• 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.

• Parasites, Hosts and Diseases
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• v.60 no.5
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• pp.371-371
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• 2022

• 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.

• 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.

• Applied Microscopy
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• v.24 no.1
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• pp.86-101
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• 1994

The development of synovial membrane from knee joint was studied by electron microscope in human fetuses ranging from 20mm to 260mm crown rump length (40days to 30weeks of gestational age). At 40mm fetus, developing synovial tissue was observed in homogenous interzone as a vascular mesenchyme around the periphery. The primitive joint space was appeared after the intermediate layer of the interzone in direct contact with chondrogenic layer at 60mm fetus. Differentiation of the synovial membrane coincided with clarification of the joint cauity. When dilatation of the synovial cavity occurred, the two types of synovial cells were well endowed with rough endoplasmic reticulum. At 100mm fetus, type A cells with a markedly attenuated cytoplasm were found as well as those cells which contained pinocytotic vesicles and vacuoles. By 150-200mm fetuses a majority of the intimal cells were type B. These cells were characterized by abundant rough endoplasmic reticulum and well developed Golgi complex. In contrast, A-type cell had numerous filopodia, pinocytotic vesicles lysosomes, and large vacuoles containing amorphous material. At 260mm fetus, the intimal cells were well developed and plentiful. The most marked difference between the synovial membrane of full-term fetus and adult was the large amount of collagen in the latter. During fetal period, the B-cells were most numerous cell type in the intimal cells. The B-cells were clearly distinguishable from the A-cells by their content of extensive rough endoplasmic reticulum and well developed Golgi complex.

• Journal of the Korean Magnetic Resonance Society
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• v.19 no.2
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• pp.74-82
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• 2015

Ryanodine receptor (RyR) is one of the two major $Ca^{2+}$ channels in membranes of intracellular $Ca^{2+}$ stores and is found in sarcoplasmic reticulum (SR), endoplasmic reticulum (ER). RyR1 is also the major calmodulin-binding protein of sarcoplasmic reticulum membranes. Residues 4064-4210 in the RyR1 polypeptide chain has similar primary sequence with calmodulin (CaM) and was designated as CaM-like domain (CaMLD). When expressed as a recombinant peptide, CaMLD showed several CaM-like properties in previous studies. Still, previous studies of CaMLD were focused on protein-protein interactions rather than its own properties. Here, we studied the expression of CaMLD and its sub-domains corresponding to each lobe of CaM in Escherichia coli. CaMLD could be obtained only as inclusion body, and it was refolded using urea solubilization followed by dialysis. Using spectroscopic approaches, such as NMR, circular dichroism, and gel filtration experiment, we found that the refolded CaMLD exists as nonspecific aggregate, even though it has alpha helical secondary structure. In comparison, the first half of CaMLD (R4061-4141) could be obtained as natively soluble protein with thioredoxin fusion. After the removal of the fusion tag, it exhibited folded and helical properties as shown by NMR and circular dichroism experiments. Its oligomeric status was different from CaMLD, existing as dimeric form in solution. However, the second half of the protein could not be obtained as soluble protein regardless of fusion tag. Based on these results, we believe that CaMLD, although similar to CaM in sequence, has quite different physicochemical properties and that the second half of the protein renders it the aggregative properties.

• 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.24 no.1
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• pp.31-41
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• 2020

We investigated the effects of endoplasmic reticulum (ER) stress inhibitor and antioxidant treatments during the micromanipulation of somatic cell nuclear transfer (SCNT) on in vitro development of SCNT embryos. Tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor and vitamin C (Vit. C), an antioxidant, were treated by alone or in combination, then, the level of X-box binding protein 1 (Xbp1) splicing and the expressions of ER stress-associated genes, oxidative stress-related genes, and apoptotic genes were confirmed in the 1-cell and blastocyst stages. In the 1-cell stage, the levels of Xbp1 splicing were significantly decreased in TUDCA and Vit. C treatment groups compared to the control (p<0.05). In addition, the expression levels of most ER stress-associated genes and oxidative stress-related genes were significantly lower in all treatment groups than the control (p<0.05), and the transcript levels of apoptotic genes were also significantly lower in all treatment groups than the control (p<0.05). In the blastocyst stage, decreased expression of ER stress-, oxidative stress-, and apoptosis-related genes were observed only in some treatments. However, the blastocyst formation rates in TUDCA and Vit. C treatment groups (24.8% and 22.0%, respectively) and mean blastocyst cell number in all treatment groups (59.7±4.3 to 63.5±3.3) were significantly higher (p<0.05) than those of control. The results showed that the TUDCA or Vit. C treatment during micromanipulation inhibited both ER and oxidative stresses in the early stage of SCNT embryos, thereby reducing cell damage and promoting in vitro development.

• The Korean Journal of Physiology and Pharmacology
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• v.8 no.4
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• pp.195-200
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• 2004

Ghrelin is a newly discovered peptide, which is released from the stomach and neurons in the hypothalamic arcuate nucleus (ARC), and potently stimulates growth hormone release and food intake. In the present study, we investigated the effect of ghrelin on $[Ca^{2+}]_i$ in thyroid FRTL-5 cells. Ghrelin (5 nM) increased $[Ca^{2+}]_i$ and TSH (1 unit/l) had an additive effect on $[Ca^{2+}]_i$ when extracellular normal solution was 1.1mM $Ca^{2+}$ containing Coon's modified Ham's F12 medium. When $Ca^{2+}-free$ medium containing 2 mM EGTA replaced the above normal solution, ghrelin also induced a similar rise in $[Ca^{2+}]_i$. In the middle of $[Ca^{2+}]_i$ increment by ghrelin, nifedipine $(1\;{\mu}M)$, nickel $(100\;{\mu}M)$ and $La^{3+}\;(100\;{\mu}M)$ had no effect on $[Ca^{2+}]_i$. After endoplasmic reticulum was depleted by cyclopiazonic acid $(CPA;10\;{\mu}M)$, ghrelin caused no visible change on $[Ca^{2+}]_i$ in $Ca^{2+}-free$/2 mM EGTA solution. These results suggest that ghrelin can increase $[Ca^{2+}]_i$ through endoplasmic reticulum in thyroid FRTL-5 cells.

• BMB Reports
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• v.29 no.1
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• pp.22-26
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• 1996

Agents that activate or inhibit the $Ca^{2+}$ release channel in cardiac sarcoplasmic reticulum (SR) were tested for their abilities to affect the activity of the SR $Ca^{2+}$-ATPase. Vesicles of junctional SR (heavy SR, HSR) from terminal cisternae were prepared from porcine cardiac muscle by density gradient centrifugation. The steady-state activity of $Ca^{2+}$-ATPases in intact HSR vesicles was/$347{\pm}5\;nmol/min{\cdot}mg$ protein (${\pm}$ SD). When the HSR vesicles were made leaky, the activity was increased to $415{\pm}5\;nmol/min{\cdot}mg$ protein. This increase is probably due to the uncoupling of HSR vesicles. Caffeine (10 mM), an agonist of the SR $Ca^{2+}$ release channel, increased $Ca^{2+}$-ATPase activity in the intact HSR vesicle preparation to $394{\pm}30\;nmol/min{\cdot}mg$ protein. However, caffeine had no significant effect in the leaky vesicle preparation and in the purified $Ca^{2+}$-ATPase preparation. The effect of caffeine on SR $Ca^{2+}$-ATPase was investigated at various concentrations of $Ca^{2+}$. Caffeine increased the pump activity over the whole range of $Ca^{2+}$ concentrations, from $1\;{\mu}M$ to $250\;{\mu}M$, in the intact HSR vesicles. When the SR $Ca^{2+}$-ATPase was inhibited by thapsigargin, no caffeine effect was observed. These results imply that the caffeine effect requires the intact vesicles and that the increase in $Ca^{2+}$-ATPase activity is not due to a direct interaction of caffeine with the enzyme. We propose that the activity of SR $Ca^{2+}$-ATPase is linked indirectly to the activity of the $Ca^{2+}$ release channel (ryanodine receptor) and may depend upon the amount of $Ca^{2+}$ released by the channels.