DOI QR코드

DOI QR Code

The role of autophagy in the placenta as a regulator of cell death

  • Gong, Jin-Sung (Department of Biomedical Science, CHA University) ;
  • Kim, Gi Jin (Department of Biomedical Science, CHA University)
  • Received : 2014.04.30
  • Accepted : 2014.08.04
  • Published : 2014.09.30

Abstract

The placenta is a temporary fetomaternal organ capable of supporting fetal growth and development during pregnancy. In particular, abnormal development and dysfunction of the placenta due to cha nges in the proliferation, differentiation, cell death, and invasion of trophoblasts induce several gynecological diseases as well as abnormal fetal development. Autophagy is a catalytic process that maintains cellular structures by recycling building blocks derived from damaged microorganelles or proteins resulting from digestion in lysosomes. Additionally, autophagy is necessary to maintain homeostasis during cellular growth, development, and differentiation, and to protect cells from nutritional deficiencies or factors related to metabolism inhibition. Induced autophagy by various environmental factors has a dual role: it facilitates cellular survival in normal conditions, but the cascade of cellular death is accelerated by over-activated autophagy. Therefore, cellular death by autophagy has been known as programmed cell death type II. Autophagy causes or inhibits cellular death via the other mechanism, apoptosis, which is programmed cell death type I. Recently, it has been reported that autophagy increases in placenta-related obstetrical diseases such as preeclampsia and intrauterine growth retardation, although the mechanisms are still unclear. In particular, abnormal autophagic mechanisms prevent trophoblast invasion and inhibit trophoblast functions. Therefore, the objectives of this review are to examine the characteristics and functions of autophagy and to investigate the role of autophagy in the placenta and the trophoblast as a regulator of cell death.

Keywords

References

  1. Benischke K, Kaufmann P. Pathology of the human placenta. New York: Springer-Verlag; 2000.
  2. Moore KL, Persaud TV. The developing human-clinically orientated embryology. 8th ed. Philadelphia: Saunders; 2008.
  3. Huppertz B. The anatomy of the normal placenta. J Clin Pathol 2008;61:1296-302. https://doi.org/10.1136/jcp.2008.055277
  4. Berry DL, Baehrecke EH. Autophagy functions in programmed cell death. Autophagy 2008;4:359-60. https://doi.org/10.4161/auto.5575
  5. Rikiishi H. Novel Insights into the Interplay between Apoptosis and Autophagy. Int J Cell Biol 2012;2012:317645.
  6. Levine B, Sinha S, Kroemer G. Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 2008;4:600-6. https://doi.org/10.4161/auto.6260
  7. Cross JC. How to make a placenta: mechanisms of trophoblast cell differentiation in mice: a review. Placenta 2005;26 Suppl A:S3-9. https://doi.org/10.1016/j.placenta.2005.01.015
  8. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004;6:463-77. https://doi.org/10.1016/S1534-5807(04)00099-1
  9. Mizushima N. Autophagy: process and function. Genes Dev 2007;21:2861-73. https://doi.org/10.1101/gad.1599207
  10. Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol 2010;12:823-30. https://doi.org/10.1038/ncb0910-823
  11. Ichimura Y, Komatsu M. Pathophysiological role of autophagy: lesson from autophagy-deficient mouse models. Exp Anim 2011;60:329-45. https://doi.org/10.1538/expanim.60.329
  12. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008;451:1069-75. https://doi.org/10.1038/nature06639
  13. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 2009;20:1992-2003. https://doi.org/10.1091/mbc.E08-12-1249
  14. Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G, Antonioli M, et al. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J Cell Biol 2010;191:155-68. https://doi.org/10.1083/jcb.201002100
  15. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 2010;141:656-67. https://doi.org/10.1016/j.cell.2010.04.009
  16. Yang Z, Klionsky DJ. An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 2009;335:1-32.
  17. Codogno P, Meijer AJ. Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 2005;12 Suppl 2:1509-18. https://doi.org/10.1038/sj.cdd.4401751
  18. Wang CW, Klionsky DJ. The molecular mechanism of autophagy. Mol Med 2003;9:65-76.
  19. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 2009;11:468-76. https://doi.org/10.1038/ncb1854
  20. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011;13:132-41. https://doi.org/10.1038/ncb2152
  21. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 2009;20:1981-91. https://doi.org/10.1091/mbc.E08-12-1248
  22. Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13. FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 2009;284:12297-305. https://doi.org/10.1074/jbc.M900573200
  23. Marquez RT, Xu L. Bcl-2:Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch. Am J Cancer Res 2012;2:214-21.
  24. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005;122:927-39. https://doi.org/10.1016/j.cell.2005.07.002
  25. Itakura E, Kishi C, Inoue K, Mizushima N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 2008;19:5360-72. https://doi.org/10.1091/mbc.E08-01-0080
  26. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and selfkilling: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 2007;8:741-52.
  27. Jaeger PA, Wyss-Coray T. All-you-can-eat: autophagy in neurodegeneration and neuroprotection. Mol Neurodegener 2009;4:16. https://doi.org/10.1186/1750-1326-4-16
  28. Grotemeier A, Alers S, Pfisterer SG, Paasch F, Daubrawa M, Dieterle A, et al. AMPK-independent induction of autophagy by cytosolic Ca2+ increase. Cell Signal 2010;22:914-25. https://doi.org/10.1016/j.cellsig.2010.01.015
  29. Zalckvar E, Berissi H, Mizrachy L, Idelchuk Y, Koren I, Eisenstein M, et al. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep 2009;10:285-92. https://doi.org/10.1038/embor.2008.246
  30. Zalckvar E, Berissi H, Eisenstein M, Kimchi A. Phosphorylation of Beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with Bcl-2 and Bcl-XL. Autophagy 2009;5:720-2. https://doi.org/10.4161/auto.5.5.8625
  31. Song ZC, Zhou W, Shu R, Ni J. Hypoxia induces apoptosis and autophagic cell death in human periodontal ligament cells through HIF-1alpha pathway. Cell Prolif 2012;45:239-48. https://doi.org/10.1111/j.1365-2184.2012.00810.x
  32. Hu YL, DeLay M, Jahangiri A, Molinaro AM, Rose SD, Carbonell WS, et al. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res 2012;72:1773-83. https://doi.org/10.1158/0008-5472.CAN-11-3831
  33. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, et al. Hypoxia-induced autophagy is mediated through hypoxiainducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 2009;29:2570-81. https://doi.org/10.1128/MCB.00166-09
  34. Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 2008;134:451-60. https://doi.org/10.1016/j.cell.2008.06.028
  35. Abida WM, Gu W. p53-Dependent and p53-independent activation of autophagy by ARF. Cancer Res 2008;68:352-7. https://doi.org/10.1158/0008-5472.CAN-07-2069
  36. Azad MB, Chen Y, Gibson SB. Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment. Antioxid Redox Signal 2009;11:777-90. https://doi.org/10.1089/ars.2008.2270
  37. Gilkerson RW, De Vries RL, Lebot P, Wikstrom JD, Torgyekes E, Shirihai OS, et al. Mitochondrial autophagy in cells with mtDNA mutations results from synergistic loss of transmembrane potential and mTORC1 inhibition. Hum Mol Genet 2012;21:978-90. https://doi.org/10.1093/hmg/ddr529
  38. Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, et al. Rapamycin induces autophagy in islets: relevance in islet transplantation. Transplant Proc 2009;41:334-8. https://doi.org/10.1016/j.transproceed.2008.10.032
  39. Lu Z, Luo RZ, Lu Y, Zhang X, Yu Q, Khare S, et al. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest 2008;118:3917-29.
  40. Nishida K, Yamaguchi O, Otsu K. Crosstalk between autophagy and apoptosis in heart disease. Circ Res 2008;103:343-51. https://doi.org/10.1161/CIRCRESAHA.108.175448
  41. Zhou F, Yang Y, Xing D. Bcl-2 and Bcl-xL play important roles in the crosstalk between autophagy and apoptosis. FEBS J 2011; 278:403-13. https://doi.org/10.1111/j.1742-4658.2010.07965.x
  42. Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 2011;18:571-80. https://doi.org/10.1038/cdd.2010.191
  43. Cui Q, Valentin M, Janumyan Y, Yang E. Bax-/- bak-/- cells exhibit p27 Thr198 phosphorylation and autophagy. Autophagy 2009;5: 263-4. https://doi.org/10.4161/auto.5.2.7618
  44. Ezaki J, Matsumoto N, Takeda-Ezaki M, Komatsu M, Takahashi K, Hiraoka Y, et al. Liver autophagy contributes to the maintenance of blood glucose and amino acid levels. Autophagy 2011;7:727-36. https://doi.org/10.4161/auto.7.7.15371
  45. Xie HJ, Noh JH, Kim JK, Jung KH, Eun JW, Bae HJ, et al. HDAC1 inactivation induces mitotic defect and caspase-independent autophagic cell death in liver cancer. PLoS One 2012;7:e34265. https://doi.org/10.1371/journal.pone.0034265
  46. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006;441:880-4. https://doi.org/10.1038/nature04723
  47. Cui D, Wang L, Qi A, Zhou Q, Zhang X, Jiang W. Propofol prevents autophagic cell death following oxygen and glucose deprivation in PC12 cells and cerebral ischemia-reperfusion injury in rats. PLoS One 2012;7:e35324. https://doi.org/10.1371/journal.pone.0035324
  48. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 2008;118:2190-9.
  49. Sciarretta S, Hariharan N, Monden Y, Zablocki D, Sadoshima J. Is autophagy in response to ischemia and reperfusion protective or detrimental for the heart? Pediatr Cardiol 2011;32:275-81. https://doi.org/10.1007/s00246-010-9855-x
  50. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 2007;100:914-22. https://doi.org/10.1161/01.RES.0000261924.76669.36
  51. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature 2004;432:1032-6. https://doi.org/10.1038/nature03029
  52. Jaffer S, Shynlova O, Lye S. Mammalian target of rapamycin is activated in association with myometrial proliferation during pregnancy. Endocrinology 2009;150:4672-80. https://doi.org/10.1210/en.2009-0419
  53. Kamei T, Jones SR, Chapman BM, KL MC, Dai G, Soares MJ. The phosphatidylinositol 3-kinase/Akt signaling pathway modulates the endocrine differentiation of trophoblast cells. Mol Endocrinol 2002;16:1469-81. https://doi.org/10.1210/mend.16.7.0878
  54. Chifenti B, Locci MT, Lazzeri G, Guagnozzi M, Dinucci D, Chiellini F, et al. Autophagy-related protein LC3 and Beclin-1 in the first trimester of pregnancy. Clin Exp Reprod Med 2013;40:33-7. https://doi.org/10.5653/cerm.2013.40.1.33
  55. Signorelli P, Avagliano L, Virgili E, Gagliostro V, Doi P, Braidotti P, et al. Autophagy in term normal human placentas. Placenta 2011;32:482-5. https://doi.org/10.1016/j.placenta.2011.03.005
  56. Oh SY, Choi SJ, Kim KH, Cho EY, Kim JH, Roh CR. Autophagy-related proteins, LC3 and Beclin-1, in placentas from pregnancies complicated by preeclampsia. Reprod Sci 2008;15:912-20. https://doi.org/10.1177/1933719108319159
  57. Crocker IP, Cooper S, Ong SC, Baker PN. Differences in apoptotic susceptibility of cytotrophoblasts and syncytiotrophoblasts in normal pregnancy to those complicated with preeclampsia and intrauterine growth restriction. Am J Pathol 2003;162:637-43. https://doi.org/10.1016/S0002-9440(10)63857-6
  58. Hung TH, Chen SF, Li MJ, Yeh YL, Hsieh TT. Differential effects of concomitant use of vitamins C and E on trophoblast apoptosis and autophagy between normoxia and hypoxia-reoxygenation. PLoS One 2010;5:e12202. https://doi.org/10.1371/journal.pone.0012202
  59. Hung TH, Hsieh TT, Chen SF, Li MJ, Yeh YL. Autophagy in the human placenta throughout gestation. PLoS One 2013;8:e83475. https://doi.org/10.1371/journal.pone.0083475
  60. Delorme-Axford E, Bayer A, Sadovsky Y, Coyne CB. Autophagy as a mechanism of antiviral defense at the maternal? fetal interface. Autophagy 2013;9:2173-4. https://doi.org/10.4161/auto.26558
  61. Chen B, Longtine MS, Nelson DM. Hypoxia induces autophagy in primary human trophoblasts. Endocrinology 2012;153:4946-54. https://doi.org/10.1210/en.2012-1472
  62. Choi JH, Lee HJ, Yang TH, Kim GJ. Effects of hypoxia inducible factors- 1alpha on autophagy and invasion of trophoblasts. Clin Exp Reprod Med 2012;39:73-80. https://doi.org/10.5653/cerm.2012.39.2.73
  63. Yamanaka-Tatematsu M, Nakashima A, Fujita N, Shima T, Yoshimori T, Saito S. Autophagy induced by HIF1alpha overexpression supports trophoblast invasion by supplying cellular energy. PLoS One 2013;8:e76605. https://doi.org/10.1371/journal.pone.0076605
  64. Hung TH, Chen SF, Lo LM, Li MJ, Yeh YL, Hsieh TT. Increased autophagy in placentas of intrauterine growth-restricted pregnancies. PLoS One 2012;7:e40957. https://doi.org/10.1371/journal.pone.0040957
  65. Curtis S, Jones CJ, Garrod A, Hulme CH, Heazell AE. Identification of autophagic vacuoles and regulators of autophagy in villous trophoblast from normal term pregnancies and in fetal growth restriction. J Matern Fetal Neonatal Med 2013;26:339-4 . https://doi.org/10.3109/14767058.2012.733764
  66. Chen Y, Klionsky DJ. The regulation of autophagy - unanswered questions. J Cell Sci 2011;124:161-70. https://doi.org/10.1242/jcs.064576
  67. Smith SC, Baker PN, Symonds EM. Increased placental apoptosis in intrauterine growth restriction. Am J Obstet Gynecol 1997;177:1395-401. https://doi.org/10.1016/S0002-9378(97)70081-4
  68. Siddiqui IA, Jaleel A, Tamimi W, Al Kadri HM. Role of oxidative stress in the pathogenesis of preeclampsia. Arch Gynecol Obstet 2010;282:469-74. https://doi.org/10.1007/s00404-010-1538-6
  69. Hung TH, Skepper JN, Charnock-Jones DS, Burton GJ. Hypoxiareoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ Res 2002;90:1274-81. https://doi.org/10.1161/01.RES.0000024411.22110.AA
  70. Chen GQ, Zhang H, Qi HB, Yao ZW, Gao L, Qiu CL. Effects and mechanisms of autophagy of trophoblast cells in severe preeclampsia. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2012;28:294-6.
  71. Leung DN, Smith SC, To KF, Sahota DS, Baker PN. Increased placental apoptosis in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 2001;184:1249-50. https://doi.org/10.1067/mob.2001.112906
  72. Saito S, Nakashima A. Review: The role of autophagy in extravillous trophoblast function under hypoxia. Placenta 2013;34 Suppl:S79-84. https://doi.org/10.1016/j.placenta.2012.11.026
  73. Nakashima A, Yamanaka-Tatematsu M, Fujita N, Koizumi K, Shima T, Yoshida T, et al. Impaired autophagy by soluble endoglin, under physiological hypoxia in early pregnant period, is involved in poor placentation in preeclampsia. Autophagy 2013;9:303-16. https://doi.org/10.4161/auto.22927
  74. Saito S, Nakashima A. A review of the mechanism for poor placentation in early-onset preeclampsia: the role of autophagy in trophoblast invasion and vascular remodeling. J Reprod Immunol 2014;101-102:80-8. https://doi.org/10.1016/j.jri.2013.06.002

Cited by

  1. Autophagy is involved in recombinant Newcastle disease virus (rL-RVG)-induced cell death of stomach adenocarcinoma cells in vitro vol.47, pp.2, 2015, https://doi.org/10.3892/ijo.2015.3039
  2. Inhibition of microRNA-101 attenuates hypoxia/reoxygenation-induced apoptosis through induction of autophagy in H9c2 cardiomyocytes vol.11, pp.5, 2015, https://doi.org/10.3892/mmr.2015.3215
  3. Atorvastatin induces autophagic cell death in prostate cancer cells in vitro vol.11, pp.6, 2014, https://doi.org/10.3892/mmr.2015.3334
  4. Deep-sequencing identification of differentially expressed miRNAs in decidua and villus of recurrent miscarriage patients vol.293, pp.None, 2014, https://doi.org/10.1007/s00404-016-4038-5
  5. The Role of Secretory Autophagy in Zika Virus Transfer through the Placental Barrier vol.6, pp.None, 2014, https://doi.org/10.3389/fcimb.2016.00206
  6. Inflammation modulates LC3 expression in human preterm delivery vol.30, pp.6, 2014, https://doi.org/10.1080/14767058.2016.1183630
  7. Death by over-eating: The Gaucher disease associated gene GBA1 , identified in a screen for mediators of autophagic cell death, is necessary for developmental cell death in Drosophila midgut vol.16, pp.21, 2014, https://doi.org/10.1080/15384101.2017.1380134
  8. Gene expression and epigenetic aberrations in F1‐placentas fathered by obese males vol.84, pp.4, 2014, https://doi.org/10.1002/mrd.22784
  9. Mechanism of deoxynivalenol effects on the reproductive system and fetus malformation: Current status and future challenges vol.41, pp.None, 2014, https://doi.org/10.1016/j.tiv.2017.02.011
  10. Maternal and cord blood cyclophilin A in severe preeclampsia and normal pregnancy and its correlation with vitamin D and zinc vol.36, pp.4, 2017, https://doi.org/10.1080/10641955.2017.1385792
  11. The trophoblast survival capacity in preeclampsia vol.12, pp.11, 2014, https://doi.org/10.1371/journal.pone.0186909
  12. Impaired placental autophagy in placental malaria vol.12, pp.11, 2017, https://doi.org/10.1371/journal.pone.0187291
  13. Hypermethylation and loss of retinoic acid receptor responder 1 expression in human choriocarcinoma vol.36, pp.1, 2014, https://doi.org/10.1186/s13046-017-0634-x
  14. Maternal one carbon metabolism through increased oxidative stress and disturbed angiogenesis can influence placental apoptosis in preeclampsia vol.206, pp.None, 2014, https://doi.org/10.1016/j.lfs.2018.05.029
  15. Increased Autophagy Enhances the Resistance to Tumor Necrosis Factor-Alpha Treatment in Rheumatoid Arthritis Human Fibroblast-Like Synovial Cell vol.2018, pp.None, 2018, https://doi.org/10.1155/2018/4941027
  16. Evaluation of Z-VAD-FMK as an anti-apoptotic drug to prevent granulosa cell apoptosis and follicular death after human ovarian tissue transplantation vol.36, pp.2, 2019, https://doi.org/10.1007/s10815-018-1353-8
  17. Autophagy regulates abnormal placentation induced by folate deficiency in mice vol.25, pp.6, 2014, https://doi.org/10.1093/molehr/gaz022
  18. Placental cell death patterns exhibit differences throughout gestation in two strains of laboratory mice vol.378, pp.2, 2014, https://doi.org/10.1007/s00441-019-03055-1
  19. Endometrial autophagy is essential for embryo implantation during early pregnancy vol.98, pp.4, 2020, https://doi.org/10.1007/s00109-019-01849-y
  20. Autophagy in preeclampsia: A new target? vol.57, pp.None, 2014, https://doi.org/10.1016/j.ebiom.2020.102864
  21. Cell dynamics in human villous trophoblast vol.27, pp.5, 2021, https://doi.org/10.1093/humupd/dmab015
  22. Inhibition of the C-X-C Motif Chemokine 12 (CXCL12) and Its Receptor CXCR4 Reduces Utero-Placental Expression of the VEGF System and Increases Utero-Placental Autophagy vol.8, pp.None, 2014, https://doi.org/10.3389/fvets.2021.650687
  23. Preeclampsia: From Cellular Wellness to Inappropriate Cell Death, and the Roles of Nutrition vol.9, pp.None, 2014, https://doi.org/10.3389/fcell.2021.726513
  24. PLAC8 promotes the autophagic activity and improves the growth priority of human trophoblast cells vol.35, pp.3, 2014, https://doi.org/10.1096/fj.202002075rr
  25. Overexpression of let‐7b exerts beneficial effects on the functions of human placental trophoblasts by activating the ERK1/2 signaling pathway vol.89, pp.1, 2022, https://doi.org/10.1002/mrd.23535