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Abstract:   (370 Views)
The endoplasmic reticulum (ER) is an important organelle responsible for protein folding, calcium homeostasis, and lipid biosynthesis. Accumulation of unfolded or misfolded proteins by hypoxia, loss of Ca2+ homeostasis, and nutrient deprivation leads to endoplasmic reticulum stress (ERS) and then the unfolded protein response (UPR) is activated as a defense mechanism to restore endoplasmic reticulum homeostasis. It is now known that the ERS and the UPR are implicated in a variety of diseases such as diabetes, inflammatory diseases, neurodegenerative diseases, and osteoporosis. Steroid hormones such as 17-βestradiol have been extensively reported to possess beneficial effects in different diseases. In this article, the concept of ERS, the underlying molecular mechanisms, and their relationship to several pathological conditions, and, finally, the role of 17-βestradiol and its receptors in moderating ERS and UPR are discussed to provide the theoretical basis for in-depth study.
Types of Manuscript: Review | Subject: Cell, Stem Cell and Cancer

1. Almanza A, Carlesso A, Chintha C, Creedican S, Doultsinos D, Leuzzi B, et al. Endoplasmic reticulum stress signalling-from basic mechanisms to clinical applications. FEBS Lett 2019; 286: 241-278. [DOI:10.1111/febs.14608]
2. Amen OM, Sarker SD, Ghildyal R, Arya A. Endoplasmic reticulum stress activates unfolded protein response signaling and mediates inflammation, obesity, and cardiac dysfunction: therapeutic and molecular approach. Front Pharmacol 2019; 10: 977. [DOI:10.3389/fphar.2019.00977]
3. Araki E, Oyadomari S, Mori M. Impact of endoplasmic reticulum stress pathway on pancreatic β-cells and diabetes mellitus. Exp Biol Med 2003; 228: 1213-1217. [DOI:10.1177/153537020322801018]
4. Ariyasu D, Yoshida H, Hasegawa Y. Endoplasmic reticulum (ER) stress and endocrine disorders. Int J Mol Sci 2017; 18: 382. [DOI:10.3390/ijms18020382]
5. Azizian H, Khaksari M, Esmailidehaj M, Farhadi Z. Cardioprotective and anti-inflammatory effects of G-protein coupled receptor 30 (GPR30) on postmenopausal type 2 diabetic rats. Biomed Pharmacother 2018; 108: 153-164. [DOI:10.1016/j.biopha.2018.09.028]
6. B'chir W, Maurin A-C, Carraro V, Averous J, Jousse C, Muranishi Y, et al. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res 2013; 41: 7683-7699. [DOI:10.1093/nar/gkt563]
7. Bjornstrom L, Sjoberg M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. J Mol Endocrinol 2005; 19: 833-842. [DOI:10.1210/me.2004-0486]
8. Bromfield JJ, Sheldon IM. Lipopolysaccharide initiates inflammation in bovine granulosa cells via the TLR4 pathway and perturbs oocyte meiotic progression in vitro. Endocrinology 2011; 152: 5029-5040. [DOI:10.1210/en.2011-1124]
9. Campos G, Schmidt-Heck W, Ghallab A, Rochlitz K, Pütter L, Medinas DB, et al. The transcription factor CHOP, a central component of the transcriptional regulatory network induced upon CCl 4 intoxication in mouse liver, is not a critical mediator of hepatotoxicity. Arch Toxicol 2014; 88: 1267-1280. [DOI:10.1007/s00204-014-1240-8]
10. Chaudhari N, Talwar P, Parimisetty A, Lefebvre d'Hellencourt C, Ravanan P. A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front Cell Neurosci 2014; 8: 213. [DOI:10.3389/fncel.2014.00213]
11. Chu SH, Sutherland K, Beck J, Kowalski J, Goldspink P, Schwertz D. Sex differences in expression of calcium-handling proteins and beta-adrenergic receptors in rat heart ventricle. Life Sci 2005; 76: 2735-2749. [DOI:10.1016/j.lfs.2004.12.013]
12. Clark S, Rainville J, Zhao X, Katzenellenbogen BS, Pfaff D, Vasudevan N. Estrogen receptor-mediated transcription involves the activation of multiple kinase pathways in neuroblastoma cells. J Steroid Biochem Mol Biol 2014; 139: 45-53. [DOI:10.1016/j.jsbmb.2013.09.010]
13. Cominacini L, Mozzini C, Garbin U, Pasini A, Stranieri C, Solani E, et al. Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases. Free Radic Biol Med 2015; 88: 233-242. [DOI:10.1016/j.freeradbiomed.2015.05.027]
14. Contreras C, González-García I, Martínez-Sánchez N, Seoane-Collazo P, Jacas J, Morgan DA, et al. Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. Cell Rep 2014; 9: 366-377. [DOI:10.1016/j.celrep.2014.08.057]
15. Contreras C, González-García I, Seoane-Collazo P, Martínez-Sánchez N, Liñares-Pose L, Rial-Pensado E, et al. Reduction of hypothalamic endoplasmic reticulum stress activates browning of white fat and ameliorates obesity. Diabetes 2017; 66: 87-99. [DOI:10.2337/db15-1547]
16. Cui W, Ma J, Wang X, Yang W, Zhang J, Ji Q. Free fatty acid induces endoplasmic reticulum stress and apoptosis of β-cells by Ca 2+/calpain-2 pathways. PloS One 2013; 8: e59921. [DOI:10.1371/journal.pone.0059921]
17. Elefteriou F, Benson MD, Sowa H, Starbuck M, Liu X, Ron D, et al. ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab 2006; 4: 441-451. [DOI:10.1016/j.cmet.2006.10.010]
18. Esmailidehaj M, Kuchakzade F, Rezvani ME, Farhadi Z, Esmaeili H, Azizian H. 17βEstradiol improves insulin signalling and insulin resistance in the aged female hearts: Role of inflammatory and anti-inflammatory cytokines. Life Sci 2020; 253: 117673. [DOI:10.1016/j.lfs.2020.117673]
19. Farhadi Z, Khaksari M, Azizian H, Dabiri S, Fallah H, Nozari M. Aging is associated with loss of beneficial effects of estrogen on leptin responsiveness in mice fed high fat diet: Role of estrogen receptor α and cytokines. Mech Ageing Dev 2020a; 186: 111198. [DOI:10.1016/j.mad.2019.111198]
20. Farhadi Z, Khaksari M, Azizian H, Mortazaeizadeh A, Shabani M, Shahrokhi N. Beneficial effects of tamoxifen on leptin sensitivity in young mice fed a high fat diet: Role of estrogen receptor alpha and cytokines. Life Sci 2020b; 246: 117384. [DOI:10.1016/j.lfs.2020.117384]
21. Garcia Dos Santos E, Dieudonne MN, Pecquery R, Le Moal V, Giudicelli Y, Lacasa D. Rapid nongenomic E2 effects on p42/p44 MAPK, activator protein-1, and cAMP response element binding protein in rat white adipocytes. Endocrinology 2002; 143: 930-940. [DOI:10.1210/endo.143.3.8678]
22. Gaub M-P, Bellard M, Scheuer I, Chambon P, Sassone-Corsi P. Activation of the ovalbumin gene by the estrogen receptor involves the fos-jun complex. Cell 1990; 63: 1267-1276. [DOI:10.1016/0092-8674(90)90422-B]
23. González-García I, Contreras C, Estévez-Salguero Á, Ruíz-Pino F, Colsh B, Pensado I, et al. Estradiol regulates energy balance by ameliorating hypothalamic ceramide-induced ER stress. Cell Rep 2018; 25: 413-423. e5. [DOI:10.1016/j.celrep.2018.09.038]
24. Gregor MF, Yang L, Fabbrini E, Mohammed BS, Eagon JC, Hotamisligil GS, et al. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 2009; 58: 693-700. [DOI:10.2337/db08-1220]
25. Gu Q, Moss RL. 17β-Estradiol potentiates kainate-induced currents via activation of the cAMP cascade. J Neurosci 1996; 16: 3620-3629. [DOI:10.1523/JNEUROSCI.16-11- 03620.1996]
26. Guo Y-S, Sun Z, Ma J, Cui W, Gao B, Zhang H-Y, et al. 17 β-Estradiol inhibits ER stressinduced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts. Lab Invest 2014; 94: 906-916. [DOI:10.1038/labinvest.2014.63]
27. Haas MJ, Raheja P, Jaimungal S, Sheikh-Ali M, Mooradian AD. Estrogen-dependent inhibition of dextrose-induced endoplasmic reticulum stress and superoxide generation in endothelial cells. Free Radic Biol Med 2012; 52: 2161-2167. [DOI:10.1016/j.freeradbiomed.2012.04.009]
28. Hamamura K, Yokota H. Stress to endoplasmic reticulum of mouse osteoblasts induces apoptosis and transcriptional activation for bone remodeling. FEBS Lett 2007; 581: 1769- 1774. [DOI:10.1016/j.febslet.2007.03.063]
29. Hamilton KJ, Hewitt SC, Arao Y, Korach KS. Estrogen hormone biology. Curr Top Dev Biol 2017; 125: 109-146. [DOI:10.1016/bs.ctdb.2016.12.005]
30. Han Z-W, Chang Y-C, Zhou Y, Zhang H, Chen L, Zhang Y, et al. GPER agonist G1 suppresses neuronal apoptosis mediated by endoplasmic reticulum stress after cerebral ischemia/reperfusion injury. Neural Regen Res 2019; 14: 1221. [DOI:10.4103/1673- 5374.251571]
31. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-1695. [DOI:10.1056/NEJMra043430]
32. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk−/− mice reveals a role for translational control in secretory cell survival. Mol Cell 2001; 7: 1153-1163. [DOI:10.1016/S1097- 2765(01)00264-7]
33. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell 2000; 5: 897-904. [DOI:10.1016/S1097-2765(00)80330-5]
34. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 2003; 11: 619-633. [DOI:10.1016/S1097-2765(03)00105-9]
35. Herath S, Williams EJ, Lilly ST, Gilbert RO, Dobson H, Bryant CE, et al. Ovarian follicular cells have innate immune capabilities that modulate their endocrine function. Reproduction 2007; 134: 683-693. [DOI:10.1530/REP-07-0229]
36. Herson PS, Koerner IP, Hurn PD. Sex, sex steroids and brain injury. Semin Reprod Med 2009; 27: 229. [DOI:10.1055/s-0029-1216276]
37. Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 2012; 13: 89-102. [DOI:10.1038/nrm3270]
38. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. Journal of Cell Biology 2009; 186: 323-331. [DOI:10.1083/jcb.200903014]
39. Hollien J, Weissman J S. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 2006; 313: 104-107. [DOI:10.1126/science.1129631]
40. Iwawaki T, Akai R, Yamanaka S, Kohno K. Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc Natl Acad Sci U S A 2009; 106: 16657-16662. [DOI:10.1073/pnas.0903775106]
41. Ji T, Han Y, Yang W, Xu B, Sun M, Jiang S, et al. Endoplasmic reticulum stress and NLRP3 inflammasome: Crosstalk in cardiovascular and metabolic disorders. J Cell Physiol 2019; 234: 14773-14782. [DOI:10.1002/jcp.28275]
42. Jia J, Guan D, Zhu W, Alkayed NJ, Wang MM, Hua Z, et al. Estrogen inhibits Fas-mediated apoptosis in experimental stroke. Exp Neurol 2009; 215: 48-52. [DOI:10.1016/j.expneurol.2008.09.015]
43. Jiang Q, Li F, Shi K, Wu P, An J, Yang Y, et al. Involvement of p38 in signal switching from autophagy to apoptosis via the PERK/eIF2 α/ATF4 axis in selenite-treated NB4 cells. Cell Death Dis 2014; 5: 1270-1270. [DOI:10.1038/cddis.2014.200]
44. Kalaitzidis D, Gilmore TD. Transcription factor cross-talk: the estrogen receptor and NF-κB. Trends Endocrinol Metab 2005; 16: 46-52. [DOI:10.1016/j.tem.2005.01.004]
45. Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2002; 2: 389-406. [DOI:10.1016/S1534-5807(02)00157-0]
46. Kim B-J, Ryu S-W, Song B-J. JNK-and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J Biol Chem 2006; 281: 21256-21265. [DOI:10.1074/jbc.M510644200]
47. Kimata Y, Ishiwata-Kimata Y, Ito T, Hirata A, Suzuki T, Oikawa D, et al. Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins. J Cell Biol 2007; 179: 75-86. [DOI:10.1083/jcb.200704166]
48. Kooptiwut S, Mahawong P, Hanchang W, Semprasert N, Kaewin S, Limjindaporn T, et al. Estrogen reduces endoplasmic reticulum stress to protect against glucotoxicity inducedpancreatic β-cell death. J Steroid Biochem Mol Biol 2014; 139: 25-32. [DOI:10.1016/j.jsbmb.2013.09.018]
49. Kousteni S, Chen J-R, Bellido T, Han L, Ali AA, O'Brien CA, et al. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 2002; 298: 843-846. [DOI:10.1126/science.1074935]
50. Krebs J, Groenendyk J, Michalak M. Ca 2+ -signaling, alternative splicing and endoplasmic reticulum stress responses. Neurochem Res 2011; 36: 1198-1211. [DOI:10.1007/s11064-011-0431-4]
51. Kropski JA, Blackwell TS. Endoplasmic reticulum stress in the pathogenesis of fibrotic disease. J Clin Invest 2018; 128: 64-73. [DOI:10.1172/JCI93560]
52. Lan B, He Y, Sun H, Zheng X, Gao Y, Li N. The roles of mitochondria-associated membranes in mitochondrial quality control under endoplasmic reticulum stress. Life Sci 2019; 231: 116587. [DOI:10.1016/j.lfs.2019.116587]
53. Lee JH, Won SM, Suh J, Son SJ, Moon GJ, Park U-J, et al. Induction of the unfolded protein response and cell death pathway in Alzheimer's disease, but not in aged Tg2576 mice. Exp Mol Med 2010; 42: 386-394. [DOI:10.3858/emm.2010.42.5.040]
54. Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 2002; 16: 452-466. [DOI:10.1101/gad.964702]
55. Lei L, Ge J, Zhao H, Wang X, Yang L. Role of endoplasmic reticulum stress in lipopolysaccharide-inhibited mouse granulosa cell estradiol production. J Reprod Dev 2019. [DOI:10.1262/jrd.2019-052]
56. Li R, Wang Y, Chen P, Meng J, Zhang H. G-protein coupled estrogen receptor activation protects the viability of hyperoxia-treated primary murine retinal microglia by reducing ER stress. Aging 2020a; 12: 17367. [DOI:10.18632/aging.103733]
57. Li R, Wang Y, Chen P, Meng J, Zhang H. G‐protein‐coupled estrogen receptor protects retinal ganglion cells via inhibiting endoplasmic reticulum stress under hyperoxia. J Cell Physiol 2020b. [DOI:10.1002/jcp.30149]
58. Li Z, Zhang T, Dai H, Liu G, Wang H, Sun Y, et al. Endoplasmic reticulum stress is involved in myocardial apoptosis of streptozocin-induced diabetic rats. J Endocrinol 2008; 196: 565- 572. [DOI:10.1677/JOE-07-0230]
59. Lin P, Yang Y, Li X, Chen F, Cui C, Hu L, et al. Endoplasmic reticulum stress is involved in granulosa cell apoptosis during follicular atresia in goat ovaries. Mol Reprod Dev 2012; 79: 423-432. [DOI:10.1002/mrd.22045]
60. Lipson KL, Fonseca SG, Ishigaki S, Nguyen LX, Foss E, Bortell R, et al. Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab 2006; 4: 245-254. [DOI:10.1016/j.cmet.2006.07.007]
61. Liu S, Le May C, Wong WP, Ward RD, Clegg DJ, Marcelli M, et al. Importance of extranuclear estrogen receptor-α and membrane G protein-coupled estrogen receptor in pancreatic islet survival. Diabetes 2009; 58: 2292-2302. [DOI:10.2337/db09-0257]
62. Liu Y, Zhou J, Zhao W, Li X, Jiang R, Liu C, et al. XBP1S associates with RUNX2 and regulates chondrocyte hypertrophy. J Biol Chem 2012; 287: 34500-34513. [DOI:10.1074/jbc.M112.385922]
63. Liu Z, Lv Y, Zhao N, Guan G, Wang J. Protein kinase R-like ER kinase and its role in endoplasmic reticulum stress-decided cell fate. Cell Death Dis 2015; 6: 1822-1822. [DOI:10.1038/cddis.2015.183]
64. Lobo RA, Davis SR, De Villiers T, Gompel A, Henderson VW, Hodis HN, et al. Prevention of diseases after menopause. Climacteric 2014; 17: 540-556. [DOI:10.3109/13697137.2014.933411]
65. Lösel R, Wehling M. Nongenomic actions of steroid hormones. Nat Rev Mol Cell Biol 2003; 4: 46-55. [DOI:10.1038/nrm1009]
66. Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol 2004; 167: 27-33. [DOI:10.1083/jcb.200408003]
67. Lu T, Jiang Y, Zhou Z, Yue X, Wei N, Chen Z, et al. Intranasal ginsenoside Rb1 targets the brain and ameliorates cerebral ischemia/reperfusion injury in rats. Biol Pharm Bull 2011; 34: 1319-1324. [DOI:10.1248/bpb.34.1319]
68. Lucke-Wold BP, Turner RC, Logsdon AF, Nguyen L, Bailes JE, Lee JM, et al. Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy. J Neurosurg 2016; 124: 687- 702. [DOI:10.3171/2015.3.JNS141802]
69. Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, et al. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia 2007; 50: 2486- 2494. [DOI:10.1007/s00125-007-0816-8]
70. Marino M, Acconcia F, Trentalance A. Biphasic estradiol-induced AKT phosphorylation is modulated by PTEN via MAP kinase in HepG2 cells. Mol Biol Cell 2003; 14: 2583-2591. [DOI:10.1091/mbc.e02-09-0621]
71. Marino M, Pallottini V, Trentalance A. Estrogens cause rapid activation of IP3-PKC-α signal transduction pathway in HEPG2 cells. Biochem Biophys Res Commun 1998; 245: 254-258. [DOI:10.1006/bbrc.1998.8413]
72. Mattson M, Duan W, Pedersen W, Culmsee C. Neurodegenerative disorders and ischemic brain diseases. Apoptosis 2001; 6: 69-81. [DOI:10.1023/A:1009676112184]
73. Mauvais-Jarvis F. Sex differences in metabolic homeostasis, diabetes, and obesity. Biol Sex Differ 2015; 6: 1-9. [DOI:10.1186/s13293-015-0033-y]
74. Mauvais-Jarvis F, Arnold AP, Reue K. A guide for the design of pre-clinical studies on sex differences in metabolism. Cell Metab 2017; 25: 1216-1230. [DOI:10.1016/j.cmet.2017.04.033]
75. Mauvais-Jarvis F, Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev 2013; 34: 309-338. [DOI:10.1210/er.2012- 1055]
76. Mehta A, Onteru SK, Singh D. HDAC inhibitor prevents LPS mediated inhibition of CYP19A1 expression and 17β-estradiol production in granulosa cells. Mol Cell Endocrinol 2015; 414: 73-81. [DOI:10.1016/j.mce.2015.07.002]
77. Meng X, Wang M, Wang X, Sun G, Ye J, Xu H, et al. Suppression of NADPH oxidase-and mitochondrion-derived superoxide by Notoginsenoside R1 protects against cerebral ischemiareperfusion injury through estrogen receptor-dependent activation of Akt/Nrf2 pathways. Free Radic Res 2014; 48: 823-838. [DOI:10.3109/10715762.2014.911853]
78. Molina L, Figueroa C D, Bhoola K D, Ehrenfeld P. GPER-1/GPR30 a novel estrogenreceptor sited in the cell membrane: therapeutic coupling to breast cancer. Expert Opin Ther Targets 2017; 21: 755-766.

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