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Modulators of Endoplasmic Reticulum Stress 2016

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 December 2016) | Viewed by 71536

Special Issue Editor


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Guest Editor
Department of Hygiene and Public Health 1, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Interests: cell survival and death; signal transduction; endoplasmic reticulum stress; cellular stress response; neurotoxicants; toxic metals; fluoride
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Dear Colleagues,

The accumulation of unfolded proteins in the lumen of endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR). The UPR alleviates stress by inhibiting protein synthesis, and by promoting the expression of molecular chaperones and other factors involved in ER-associated protein degradation (ERAD). Under cellular stress, the ER activates three branches of the UPR: (i) the protein kinase RNA-activated-like ER kinase–eukaryotic translation initiation factor 2 alpha (PERK-eIF2α) pathway, (ii) the inositol-requiring enzyme 1–X-box binding protein 1 (IRE1-XBP1) pathway, and (iii) the activating transcription factor 6 (ATF6) pathway. However, if ER stress is prolonged and severe, the UPR can result in cell death through the activation of apoptotic pathways. Accumulating evidence indicates that the ER stress is involved in the pathogenesis of not only the protein misfolding disorders such as neurodegenerative disease, but also in the cytotoxicity of drugs, environmental pollutants, and industrial chemicals. Thus, the determination of the modulators that activate or inhibit ER stress signaling pathways is an important field of research. The articles in this special issue will address research aspects related to the inducers or modulators of ER stress in the biological, toxicological, and medical fields.

Prof. Dr. Masato Matsuoka
Guest Editor

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Keywords

  • endoplasmic reticulum stress
  • unfolded protein response
  • molecular chaperones
  • signal transduction
  • cell survival and death
  • protein misfolding disorders
  • drugs
  • toxicants

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Related Special Issue

Published Papers (8 papers)

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Research

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1499 KiB  
Article
Modulation of the Unfolded Protein Response by Tauroursodeoxycholic Acid Counteracts Apoptotic Cell Death and Fibrosis in a Mouse Model for Secondary Biliary Liver Fibrosis
by Annelies Paridaens, Sarah Raevens, Lindsey Devisscher, Eliene Bogaerts, Xavier Verhelst, Anne Hoorens, Hans Van Vlierberghe, Leo A. Van Grunsven, Anja Geerts and Isabelle Colle
Int. J. Mol. Sci. 2017, 18(1), 214; https://doi.org/10.3390/ijms18010214 - 20 Jan 2017
Cited by 23 | Viewed by 6314
Abstract
The role of endoplasmic reticulum stress and the unfolded protein response (UPR) in cholestatic liver disease and fibrosis is not fully unraveled. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been shown to reduce endoplasmic reticulum (ER) stress and counteract apoptosis in different [...] Read more.
The role of endoplasmic reticulum stress and the unfolded protein response (UPR) in cholestatic liver disease and fibrosis is not fully unraveled. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been shown to reduce endoplasmic reticulum (ER) stress and counteract apoptosis in different pathologies. We aimed to investigate the therapeutic potential of TUDCA in experimental secondary biliary liver fibrosis in mice, induced by common bile duct ligation. The kinetics of the hepatic UPR and apoptosis during the development of biliary fibrosis was studied by measuring markers at six different timepoints post-surgery by qPCR and Western blot. Next, we investigated the therapeutic potential of TUDCA, 10 mg/kg/day in drinking water, on liver damage (AST/ALT levels) and fibrosis (Sirius red-staining), in both a preventive and therapeutic setting. Common bile duct ligation resulted in the increased protein expression of CCAAT/enhancer-binding protein homologous protein (CHOP) at all timepoints, along with upregulation of pro-apoptotic caspase 3 and 12, tumor necrosis factor receptor superfamily, member 1A (TNFRsf1a) and Fas-Associated protein with Death Domain (FADD) expression. Treatment with TUDCA led to a significant reduction of liver fibrosis, accompanied by a slight reduction of liver damage, decreased hepatic protein expression of CHOP and reduced gene and protein expression of pro-apoptotic markers. These data indicate that TUDCA exerts a beneficial effect on liver fibrosis in a model of cholestatic liver disease, and suggest that this effect might, at least in part, be attributed to decreased hepatic UPR signaling and apoptotic cell death. Full article
(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress 2016)
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5652 KiB  
Article
Cytotoxicity of 11-epi-Sinulariolide Acetate Isolated from Cultured Soft Corals on HA22T Cells through the Endoplasmic Reticulum Stress Pathway and Mitochondrial Dysfunction
by Jen-Jie Lin, Robert Y. L. Wang, Jiing-Chuan Chen, Chien-Chih Chiu, Ming-Hui Liao and Yu-Jen Wu
Int. J. Mol. Sci. 2016, 17(11), 1787; https://doi.org/10.3390/ijms17111787 - 27 Oct 2016
Cited by 16 | Viewed by 5621
Abstract
Natural compounds from soft corals have been increasingly used for their antitumor therapeutic properties. This study examined 11-epi-sinulariolide acetate (11-epi-SA), an active compound isolated from the cultured soft coral Sinularia flexibilis, to determine its potential antitumor effect on [...] Read more.
Natural compounds from soft corals have been increasingly used for their antitumor therapeutic properties. This study examined 11-epi-sinulariolide acetate (11-epi-SA), an active compound isolated from the cultured soft coral Sinularia flexibilis, to determine its potential antitumor effect on four hepatocellular carcinoma cell lines. Cell viability was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the results demonstrated that 11-epi-SA treatment showed more cytotoxic effect toward HA22T cells. Protein profiling of the 11-epi-SA-treated HA22T cells revealed substantial protein alterations associated with stress response and protein synthesis and folding, suggesting that the mitochondria and endoplasmic reticulum (ER) play roles in 11-epi-SA-initiated apoptosis. Moreover, 11-epi-SA activated caspase-dependent apoptotic cell death, suggesting that mitochondria-related apoptosis genes were involved in programmed cell death. The unfolded protein response signaling pathway-related proteins were also activated on 11-epi-SA treatment, and these changes were accompanied by the upregulated expression of growth arrest and DNA damage-inducible protein (GADD153) and CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), the genes encoding transcription factors associated with growth arrest and apoptosis under prolonged ER stress. Two inhibitors, namely salubrinal (Sal) and SP600125, partially abrogated 11-epi-SA-related cell death, implying that the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)–activating transcription factor (ATF) 6–CHOP or the inositol-requiring enzyme 1 alpha (IRE1α)–c-Jun N-terminal kinase (JNK)–cJun signal pathway was activated after 11-epi-SA treatment. In general, these results suggest that 11-epi-SA exerts cytotoxic effects on HA22T cells through mitochondrial dysfunction and ER stress cell death pathways. Full article
(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress 2016)
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Review

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3155 KiB  
Review
Endoplasmic Reticulum Stress and Homeostasis in Reproductive Physiology and Pathology
by Elif Guzel, Sefa Arlier, Ozlem Guzeloglu-Kayisli, Mehmet Selcuk Tabak, Tugba Ekiz, Nihan Semerci, Kellie Larsen, Frederick Schatz, Charles Joseph Lockwood and Umit Ali Kayisli
Int. J. Mol. Sci. 2017, 18(4), 792; https://doi.org/10.3390/ijms18040792 - 8 Apr 2017
Cited by 188 | Viewed by 12400
Abstract
The endoplasmic reticulum (ER), comprises 60% of the total cell membrane and interacts directly or indirectly with several cell organelles i.e., Golgi bodies, mitochondria and proteasomes. The ER is usually associated with large numbers of attached ribosomes. During evolution, ER developed as the [...] Read more.
The endoplasmic reticulum (ER), comprises 60% of the total cell membrane and interacts directly or indirectly with several cell organelles i.e., Golgi bodies, mitochondria and proteasomes. The ER is usually associated with large numbers of attached ribosomes. During evolution, ER developed as the specific cellular site of synthesis, folding, modification and trafficking of secretory and cell-surface proteins. The ER is also the major intracellular calcium storage compartment that maintains cellular calcium homeostasis. During the production of functionally effective proteins, several ER-specific molecular steps sense quantity and quality of synthesized proteins as well as proper folding into their native structures. During this process, excess accumulation of unfolded/misfolded proteins in the ER lumen results in ER stress, the homeostatic coping mechanism that activates an ER-specific adaptation program, (the unfolded protein response; UPR) to increase ER-associated degradation of structurally and/or functionally defective proteins, thus sustaining ER homeostasis. Impaired ER homeostasis results in aberrant cellular responses, contributing to the pathogenesis of various diseases. Both female and male reproductive tissues undergo highly dynamic cellular, molecular and genetic changes such as oogenesis and spermatogenesis starting in prenatal life, mainly controlled by sex-steroids but also cytokines and growth factors throughout reproductive life. These reproductive changes require ER to provide extensive protein synthesis, folding, maturation and then their trafficking to appropriate cellular location as well as destroying unfolded/misfolded proteins via activating ER-associated degradation mediated proteasomes. Many studies have now shown roles for ER stress/UPR signaling cascades in the endometrial menstrual cycle, ovarian folliculogenesis and oocyte maturation, spermatogenesis, fertilization, pre-implantation embryo development and pregnancy and parturition. Conversely, the contribution of impaired ER homeostasis by severe/prolong ER stress-mediated UPR signaling pathways to several reproductive tissue pathologies including endometriosis, cancers, recurrent pregnancy loss and pregnancy complications associated with pre-term birth have been reported. This review focuses on ER stress and UPR signaling mechanisms, and their potential roles in female and male reproductive physiopathology involving in menstrual cycle changes, gametogenesis, preimplantation embryo development, implantation and placentation, labor, endometriosis, pregnancy complications and preterm birth as well as reproductive system tumorigenesis. Full article
(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress 2016)
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1097 KiB  
Review
Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Nexus Implicated in Bowel Disease Pathophysiology
by Wai Chin Chong, Madhur D. Shastri and Rajaraman Eri
Int. J. Mol. Sci. 2017, 18(4), 771; https://doi.org/10.3390/ijms18040771 - 5 Apr 2017
Cited by 229 | Viewed by 10564
Abstract
The endoplasmic reticulum (ER) is a complex protein folding and trafficking organelle. Alteration and discrepancy in the endoplasmic reticulum environment can affect the protein folding process and hence, can result in the production of misfolded proteins. The accumulation of misfolded proteins causes cellular [...] Read more.
The endoplasmic reticulum (ER) is a complex protein folding and trafficking organelle. Alteration and discrepancy in the endoplasmic reticulum environment can affect the protein folding process and hence, can result in the production of misfolded proteins. The accumulation of misfolded proteins causes cellular damage and elicits endoplasmic reticulum stress. Under such stress conditions, cells exhibit reduced functional synthesis, and will undergo apoptosis if the stress is prolonged. To resolve the ER stress, cells trigger an intrinsic mechanism called an unfolded protein response (UPR). UPR is an adaptive signaling process that triggers multiple pathways through the endoplasmic reticulum transmembrane transducers, to reduce and remove misfolded proteins and improve the protein folding mechanism, in order to improve and maintain endoplasmic reticulum homeostasis. An increasing number of studies support the view that oxidative stress has a strong connection with ER stress. During the protein folding process, reactive oxygen species are produced as by-products, leading to impaired reduction-oxidation (redox) balance conferring oxidative stress. As the protein folding process is dependent on redox homeostasis, the oxidative stress can disrupt the protein folding mechanism and enhance the production of misfolded proteins, causing further ER stress. It is proposed that endoplasmic reticulum stress and oxidative stress together play significant roles in the pathophysiology of bowel diseases. Full article
(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress 2016)
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923 KiB  
Review
Endoplasmic Reticulum (ER) Stress and Endocrine Disorders
by Daisuke Ariyasu, Hiderou Yoshida and Yukihiro Hasegawa
Int. J. Mol. Sci. 2017, 18(2), 382; https://doi.org/10.3390/ijms18020382 - 11 Feb 2017
Cited by 83 | Viewed by 10538
Abstract
The endoplasmic reticulum (ER) is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR), which protects cells [...] Read more.
The endoplasmic reticulum (ER) is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR), which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI), Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2) are discussed in this article. Full article
(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress 2016)
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440 KiB  
Review
HDAC Inhibitors and RECK Modulate Endoplasmic Reticulum Stress in Tumor Cells
by Yun Chen, Ya-Hui Tsai and Sheng-Hong Tseng
Int. J. Mol. Sci. 2017, 18(2), 258; https://doi.org/10.3390/ijms18020258 - 26 Jan 2017
Cited by 22 | Viewed by 5922
Abstract
In the tumor microenvironment hypoxia and nutrient deprived states can induce endoplasmic reticulum (ER) stress. If ER stress is not relieved, the tumor cells may become apoptotic. Therefore, targeting ER homeostasis is a potential strategy for cancer treatment. Various chemotherapeutic agents including histone [...] Read more.
In the tumor microenvironment hypoxia and nutrient deprived states can induce endoplasmic reticulum (ER) stress. If ER stress is not relieved, the tumor cells may become apoptotic. Therefore, targeting ER homeostasis is a potential strategy for cancer treatment. Various chemotherapeutic agents including histone deacetylase (HDAC) inhibitors can induce ER stress to cause cell death in cancers. Some HDAC inhibitors can prevent HDAC from binding to the specificity protein 1-binding site of the promoter of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and up-regulate RECK expression. Up-regulation of RECK expression by HDAC inhibitors has been observed in various cancer types. RECK is a tumor and metastasis suppressor gene and is critical for regulating tumor cell invasiveness and metastasis. RECK also modulates ER stress via binding to and sequestering glucose-regulated protein 78 protein, so that the transmembrane sensors, such as protein kinase RNA-like ER kinase are released to activate eukaryotic translational initiation factor 2α phosphorylation and enhance ER stress. Therefore, HDAC inhibitors may directly induce ER stress or indirectly induce this stress by up-regulating RECK in cancer cells. Full article
(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress 2016)
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1966 KiB  
Review
Neuroprotective Strategy in Retinal Degeneration: Suppressing ER Stress-Induced Cell Death via Inhibition of the mTOR Signal
by Bin Fan, Ying-Jian Sun, Shu-Yan Liu, Lin Che and Guang-Yu Li
Int. J. Mol. Sci. 2017, 18(1), 201; https://doi.org/10.3390/ijms18010201 - 19 Jan 2017
Cited by 14 | Viewed by 10148
Abstract
The retina is a specialized sensory organ, which is essential for light detection and visual formation in the human eye. Inherited retinal degenerations are a heterogeneous group of eye diseases that can eventually cause permanent vision loss. UPR (unfolded protein response) and ER [...] Read more.
The retina is a specialized sensory organ, which is essential for light detection and visual formation in the human eye. Inherited retinal degenerations are a heterogeneous group of eye diseases that can eventually cause permanent vision loss. UPR (unfolded protein response) and ER (endoplasmic reticulum) stress plays an important role in the pathological mechanism of retinal degenerative diseases. mTOR (the mammalian target of rapamycin) kinase, as a signaling hub, controls many cellular processes, covering protein synthesis, RNA translation, ER stress, and apoptosis. Here, the hypothesis that inhibition of mTOR signaling suppresses ER stress-induced cell death in retinal degenerative disorders is discussed. This review surveys knowledge of the influence of mTOR signaling on ER stress arising from misfolded proteins and genetic mutations in retinal degenerative diseases and highlights potential neuroprotective strategies for treatment and therapeutic implications. Full article
(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress 2016)
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1398 KiB  
Review
Role of IRE1α/XBP-1 in Cystic Fibrosis Airway Inflammation
by Carla M. P. Ribeiro and Bob A. Lubamba
Int. J. Mol. Sci. 2017, 18(1), 118; https://doi.org/10.3390/ijms18010118 - 9 Jan 2017
Cited by 30 | Viewed by 9266
Abstract
Cystic fibrosis (CF) pulmonary disease is characterized by chronic airway infection and inflammation. The infectious and inflamed CF airway environment impacts on the innate defense of airway epithelia and airway macrophages. The CF airway milieu induces an adaptation in these cells characterized by [...] Read more.
Cystic fibrosis (CF) pulmonary disease is characterized by chronic airway infection and inflammation. The infectious and inflamed CF airway environment impacts on the innate defense of airway epithelia and airway macrophages. The CF airway milieu induces an adaptation in these cells characterized by increased basal inflammation and a robust inflammatory response to inflammatory mediators. Recent studies have indicated that these responses depend on activation of the unfolded protein response (UPR). This review discusses the contribution of airway epithelia and airway macrophages to CF airway inflammatory responses and specifically highlights the functional importance of the UPR pathway mediated by IRE1/XBP-1 in these processes. These findings suggest that targeting the IRE1/XBP-1 UPR pathway may be a therapeutic strategy for CF airway disease. Full article
(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress 2016)
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