• Journal of Nutrition and Health
• /
• 제45권5호
• /
• pp.420-428
• /
• 2012

The purpose of this study is to investigate the effects of eight weeks high fat intake and regular exercise in skeletal muscle and adipose tissue for Endoplasmic Reticulum (ER) stress in rats. This experiment involved 32 subjects (sprague-dawley rats) divided into four groups as follows: chow group (Chow, n = 8), chow and exercise group (Chow + EX, n = 8), high fat diet-induced hyperlipidemia group (HF, n = 8), and HF and exercise group (HF + EX, n = 8). As a result, there were significant decrease in body weight and abdominal fat, and blood lipid level was significantly improved by exercise for eight weeks (p < .05). There were variables changed about the skeletal muscle and ER stress in GRP78, XBP-1, ATF4, CHOP and JNK mRNA. There increased in mRNA factor by exercise, especially GRP78, and ATF4 mRNA were significantly increased in exercise (p < .05). However, there were increased in adipose tissue by exercise and there were significantly decreased in mRNA factor by high fat diet (p < .05). Consequently, this study suggests that the consistent exercise was more improved of obesity factor, such as dyslipidemia, hyperlipidemia, hyperglycemia, as well as body weight or abdominal fat. The response of ER stress in adipose tissue and skeletal muscle were more sensitive in exercise than high fat diet feed.

• BMB Reports
• /
• 제38권6호
• /
• pp.709-716
• /
• 2005

Apoptosis and necrosis are distinguished by modality primarily. Here we show an apoptosis occurred instantly, induced by $300\;{\mu}M$ W-7 ((N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride), inhibitor of calmodulin), which demonstrated necrotic modality. As early as 30 min after W-7 addition, apoptotic (sub-diploid) peak could be detected by fluorescence-activated cell sorter (FACS), “DNA ladders” began to emerge also at this time point, activity of caspase-3 elevated obviously within this period. Absence of mitochondrial membrane potential (MMP) reduction and cytochrome c, AIF (apoptosis inducing factor) release, verified that this rapid apoptosis did not proceed through mitochondria pathway. Activation of caspase-12 and changes of other endoplasmic reticulum (ER) located proteins ascertained that ER pathway mediated this necrosis-like apoptosis. Our findings suggest that it is not credible to judge apoptosis by modality. Elucidation of ER pathway is helpful to comprehend the pathology of diseases associated with ER stress, and may offer a new approach to the therapy of cancer and neurodegenerative diseases.

• Molecules and Cells
• /
• 제21권3호
• /
• pp.356-359
• /
• 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.

• 대한한의학방제학회지
• /
• 제26권4호
• /
• pp.307-318
• /
• 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.

• 생명과학회지
• /
• 제26권4호
• /
• pp.490-495
• /
• 2016

Brefeldin A (BFA)는 Eupenicillium brefeldianum에서 분리한 lactone계열의 항생제이며 ER에서 Golgi로 단백질 이송/전달을 억제히는 기능이 있다. 따라서 BFA를 세포에 처리 시 Golgi 기능 장애와 ER에서 단백질의 폴딩/조립의 문제로 인하여 ER에 기능 장애가 발생하는데 이를 소포체 스트레스(ER stress)라고 한다. 본 연구에서는 정상 astrocyte 세포와 C6 glioma 세포에서의 BFA처리에 따라 ER stress marker 단백질인 CHOP 발현 차이를 확인하였다. BFA 처리 시 CHOP 발현이 정상 astrocyte 세포에서 C6 glioma 세포에 비해 현저히 낮은 발현을 확인하였다. 하지만 CHOP mRNA 발현에서는 astrocyte 세포에서 발현 됨을 RT-PCR로 확인하였다. C6 glioma 세포와 비교하여 astrocyte 세포에서 BFA유도의 CHOP 단백질 발현이 낮은 원인은 proteasome 활성이 높음으로 기인됨을 proteasome inhibitor 실험과 proteasome 활성 측정을 통하여 확인하였다.

• 생명과학회지
• /
• 제22권2호
• /
• pp.281-284
• /
• 2012

갑상선 배양세포(FRTL5)에서 ER stress에 의해서 ER chaperone (Bip, ERp29, Calnexin and PDI), ER stress sensor (PERK, ATF6 and Ire1)와 cAMP phosphodiesterase 7A1 (cAMP PDE7A1) 유전자발현이 증가하는 것을 알았다. 세포배양배지에서 A23187을 제거하면 cAMP PDE7A1 유전자발현이 회복되지만, thapsigagin의 경우는 회복되지 않았다. 그리고 A23187과 TSH를 함께 처리한 경우는 아주 강하게 cAMP PDE7A1 유전자의 발현이 억제되었다. 이 같은 결과는 ER stress에 의해서 cAMP PDE7A1 유전자발현이 상승 발현된다는 첫 보고이다.

• Biomolecules & Therapeutics
• /
• 제32권2호
• /
• pp.183-191
• /
• 2024

The Unfolded Protein Response (UPR) serves as a critical cellular mechanism dedicated to maintaining protein homeostasis, primarily within the endoplasmic reticulum (ER). This pathway diligently responds to a variety of intracellular indicators of ER stress with the objective of reinstating balance by diminishing the accumulation of unfolded proteins, amplifying the ER's folding capacity, and eliminating slow-folding proteins. Prolonged ER stress and UPR irregularities have been linked to a range of neuropsychiatric disorders, including major depressive disorder, bipolar disorder, and schizophrenia. This review offers a comprehensive overview of the UPR pathway, delineating its activation mechanisms and its role in the pathophysiology of neuropsychiatric disorders. It highlights the intricate interplay within the UPR and its profound influence on brain function, synaptic perturbations, and neural developmental processes. Additionally, it explores evolving therapeutic strategies targeting the UPR within the context of these disorders, underscoring the necessity for precision and further research to effective treatments. The research findings presented in this work underscore the promising potential of UPR-focused therapeutic approaches to address the complex landscape of neuropsychiatric disorders, giving rise to optimism for improving outcomes for individuals facing these complex conditions.

• 한국발생생물학회지:발생과생식
• /
• 제22권3호
• /
• pp.235-244
• /
• 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.

• Molecules and Cells
• /
• 제38권2호
• /
• pp.145-150
• /
• 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.

• 한국발생생물학회지:발생과생식
• /
• 제23권1호
• /
• pp.43-54
• /
• 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.