancer. Free Radical Biology and Medicine. 2019; 133: 186\u2013192.","DOI":"10.1016\/j.freeradbiomed.2018.12.015"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"Zhang M, Zhang Y, Li L, Ma L, Zhou C. Dysregulation of miR-202-3p Affects Migration and Invasion of Endometrial Stromal Cells in Endometriosis via Targeting ROCK1. Reproductive Sciences. 2020; 27: 731\u2013742.","DOI":"10.1007\/s43032-019-00079-4"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008; 451: 1069\u20131075.","DOI":"10.1038\/nature06639"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"Zhan L, Li J, Wei B. Autophagy in endometriosis: Friend or foe? Biochemical and Biophysical Research Communications. 2018; 495: 60\u201363.","DOI":"10.1016\/j.bbrc.2017.10.145"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Allavena G, Carrarelli P, Del Bello B, Luisi S, Petraglia F, Maellaro E. Autophagy is upregulated in ovarian endometriosis: a possible interplay with p53 and heme oxygenase-1. Fertility and Sterility. 2015; 103: 1244\u20131251.e1241.","DOI":"10.1016\/j.fertnstert.2015.02.007"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Liu H, Zhang Z, Xiong W, Zhang L, Xiong Y, Li N, et al. Hypoxia-inducible factor-1\u03b1 promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis. Reproduction. 2017; 153: 809\u2013820.","DOI":"10.1530\/REP-16-0643"},{"key":"ref10","unstructured":"Sajdak S, Markowska A, Krygowska-Zieli\u0144ska J, Szarszewska M, Witek A, Olejek A, et al. Effect of metformin on clinical-pathological variables in women with endometrial cancer. A multicenter study. European Journal of Gynaecological Oncology. 2019; 40: 775\u2013780."},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Zhang L, Li DC, Liu LF. Paeonol: pharmacological effects and mechanisms of action. International Immunopharmacology. 2019; 72: 413\u2013421.","DOI":"10.1016\/j.intimp.2019.04.033"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"Liu LH, Shi RJ, Chen ZC. Paeonol exerts anti-tumor activity against colorectal cancer cells by inducing G0\/G1 phase arrest and cell apoptosis via inhibiting the Wnt\/\u03b2-catenin signaling pathway. International Journal of Molecular Medicine. 2020; 46: 675\u2013684.","DOI":"10.3892\/ijmm.2020.4629"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"Zhang J, Cai L, Pang K, Dong Y, Zhang Z, Li B, et al. Paeonol inhibits proliferation and induces cell apoptosis of human T24 and 5637 bladder cancer cells in vitro and in vivo. Clinical and Translational Oncology. 2021; 23: 601\u2013611.","DOI":"10.1007\/s12094-020-02455-y"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"Zhou H-M, Sun Q-X, Cheng Y. Paeonol enhances the sensitivity of human ovarian cancer cells to radiotherapy-induced apoptosis due to downregulation of the phosphatidylinositol-3-kinase\/Akt\/phosphatase and tensin homolog pathway and inhibition of vascular endothelial growth factor. Experimental and Therapeutic Medicine. 2017; 14: 3213\u20133220.","DOI":"10.3892\/etm.2017.4877"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Gao L, Wang Z, Lu D, Huang J, Liu J, Hong L. Paeonol induces cytoprotective autophagy via blocking the Akt\/mTOR pathway in ovarian cancer cells. Cell Death and Disease. 2019; 10: 609\u2013609.","DOI":"10.1038\/s41419-019-1849-x"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Wu H, Song A, Hu W, Dai M. The Anti-atherosclerotic Effect of Paeonol against Vascular Smooth Muscle Cell Proliferation by Up-regulation of Autophagy via the AMPK\/mTOR Signaling Pathway. Frontiers in Pharmacology. 2018; 8: 948.","DOI":"10.3389\/fphar.2017.00948"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"Li C, Yang L, Wu H, Dai M. Paeonol Inhibits Oxidized Low-Density Lipoprotein-Induced Vascular Endothelial Cells Autophagy by Upregulating the Expression of miRNA-30a. Frontiers in Pharmacology. 2018; 9: 95.","DOI":"10.3389\/fphar.2018.00095"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Santoro A, Angelico G, Inzani F, Spadola S, Arciuolo D, Valente M, et al. The Many Faces of Endometriosis-Related Neoplasms in the Same Patient: A Brief Report. Gynecologic and Obstetric Investigation. 2020; 85: 371\u2013376.","DOI":"10.1159\/000508225"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Erekat NS. Autophagy precedes apoptosis among at risk cerebellar Purkinje cells in the shaker mutant rat: an ultrastructural study. Ultrastructural Pathology. 2018; 42: 162\u2013169.","DOI":"10.1080\/01913123.2018.1424744"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Li Y, Wang X, Wang X, Wan L, Liu Y, Shi Y, et al. PDCD4 suppresses proliferation, migration, and invasion of endometrial cells by inhibiting autophagy and NF-\u03baB\/MMP2\/MMP9 signal pathway\u2020. Biology of Reproduction. 2018; 99: 360\u2013372.","DOI":"10.1093\/biolre\/ioy052"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Li J, Ma J, Fei X, Zhang T, Zhou J, Lin J. Roles of cell migration and invasion mediated by Twist in endometriosis. Journal of Obstetrics and Gynaecology Research. 2019; 45: 1488\u20131496.","DOI":"10.1111\/jog.14001"},{"key":"ref22","unstructured":"Zhong H, Hao L, Li X, Wang C, Wu X. Anti-inflammatory Role of Trilobatin on Lipopolysaccharide-induced Acute Lung Injury through Activation of AMPK\/GSK3\u03b2-Nrf2 Pathway. Signa Vitae. 2020; 16: 160\u2013166."},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Konrad L, Dietze R, Riaz MA, Scheiner-Bobis G, Behnke J, Horn\u00e9 F, et al. Epithelial-Mesenchymal Transition in Endometriosis-When Does It Happen? Journal of Clinical Medicine. 2020; 9: 1915.","DOI":"10.3390\/jcm9061915"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"Choi J, Jo M, Lee E, Kim HJ, Choi D. Differential induction of autophagy by mTOR is associated with abnormal apoptosis in ovarian endometriotic cysts. Molecular Human Reproduction. 2014; 20: 309\u2013317.","DOI":"10.1093\/molehr\/gat091"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Liu H, Du Y, Zhang Z, Lv L, Xiong W, Zhang L, et al. Autophagy contributes to hypoxia-induced epithelial to mesenchymal transition of endometrial epithelial cells in endometriosis. Biology of Reproduction. 2018; 99: 968\u2013981.","DOI":"10.1093\/biolre\/ioy128"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"Rhee JS, Saben JL, Mayer AL, Schulte MB, Asghar Z, Stephens C, et al. Diet-induced obesity impairs endometrial stromal cell decidualization: a potential role for impaired autophagy. Human Reproduction. 2016; 31: 1315\u20131326.","DOI":"10.1093\/humrep\/dew048"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"Mei J, Zhou W-J, Zhu X-Y, Lu H, Wu K, Yang H-L, et al. Suppression of autophagy and HCK signaling promotes PTGS2(high) FCGR3(-) NK cell differentiation triggered by ectopic endometrial stromal cells. Autophagy. 2018; 14: 1376\u20131397.","DOI":"10.1080\/15548627.2018.1476809"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"Xiong Y, Liu Y, Xiong W, Zhang L, Liu H, Du Y, et al. Hypoxia-inducible factor 1\u03b1-induced epithelial\u2013mesenchymal transition of endometrial epithelial cells may contribute to the development of endometriosis. Human Reproduction. 2016; 31: 1327\u20131338.","DOI":"10.1093\/humrep\/dew081"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Foster WG. Hypoxia-induced autophagy, epithelial to mesenchymal transition, and invasion in the pathophysiology of endometriosis: a perspective. Biology of Reproduction. 2018; 99: 905\u2013906.","DOI":"10.1093\/biolre\/ioy137"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"Liu H, Zhang Z, Xiong W, Zhang L, Du Y, Liu Y, et al. Long non-coding RNA MALAT1 mediates hypoxia-induced pro-survival autophagy of endometrial stromal cells in endometriosis. Journal of Cellular and Molecular Medicine. 2019; 23: 439\u2013452.","DOI":"10.1111\/jcmm.13947"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"Wu M-H, Hsiao K-Y, Tsai S-J. Endometriosis and possible inflammation markers. Gynecology and Minimally Invasive Therapy. 2015; 4: 61\u201367.","DOI":"10.1016\/j.gmit.2015.05.001"},{"key":"ref32","doi-asserted-by":"crossref","unstructured":"Mei L, He M, Zhang C, Miao J, Wen Q, Liu X, et al. Paeonol attenuates inflammation by targeting HMGB1 through upregulating miR-339-5p. Scientific Reports. 2019; 9: 19370.","DOI":"10.1038\/s41598-019-55980-4"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"Zhang H, Geng X, Li Z, Li Y, Xu K, Wu H, et al. Paeonol at certain doses alleviates aggressive and anxiety-like behaviours in two premenstrual dysphoric disorder rat models. Frontiers in Psychiatry. 2020; 11: 295.","DOI":"10.3389\/fpsyt.2020.00295"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/26\/9\/10.52586\/4961","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T11:16:29Z","timestamp":1732706189000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/26\/9\/10.52586\/4961"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,30]]},"references-count":33,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2021]]}},"alternative-id":["s2768-6701(21)00022-8"],"URL":"https:\/\/doi.org\/10.52586\/4961","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,30]]},"article-number":"485"}}