• Molecules and Cells
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• v.41 no.8
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• pp.705-716
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• 2018

The endoplasmic reticulum (ER) is a critical organelle for protein synthesis, folding and modification, and lipid synthesis and calcium storage. Dysregulation of ER functions leads to the accumulation of misfolded- or unfolded-protein in the ER lumen, and this triggers the unfolded protein response (UPR), which restores ER homeostasis. The UPR is characterized by three distinct downstream signaling pathways that promote cell survival or apoptosis depending on the stressor, the intensity and duration of ER stress, and the cell type. Mammalian cells express the UPR transducers IRE1, PERK, and ATF6, which control transcriptional and translational responses to ER stress. Direct links between ER stress and immune responses are also evident, but the mechanisms by which UPR signaling cascades are coordinated with immunity remain unclear. This review discusses recent investigations of the roles of ER stress in immune responses that lead to differentiation, maturation, and cytokine expression in immune cells. Further understanding of how ER stress contributes to the pathogenesis of immune disorders will facilitate the development of novel therapies that target UPR pathways.

• Clinical and Experimental Reproductive Medicine
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• v.42 no.1
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• pp.1-7
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• 2015

Stress coping mechanisms are critical to minimize or overcome damage caused by ever changing environmental conditions. They are designed to promote cell survival. The unfolded protein response (UPR) pathway is mobilized in response to the accumulation of unfolded proteins, ultimately in order to regain endoplasmic reticulum (ER) homeostasis. Various elements of coping responses to ER stress including Perk, Ask1, Bip, Chop, Gadd34, Ire1, Atf4, Atf6, and Xbp1 have been identified and were found to be inducible in oocytes and preimplantation embryos, suggesting that, as a normal part of the cellular adaptive mechanism, these coping responses, including the UPR, play a pivotal role in the development of preimplantation embryos. As such, the UPR-associated molecules and pathways may become useful markers for the potential diagnosis of stress conditions for preimplantation embryos. After implantation, ER stress-induced coping responses become physiologically important for a normal decidual response, placentation, and early organogenesis. Attenuation of ER stress coping responses by tauroursodeoxycholate and salubrinal was effective for prevention of cell death of cultured embryos. Further elucidation of new and relevant ER stress coping responses in periimplantation embryos might contribute to a comprehensive understanding of the regulation of normal development of embryonic development and potentiation of embryonic development in vitro.

• Journal of Life Science
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• v.17 no.6 s.86
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• pp.847-858
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• 2007

The endoplasmic reticulum (ER) is an important intracellular organelle for folding and maturation of newly synthesized transmembrane and secretory proteins. The ER provides stringent quality control systems to ensure that only correctly folded proteins exit the ER and unfolded or misfolded proteins are retained and ultimately degraded. The ER has evolved stress response both signaling pathways the unfolded protein response (UPR) to cope with the accmulation of unfolded or misfolded proteins and ER overload response (EOR). Accumulating evidence suggests that, in addition to responsibility for protein processing, ER is also an important signaling compartment and a sensor of cellular stress. In this respect, production of bio-functional recombinant-proteins requires efficient functioning of the ER secretory pathway in host cells. This review briefly summarizes our understanding of the ER signaling developed in the recent years to help of the secretion capacities of recombinant cells.

• Molecules and Cells
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• v.21 no.3
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• pp.356-359
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• 2006

The transcription factor E2F1 coordinates cell cycle progression and induces apoptosis in response to DNA damage stress. Aside from DNA damage, the role of E2F1 in the endoplasmic reticulum (ER) stress signaling pathways is unclear. We found that $E2F1^{-/-}$ murine embryonic fibroblasts (MEFs) are resistant to apoptosis triggered by the ER stress inducer thapsigargin. In addition, E2F1 deficiency results in enhanced phosphorylation of eukaryotic translation initiation factor $2{\alpha}$ ($elF2{\alpha}$). These results therefore indicate that E2F1 deficiency increases phosphorylation of $elF2{\alpha}$ in response to ER stress triggered by thapsigargin, and suggest that the reduction in ER stress-induced apoptosis in E2F1-deficient cells is related to the high level of $elF2{\alpha}$ phosphorylation.

• Journal of Life Science
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• v.26 no.4
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• pp.490-495
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• 2016

Brefeldin A (BFA), a lactone antibiotic isolated from the fungus Eupenicillium brefeldianum, inhibits the transport of secreted and membrane proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. BFA disrupts Golgi function, the accumulation of unfolded proteins in ER, and the induction of ER stress. Prolonged ER stress induces apoptosis at least in part through the transcription factor C/EBP (CCAAT/enhancer binding protein) homologous protein (CHOP),which is activated by the unfolded protein response (UPR). In this paper, we demonstrate that BFA-induced endoplasmic reticulum stress leads to different CHOP expression in primary astrocyte cells and C6 glioma cells. BFA induced lower CHOP expression levels in primary astrocyte cells than in C6 glioma cells; however, other ER stress inducers (thapsigargin and tunicamycin) resulted in similar expression patterns in these two cell types. Interestingly, the three different ER stress inducers (BFA, thapsigargin, and tunicamycin) induced similar levels of CHOP mRNA expression in primary astrocyte cells. The ubiquitin-proteasome inhibitor MG132 also markedly up-regulated the BFA-mediated CHOP protein expression in primary astrocyte cells. BFA also induced higher proteasome activity in primary astrocyte cells than in C6 glioma cells. Taken together, our results suggest that higher proteasomal activity might down-regulate BFA-induced CHOP expression in primary astrocyte cells.

• Herbal Formula Science
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• v.26 no.4
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• pp.307-318
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• 2018

Objectives : Endoplasmic reticulum (ER) stress designates cellular responses to the accumulation of misfolded and unfolded proteins in ER, which is related to a variety of liver diseases. Present study investigated the inhibitory effects of Litsea japonica flesh water extract (LJE) aganist ER stress. Methods : After HepG2 cells were pretreated with LJE and subsequently exposed to tunicamycin (Tm) or thapsigargin (Tg), expression of C/EBP homologous protein (CHOP), glucose regulated protein 78 kDa (GRP78), asparagine synthetase (ASNS), and endoplasmic reticulum DnaJ homologue 4 (ERDJ4) were determined by immunoblot and real-time PCR analysis. Three canonical signaling pathways in response to ER stress were examined to explore molecular mechanisms involved. Results : Pretreatment of 1 mg/mL LJE inhibited Tm- or Tg-induced CHOP expression, while L. japonica fruit water extract did not. In addition, LJE decreased the levels of GRP78, ASNS, and ERDJ4 mRNA by Tm. Moreover, phosphorylations of eukaryotic translation initiation factor $2{\alpha}$ and inositol-requiring enzyme 1, expression of nuclear form of activating transcription factor $6{\alpha}$, and transactivation of ER stress response element- and unfolded protein response element-harboring luciferase activities were inhibited by LJE pretreatment. Conclusions : Present results suggest that LJE would be a candidate to prevent or treat ER stress-mediated liver injuries.

• Biomedical Science Letters
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• v.13 no.2
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• pp.153-155
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• 2007

Ferritin heavy chain 1 (FTH1) is an ubiquitous and highly conserved protein which plays a major role in iron homeostasis. The expression of FTH1 was specifically enhanced under various condition of endoplasmic reticulum (ER) stresses drugs such as Brefeldin A (BFA), DTT (Dithiothreitol), calcium ionophore A23187 and tunicamycin. We firstly report here that ER-stress induces up-regulated expression of FTH1 in FRTL-5 culture thyrocytes.

• Development and Reproduction
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• v.22 no.3
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• pp.235-244
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• 2018

We investigate the effect of endoplasmic reticulum (ER) stress inhibitor treatment during parthenogenetic activation of oocytes on the ER stress generation, apoptosis, and in vitro development of parthenogenetic porcine embryos. Porcine in vitro matured oocytes were activated by 1) electric stimulus (E) or 2) $E+10{\mu}M$ Ca-ionophore (A23187) treatment (EC). Oocytes were then treated by ER stress inhibitors such as salubrinal (200 nM) and tauroursodeoxychloic acid (TUDCA, $100{\mu}M$) for 3 h prior to in vitro culture. Parthenogenetic embryos were sampled to analyze ER stress and apoptosis at the 1-cell and blastocyst stages. The x-box binding protein 1 (Xbp1) mRNA and ER stress-associated genes were analyzed by RT-PCR or RT-qPCR. Apoptotic gene expression was analyzed by RT-PCR. At the 1-cell stage, although no difference was observed in Xbp1 splicing among treatments, BiP transcription level in the E group was significantly reduced by salubrinal treatment, and GRP94 and ATF4 transcription levels in EC group were significantly reduced by all treatments (p<0.05) compared to control. In the EC group, both apoptotic genes were reduced by ER stress inhibitor treatments compared to control (p<0.05) except Caspase-3 gene by TUDCA treatment. These results suggest that the treatment of ER stress inhibitor during parthenogenetic activation can reduce ER stress, and thereby reduce apoptosis and promote in vitro development of porcine parthenogenetic embryos.

• Development and Reproduction
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• v.23 no.1
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• pp.43-54
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• 2019

We examined the effects of endoplasmic reticulum (ER) stress inhibitor treatment during the micromanipulation of porcine somatic cell nuclear transfer (SCNT) on the in vitro development of SCNT embryos. ER stress inhibitors such as salubrinal (200 nM) and tauroursodeoxycholic acid (TUDCA; $100{\mu}M$) were added to the micromanipulation medium and holding medium. The expression of X-box binding protein 1 (Xbp1), ER-stress-associated genes, and apoptotic genes in SCNT embryos was confirmed at the one-cell and blastocyst stages. Levels of Xbp1 splicing and expression of ER-stress-associated genes in SCNT embryos at the one-cell stage decreased significantly with TUDCA treatment (p<0.05). The expression of ER-stress-associated genes also decreased slightly with the addition of both salubrinal and TUDCA (Sal+TUD). The expression levels of caspase-3 and Bcl2-associated X protein (Bax) mRNA were also significantly lower in the TUDCA and Sal+TUD treatments (p<0.05). At the blastocyst stage, there were no differences in levels of Xbp1 splicing, and transcription of ER-stress-associated genes and apoptosis genes between control and treatment groups. However, the blastocyst formation rate (20.2%) and mean blastocyst cell number ($63.0{\pm}7.2$) were significantly higher (p<0.05) for embryos in the TUDCA treatment compared with those for control (12.6% and $41.7{\pm}3.1$, respectively). These results indicate that the addition of ER-stress inhibitors, especially TUDCA, during micromanipulation can inhibit cellular damage and enhance in vitro development of SCNT embryos by reducing stress levels in the ER.

• Molecules and Cells
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• v.38 no.2
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• pp.145-150
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• 2015

Continuous intra- and extracellular stresses induce disorder of $Ca^{2+}$ homeostasis and accumulation of unfolded protein in the endoplasmic reticulum (ER), which results in ER stress. Severe long-term ER stress triggers apoptosis signaling pathways, resulting in cell death. Neural epidermal growth factor-like like protein 2 (NELL2) has been reported to be important in protection of cells from cell death-inducing environments. In this study, we investigated the cytoprotective effect of NELL2 in the context of ER stress induced by thapsigargin, a strong ER stress inducer, in Cos7 cells. Overexpression of NELL2 prevented ER stress-mediated apoptosis by decreasing expression of ER stress-induced C/EBP homologous protein (CHOP) and increasing ER chaperones. In this context, expression of anti-apoptotic Bcl-xL was increased by NELL2, whereas NELL2 decreased expression of pro-apoptotic proteins, such as cleaved caspases 3 and 7. This anti-apoptotic effect of NELL2 is likely mediated by extracellular signal-regulated kinase (ERK) signaling, because its inhibitor, U0126, inhibited effects of NELL2 on the expression of anti- and pro-apoptotic proteins and on the protection from ER stress-induced cell death.