{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:58:23Z","timestamp":1791907103266,"version":"4.3.4"},"reference-count":53,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T00:00:00Z","timestamp":1589846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 108-2314-B-038-003"],"award-info":[{"award-number":["MOST 108-2314-B-038-003"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["GA-18-11275S"],"award-info":[{"award-number":["GA-18-11275S"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ovarian follicle steroidogenesis associated with embryo quality results in a successful pregnancy. Each follicle consists of an oocyte surrounded by granulosa cells, which secrete several steroid and peptide hormones. Follicles harvested from women who conceived after assisted reproductive therapy (ART) had significantly higher estradiol levels in follicular fluids than the follicles from women who failed to conceive after ART. The higher follicular estradiol levels correlate well with successful fertilization following ART. Mitochondria are the central sites for steroid hormone biosynthesis. The first and rate-limiting step in the biosynthesis of steroid hormones occurs in the mitochondria of granulosa cells. In the present study, we hypothesized that the mitochondria in granulosa cells are critical for maintaining oocyte quality and fertility capacity. This study aims to clarify the relationship between mitochondrial function and granulosa cell steroidogenesis, and the relationship between hormone levels and fertility capacity. Sera, follicular fluids and granulosa cells were obtained from individuals undergoing IVF-ET treatment. The oocyte numbers, oocyte quality, fertilization rate, and pregnancy rate were also recorded. The patients who provided the granulosa cells were further classified into four groups: endometriosis, ovarian endometrioma, endometriosis without ovarian endometrioma, and polycystic ovary syndrome (PCOS); patients with other female factor infertility and male factor infertility were used as controls. We measured the levels of estradiol (E2) by radioimmunoassay. Concurrently, we analyzed the mitochondrial mass and membrane potential, and apoptosis by flow cytometry using nonyl acridine orange, TMRE, Annexin V-FITC and PI. Mitochondrial morphology was visualized by transfection with pLV-mitoDsRed. In addition, we assessed the protein levels of steroidogenic enzymes, steroidogenic acute regulatory protein (StAR) and 3\u03b2-hydroxysteroid dehydrogenase (3\u03b2-HSD) by Western blot. The results showed significantly decreased serum E2 and follicular E2 levels, and decreased IVF outcomes, in the patients with endometriosis. Reduced mitochondrial mass and decreased mitochondrial membrane potential were correlated with lower E2. Furthermore, a significant decrease in StAR and 3\u03b2-HSD was found in patients with ovarian endometrioma. The enzyme levels of StAR and 3\u03b2-HSD were highly correlated with E2 levels. Finally, elevated cumulus cell apoptosis was found in the patient group with ovarian endometrioma and PCOS. In conclusion, mitochondrial dysfunction of human granulosa cells may contribute to the decline of steroidogenesis, decreased fertilization rate, oocyte maturation rate, and oocyte quality, and it can ultimately jeopardize fertility.<\/jats:p>","DOI":"10.3390\/ijms21103592","type":"journal-article","created":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T02:48:24Z","timestamp":1589942904000},"page":"3592","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":177,"title":["Mitochondrial Function in Modulating Human Granulosa Cell Steroidogenesis and Female Fertility"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1989-8749","authenticated-orcid":false,"given":"Dilip Bhargava","family":"Sreerangaraja Urs","sequence":"first","affiliation":[{"name":"Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Han","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6837-2148","authenticated-orcid":false,"given":"Katerina","family":"Komrskova","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic"},{"name":"Department of Zoology, Faculty of Science, Charles University, Vinicna 7, 128 44 Prague 2, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavla","family":"Postlerova","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic"},{"name":"Department of Veterinary Sciences, Faculty of Agrobiology, Food and Natural Resources, University of Life Sciences Prague, Kamycka 129, 165 00 Prague 6, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3165-9177","authenticated-orcid":false,"given":"Yung-Feng","family":"Lin","sequence":"additional","affiliation":[{"name":"Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7445-0261","authenticated-orcid":false,"given":"Chii-Ruey","family":"Tzeng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4618-0898","authenticated-orcid":false,"given":"Shu-Huei","family":"Kao","sequence":"additional","affiliation":[{"name":"Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Practice Committee of American Society for Reproductive Medicine (2013). Definitions of infertility and recurrent pregnancy loss: A committee opinion. Fertil. Steril., 99, 63.","DOI":"10.1016\/j.fertnstert.2012.09.023"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Practice Committee of the American Society for Reproductive Medicine (2015). Testing and interpreting measures of ovarian reserve: A committee opinion. Fertil. Steril., 103, e9\u2013e17.","DOI":"10.1016\/j.fertnstert.2014.12.093"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Committee on Gynecologic Practice (2015). Committee opinion no. 618: Ovarian reserve testing. Obstet. Gynecol., 125, 268\u2013273.","DOI":"10.1097\/01.AOG.0000459864.68372.ec"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1001\/jama.290.13.1767","article-title":"Diagnosis and management of female infertility","volume":"290","author":"Smith","year":"2003","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0377-1237(17)30435-5","article-title":"Understanding male factor in infertility","volume":"55","author":"Chattopadhyay","year":"1999","journal-title":"Med. J. Armed Forces India"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/S0090-4295(00)00803-7","article-title":"WHO manual for the standardized investigation, diagnosis and management of the infertile male","volume":"57","author":"Niederberger","year":"2001","journal-title":"Urology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1136\/bmj.39073.736829.BE","article-title":"Endometriosis","volume":"334","author":"Farquhar","year":"2007","journal-title":"BMJ"},{"key":"ref_8","first-page":"581","article-title":"Endometriosis, a modern syndrome","volume":"133","author":"Brosens","year":"2011","journal-title":"Indian J. Med. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lagana, A.S., Garzon, S., Gotte, M., Vigano, P., Franchi, M., Ghezzi, F., and Martin, D.C. (2019). The pathogenesis of endometriosis: Molecular and cell biology insights. Int. J. Mol. Sci, 20.","DOI":"10.3390\/ijms20225615"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrendo.2013.255","article-title":"Endometriosis: Pathogenesis and treatment","volume":"10","author":"Vercellini","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1016\/S0015-0282(16)56752-1","article-title":"The endoscopic localization of endometrial implants in the ovarian chocolate cyst","volume":"61","author":"Brosens","year":"1994","journal-title":"Fertil. Steril."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s12958-019-0509-4","article-title":"Polycystic ovary syndrome and mitochondrial dysfunction","volume":"17","author":"Zhang","year":"2019","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.fertnstert.2018.05.004","article-title":"Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome","volume":"110","author":"Teede","year":"2018","journal-title":"Fertil. Steril."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.fertnstert.2013.01.129","article-title":"Cumulus and granulosa cell markers of oocyte and embryo quality","volume":"99","author":"Uyar","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.fertnstert.2012.02.015","article-title":"A persistent misperception: Assisted reproductive technology can reverse the aged biological clock","volume":"97","author":"Wyndham","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1073\/pnas.1519990113","article-title":"Dynamic secretion during meiotic reentry integrates the function of the oocyte and cumulus cells","volume":"113","author":"Cakmak","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0303-7207(94)90278-X","article-title":"Follicular oestrogen synthesis: The two-cell, two-gonadotrophin model revisited","volume":"100","author":"Hillier","year":"1994","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1093\/humrep\/dev119","article-title":"Differential effects of estrogen and progesterone on development of primate secondary follicles in a steroid-depleted milieu in vitro","volume":"30","author":"Ting","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1093\/humrep\/den048","article-title":"Identification of differentially expressed markers in human follicular cells associated with competent oocytes","volume":"23","author":"Hamel","year":"2008","journal-title":"Hum. Reprod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.fertnstert.2012.05.007","article-title":"New candidate genes to predict pregnancy outcome in single embryo transfer cycles when using cumulus cell gene expression","volume":"98","author":"Wathlet","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.1093\/humrep\/dem336","article-title":"Gene expression in human cumulus cells: One approach to oocyte competence","volume":"22","author":"Feuerstein","year":"2007","journal-title":"Hum. Reprod."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jsbmb.2016.03.009","article-title":"Disorders in the initial steps of steroid hormone synthesis","volume":"165","author":"Miller","year":"2017","journal-title":"J. Steroid. Biochem. Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.mce.2013.04.014","article-title":"Steroid hormone synthesis in mitochondria","volume":"379","author":"Miller","year":"2013","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3924","DOI":"10.1210\/en.2005-1204","article-title":"Energized, polarized, and actively respiring mitochondria are required for acute Leydig cell steroidogenesis","volume":"147","author":"Allen","year":"2006","journal-title":"Endocrinology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"46583","DOI":"10.1074\/jbc.M107815200","article-title":"Mitochondrial processing of newly synthesized steroidogenic acute regulatory protein (StAR), but not total StAR, mediates cholesterol transfer to cytochrome P450 side chain cleavage enzyme in adrenal cells","volume":"276","author":"Artemenko","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1196\/annals.1338.014","article-title":"Deleted mitochondrial DNA in human luteinized granulosa cells","volume":"1042","author":"Au","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1089\/ars.2019.7984","article-title":"Redox biology of human cumulus cells: Basic concepts, impact on oocyte quality, and potential clinical use","volume":"32","author":"Klamt","year":"2020","journal-title":"Antioxid. Redox Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3109\/19396368.2012.743197","article-title":"Oxidative status in granulosa cells of infertile women undergoing IVF","volume":"59","author":"Karuputhula","year":"2013","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.fertnstert.2014.11.002","article-title":"Endometriosis may be associated with mitochondrial dysfunction in cumulus cells from subjects undergoing in vitro fertilization-intracytoplasmic sperm injection, as reflected by decreased adenosine triphosphate production","volume":"103","author":"Hsu","year":"2015","journal-title":"Fertil. Steril."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1002\/rmb2.12245","article-title":"Updating the markers for oocyte quality evaluation: Intracellular temperature as a new index","volume":"17","author":"Hoshino","year":"2018","journal-title":"Reprod. Med. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1002\/mrd.10102","article-title":"Minireview: Functions of the cumulus oophorus during oocyte maturation, ovulation, and fertilization","volume":"61","author":"Tanghe","year":"2002","journal-title":"Mol. Reprod. Dev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1093\/molehr\/gaq031","article-title":"The human oocyte and cumulus cells relationship: New insights from the cumulus cell transcriptome","volume":"16","author":"Huang","year":"2010","journal-title":"Mol. Hum. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1093\/humrep\/dev114","article-title":"Relationship between diminished ovarian reserve and mitochondrial biogenesis in cumulus cells","volume":"30","author":"Boucret","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.fertnstert.2016.03.037","article-title":"Impact of endometriosis on in vitro fertilization outcomes: An evaluation of the Society for Assisted Reproductive Technologies Database","volume":"106","author":"Senapati","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1111\/1471-0528.12366","article-title":"The effect of endometriosis on in vitro fertilization outcome: A systematic review and meta-analysis","volume":"120","author":"Harb","year":"2013","journal-title":"BJOG"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1111\/j.1600-0412.2011.01247.x","article-title":"Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women: A stage-dependent interference","volume":"90","author":"Coccia","year":"2011","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/j.fertnstert.2004.11.028","article-title":"Impact of ovarian endometrioma on oocytes and pregnancy outcome in in vitro fertilization","volume":"83","author":"Suzuki","year":"2005","journal-title":"Fertil. Steril."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1016\/j.fertnstert.2012.01.112","article-title":"In vitro fertilization is a successful treatment in endometriosis-associated infertility","volume":"97","author":"Opoien","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12014-015-9077-6","article-title":"Proteomic analysis of human follicular fluid from fertile women","volume":"12","author":"Zamah","year":"2015","journal-title":"Clin. Proteomics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1095\/biolreprod.109.082941","article-title":"Formation of the ovarian follicular antrum and follicular fluid","volume":"82","author":"Rodgers","year":"2010","journal-title":"Biol. Reprod."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13048-017-0341-4","article-title":"Is the oocyte quality affected by endometriosis? A review of the literature","volume":"10","author":"Sanchez","year":"2017","journal-title":"J. Ovarian Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"343706","DOI":"10.1155\/2015\/343706","article-title":"Protective actions of 17beta-estradiol and progesterone on oxidative neuronal injury induced by organometallic compounds","volume":"2015","author":"Ishihara","year":"2015","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/j.fertnstert.2009.04.010","article-title":"Follicular fluid steroid hormone levels are associated with fertilization outcome after intracytoplasmic sperm injection","volume":"94","author":"Lamb","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"187","DOI":"10.4103\/0974-1208.142479","article-title":"Follicular steroid hormones as markers of oocyte quality and oocyte development potential","volume":"7","author":"Carpintero","year":"2014","journal-title":"J. Hum. Reprod. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S0015-0282(16)47293-6","article-title":"The importance of the follicular phase to success and failure in in vitro fertilization","volume":"40","author":"Jones","year":"1983","journal-title":"Fertil. Steril."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1093\/humrep\/deh543","article-title":"Falling estradiol levels as a result of intentional reduction in gonadotrophin dose are not associated with poor IVF outcomes, whereas spontaneously falling estradiol levels result in low clinical pregnancy rates","volume":"20","author":"Fisher","year":"2005","journal-title":"Hum. Reprod."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12958-015-0051-y","article-title":"Changes in estrone and estradiol levels during follicle development: A retrospective large-scale study","volume":"13","author":"Segawa","year":"2015","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"20120431","DOI":"10.1098\/rstb.2012.0431","article-title":"Human cytochromes P450 in health and disease","volume":"368","author":"Nebert","year":"2013","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9534","DOI":"10.1074\/jbc.M111.333278","article-title":"Mitochondrial 3beta-hydroxysteroid dehydrogenase enzyme activity requires reversible pH-dependent conformational change at the intermembrane space","volume":"287","author":"Prasad","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.mce.2014.12.011","article-title":"The role of mitochondrial fusion and StAR phosphorylation in the regulation of StAR activity and steroidogenesis","volume":"408","author":"Castillo","year":"2015","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3389\/fendo.2018.00061","article-title":"Granulosa cell apoptosis in the ovarian follicle-a changing view","volume":"9","author":"Regan","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s12967-016-1108-1","article-title":"Advances in rare cell isolation: An optimization and evaluation study","volume":"15","author":"Schreier","year":"2017","journal-title":"J. Transl. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1071\/RD13251","article-title":"FSH and LH receptors are differentially expressed in cumulus cells surrounding developmentally competent and incompetent mouse fully grown antral oocytes","volume":"27","author":"Vigone","year":"2015","journal-title":"Reprod. Fertil. Dev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/10\/3592\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:30:26Z","timestamp":1760175026000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/10\/3592"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,19]]},"references-count":53,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["ijms21103592"],"URL":"https:\/\/doi.org\/10.3390\/ijms21103592","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,19]]}}}