• Journal of Life Science
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• v.27 no.2
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• pp.233-240
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• 2017

Previously, we have shown that Schisandra chinensis (Turcz.) Baill. (S. chinensis) has a protective effect against endoplasmic reticulum (ER) stress-induced hepatic steatosis. Gomisin A is a bioactive phytoestrogen derived from S. chinensis. In the present study, the in vitro and in vivo effects of gomisin A on ER stress and hepatic steatosis were investigated. We quantified the expression of markers of ER stress, including glucose regulated protein 78 (GRP78), C/EBP homolog protein (CHOP), and X-box-binding protein-1 (XBP-1), in HepG2 cells treated with tunicamycin or palmitate. Tunicamycin treatment in HepG2 cells induced the expression of markers of ER stress, including GRP78, CHOP, and XBP-1c. However, treatment with gomisin A reduced the expression of markers of ER stress. These inhibitory effects were also observed in palmitate-incubated HepG2 cells. The in vivo inhibitory effects of gomisin A were assessed in mice injected with tunicamycin or fed with a high fat diet (HFD). Gomisin A reduced the expression of markers of ER stress and decreased triglyceride levels in the livers of mice after tunicamycin injection or HFD feeding. Furthermore, gomisin A decreased the expression of inflammatory genes in palmitate-incubated HepG2 cells and the liver of HFD-fed obese mice. These results suggest that gomisin A inhibits ER stress and ameliorates hepatic steatosis induced by ER stress.

• Proceedings of the Korean Society of Life Science Conference
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• 2005.09a
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• pp.25-26
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• 2005

• Molecules and Cells
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• v.42 no.6
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• pp.501-501
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• 2019

• Journal of Life Science
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• v.22 no.2
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• pp.281-284
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• 2012

This study demonstrated that upregulation of gene expression of endoplasmic reticulum (ER) stress chaperones (Bip, ERp29, calnexin, and PDI), ER stress sensors (PERK, ATF6, and Ire1), and cAMP phosphodiesterase 7A1 (cAMP PDE7A1) was induced by ER stresses in FRTL5 cells. While removing A23187 from the culture medium restored upregulation of cAMP PDE7A1 gene expression, removal of thapsigargin did not recover its expression. In addition, cAMP PDE7A1 gene expression was strongly inhibited by treatment with A23187 combined with thyroid stimulating hormone (TSH). The results are the first to show that ER stress induces cAMP PDE7A1 gene expression.

• Biomolecules & Therapeutics
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• v.30 no.3
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• pp.265-273
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• 2022

Resistance to chemotherapeutic drugs is a significant problem in the treatment of colorectal cancer, resulting in low response rates and decreased survival. Recent studies have shown that shikonin, a naphthoquinone derivative, promotes apoptosis in colon cancer cells and cisplatin-resistant ovarian cells, raising the possibility that this compound may be effective in drug-resistant colorectal cancer. The aim of this study was to characterize the molecular mechanisms underpinning shikonin-induced apoptosis, with a focus on endoplasmic reticulum (ER) stress, in a 5-fluorouracil-resistant colorectal cancer cell line, SNU-C5/5-FUR. Our results showed that shikonin significantly increased the proportion of sub-G₁ cells and DNA fragmentation and that shikonin-induced apoptosis is mediated by mitochondrial Ca²⁺ accumulation. Shikonin treatment also increased the expression of ER-related proteins, such as glucose regulatory protein 78 (GRP78), phospho-protein kinase RNA-like ER kinase (PERK), phospho-eukaryotic initiation factor 2 (eIF2α), phospho-phosphoinositol-requiring protein-1 (IRE1), spliced X-box-binding protein-1 (XBP-1), cleaved caspase-12, and C/EBP-homologous protein (CHOP). In addition, siRNA-mediated knockdown of CHOP attenuated shikonin-induced apoptosis, as did the ER stress inhibitor TUDCA. These data suggest that ER stress is a key factor mediating the cytotoxic effect of shikonin in SNU-C5/5-FUR cells. Our findings provide an evidence for a mechanism in which ER stress leads to apoptosis in shikonin-treated SNU-C5/5-FUR cells. Our study provides evidence to support further investigations on shikonin as a therapeutic option for 5-fluorouracil-resistant colorectal cancer.

• Biomolecules & Therapeutics
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• v.32 no.2
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• pp.183-191
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• 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.

• Animal Bioscience
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• v.35 no.1
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• pp.22-28
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• 2022

Objective: Endoplasmic reticulum (ER) stress engages the unfolded protein response (UPR) that serves as an important mechanism for modulating hepatic fatty acid oxidation and lipogenesis. Chronic fasting in mice induced the UPR activation to regulate lipid metabolism. However, there is no direct evidence of whether negative energy balance (NEB) induces ER stress in the liver of cows. This study aimed to elucidate the relationship between the NEB attributed to feed deprivation and ER stress in bovine hepatocytes. Methods: Blood samples and liver biopsy tissues were collected from 6 non-lactating cows before and after their starvation for 48 h. The blood non-esterified fatty acids (NEFA), β-hydroxybutyric acid (BHBA) and glucose level were analyzed. Real-time quantitative polymerase chain reaction and Western blotting were used to explore the regulation of genes associated with UPR and lipid metabolism. Results: The starvation increased the plasma BHBA and NEFA levels and decreased the glucose level. Additionally, the starvation caused significant increases in the mRNA expression level of spliced X-box binding protein 1 (XBP1s) and the protein level of phosphorylated inositol-requiring kinase 1 alpha (p-IRE1α; an upstream protein of XBP1) in the liver. The mRNA expression levels of peroxisome proliferator-activated receptor alpha and its target fatty acid oxidation- and ketogenesis-related genes were significantly upregulated by the starvation-mediated NEB. Furthermore, we found that the mRNA expression levels of lipogenic genes were not significantly changed after starvation. Conclusion: These findings suggest that in the initial stage of NEB in dairy cows, the liver coordinates an adaptive response by activating the IRE1 arm of the UPR to enhance ketogenesis, thereby avoiding a fatty liver status.

• Animal Bioscience
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• v.34 no.6
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• pp.1006-1013
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• 2021

Objective: Cells have increased susceptibility to activation of apoptosis when suffering heat stress (HS). An effective supplementation strategy to mimic heat-induced apoptosis of bovine mammary epithelial cells (MECs) is necessary to maintain optimal milk production. This study aimed to investigate possible protective effects of the anti-apoptotic activity of 5-aminolevulinic acid (5-ALA) against HS-induced damage of bovine MECs. Methods: Bovine MECs were pretreated with or without 5-ALA at concentrations of 10, 100, and 500 µM for 24 h followed by HS (42.5℃ for 24 h and 48 h). Cell viability was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Real-time quantitative polymerase chain reaction and Western blotting were used to explore the regulation of genes associated with apoptosis, oxidative stress, and endoplasmic reticulum (ER) stress genes. Results: We found that 5-ALA induces cytoprotection via inhibition of apoptosis markers after HS-induced damage. Pretreatment of bovine MECs with 5-ALA resulted in dramatic upregulation of mRNA for nuclear factor erythroid-derived 2-like factor 2, heme oxygenase-1, and NAD(P)H quinone oxidoreductase 1, all of which are antioxidant stress genes. Moreover, 5-ALA pretreatment significantly suppressed HS-induced ER stress-associated markers, glucose-regulated protein 78, and C/EBP homologous protein expression levels. Conclusion: 5-ALA can ameliorate the ER stress in heat stressed bovine MEC via enhancing the expression of antioxidant gene.

• Biomolecules & Therapeutics
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• v.27 no.4
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• pp.386-394
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• 2019

Trypanosoma cruzi infection results in debilitating cardiomyopathy, which is a major cause of mortality and morbidity in the endemic regions of Chagas disease (CD). The pathogenesis of Chagasic cardiomyopathy (CCM) has been intensely studied as a chronic inflammatory disease until recent observations reporting the role of cardio-metabolic dysfunctions. In particular, we demonstrated accumulation of lipid droplets and impaired cardiac lipid metabolism in the hearts of cardiomyopathic mice and patients, and their association with impaired mitochondrial functions and endoplasmic reticulum (ER) stress in CD mice. In the present study, we examined whether treating infected mice with an ER stress inhibitor can modify the pathogenesis of cardiomyopathy during chronic stages of infection. T. cruzi infected mice were treated with an ER stress inhibitor 2-Aminopurine (2AP) during the indeterminate stage and evaluated for cardiac pathophysiology during the subsequent chronic stage. Our study demonstrates that inhibition of ER stress improves cardiac pathology caused by T. cruzi infection by reducing ER stress and downstream signaling of phosphorylated eukaryotic initiation factor ($P-elF2{\alpha}$) in the hearts of chronically infected mice. Importantly, cardiac ultrasound imaging showed amelioration of ventricular enlargement, suggesting that inhibition of ER stress may be a valuable strategy to combat the progression of cardiomyopathy in Chagas patients.

• Biomolecules & Therapeutics
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• v.20 no.3
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• pp.346-351
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• 2012

Cells show various stress signs when they are challenged with severe physiological problems. Majority of such cellular stresses are conveyed to endoplasmic reticulum (ER) and unfolded protein response (UPR) serves as typical defense mechanism against ER stress. This study investigated an interaction between ER stress agents using macropage cell line Raw 264.7. When activated by lipopolysaccharide (LPS), the cell lines showed typical indicators of ER stress. Along with molecular chaperones, the activation process leads to the production of additional inflammatory mediators. Following activation, the macrophage cell line was further treated with TUN and characterized in terms of chaperone expression and cytokine secretion. When treated with TUN, the activated macrophage cell leads to increased secretion of IL-6 although expression of ER stress markers, GRP94 and GRP78 increased. The secretion of cytokines continued until the addition of BFA which inhibits protein targeting from ER to Golgi. However, secretion of cytokines was ceased upon dual treatments with BFA and TG. This result strongly implies that cells may differently deal with various polypeptides depending on the urgency in cellular function under ER stress. Considering IL-6 is one of the most important signal molecules in macrophage, the molecule might be able to circumvent ER stress and UPR to reach its targeting site.