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Special Issue "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)

Special Issue Editor

Guest Editor
Prof. Dr. Masato Matsuoka

Department of Hygiene and Public Health 1, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Website | E-Mail
Phone: 81 3 5269 7418
Interests: cell survival and death; signal transduction; endoplasmic reticulum stress; cellular stress response; neurotoxicants; toxic metals; fluoride

Special Issue Information

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

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Related Special Issue

Published Papers (8 papers)

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Research

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Open AccessArticle Modulation of the Unfolded Protein Response by Tauroursodeoxycholic Acid Counteracts Apoptotic Cell Death and Fibrosis in a Mouse Model for Secondary Biliary Liver Fibrosis
Int. J. Mol. Sci. 2017, 18(1), 214; doi:10.3390/ijms18010214
Received: 29 August 2016 / Revised: 9 January 2017 / Accepted: 13 January 2017 / Published: 20 January 2017
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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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Open AccessArticle Cytotoxicity of 11-epi-Sinulariolide Acetate Isolated from Cultured Soft Corals on HA22T Cells through the Endoplasmic Reticulum Stress Pathway and Mitochondrial Dysfunction
Int. J. Mol. Sci. 2016, 17(11), 1787; doi:10.3390/ijms17111787
Received: 2 May 2016 / Revised: 29 August 2016 / Accepted: 12 October 2016 / Published: 27 October 2016
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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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Open AccessReview Endoplasmic Reticulum Stress and Homeostasis in Reproductive Physiology and Pathology
Int. J. Mol. Sci. 2017, 18(4), 792; doi:10.3390/ijms18040792
Received: 13 January 2017 / Revised: 30 March 2017 / Accepted: 31 March 2017 / Published: 8 April 2017
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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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Open AccessReview Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Nexus Implicated in Bowel Disease Pathophysiology
Int. J. Mol. Sci. 2017, 18(4), 771; doi:10.3390/ijms18040771
Received: 23 March 2017 / Accepted: 30 March 2017 / Published: 5 April 2017
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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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Open AccessReview Endoplasmic Reticulum (ER) Stress and Endocrine Disorders
Int. J. Mol. Sci. 2017, 18(2), 382; doi:10.3390/ijms18020382
Received: 22 December 2016 / Revised: 24 January 2017 / Accepted: 3 February 2017 / Published: 11 February 2017
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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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Open AccessReview HDAC Inhibitors and RECK Modulate Endoplasmic Reticulum Stress in Tumor Cells
Int. J. Mol. Sci. 2017, 18(2), 258; doi:10.3390/ijms18020258
Received: 29 December 2016 / Revised: 22 January 2017 / Accepted: 23 January 2017 / Published: 26 January 2017
Cited by 1 | PDF Full-text (440 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Neuroprotective Strategy in Retinal Degeneration: Suppressing ER Stress-Induced Cell Death via Inhibition of the mTOR Signal
Int. J. Mol. Sci. 2017, 18(1), 201; doi:10.3390/ijms18010201
Received: 25 October 2016 / Revised: 13 January 2017 / Accepted: 16 January 2017 / Published: 19 January 2017
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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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Open AccessReview Role of IRE1α/XBP-1 in Cystic Fibrosis Airway Inflammation
Int. J. Mol. Sci. 2017, 18(1), 118; doi:10.3390/ijms18010118
Received: 8 December 2016 / Revised: 3 January 2017 / Accepted: 4 January 2017 / Published: 9 January 2017
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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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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Neuroprotection Strategy in Retinal Degeneration: Suppressing ER Stress-Induced Cell Death via Inhibition of mTOR Signal
Authors: Bin Fan, Ying-Jian Sun, Shu-Yan Liu, Lin Che, Guang-Yu Li
Affiliation: Department of Ophthalmology, Second Hospital of JiLin University, ChangChun 130041, China
Abstract: Retina is specialized sensory organ essential for light detection and visual formation in the human eye. Retinal neurons dysfunction and death cause vision loss in many eye diseases such as retinitis pigmentosa and achromatopsia. Endoplasmic reticulum (ER) stress plays an important role in the development and pathology of retinal degeneration diseases. However, mammalian target of rapamycin (mTOR) kinase, as a signaling node, controls many cellular processes including protein synthesis, translation, energy metabolism, apoptosis, autophagy and ER stress as well. mTOR complex 1 (mTORC1) operates both upstream and downstream of ER stress signals, which can either enhance or suppress ER stress-induced cell death. This review surveys our knowledge about the influence of mTOR signal on ER stress arising from misfolded proteins and genetic mutations in retinal degeneration diseases and highlights potential neuroprotection strategy and therapeutic implications.
Keywords: mTOR; ER stress; retinal degeneration; unfolded protein response; cell death; apoptosis

Title: ER Stress in Monogenic Endocrine Disorders
Authors: Daisuke Ariyasu 1, Yukihiro Hasegawa 2, Hiderou Yoshida 3
1   
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
2    Department of Endocrinology and Metabolism, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan
3    Department of Biochemistry and Molecular Biology, Graduate School of Life Science, University of Hyogo, Hyogo, Japan
Abstract: Unfolded proteins, accumulated in the endoplasmic reticulum (ER), cause ER stress, which contributes to the development of endocrine disorders such as Ins2Akita diabetes, familial neurohypophysial diabetes insipidus, and Wolfram syndrome. Here, we summarize recent findings on monogenic endocrine disorders in which ER stress is involved. In particular, growth hormone deficiency, caused by heterozygous intron 3 splice-site mutations in the GH1 gene, was clarified to be one of the ER stress-related diseases, suggesting that the anterior pituitary gland is one of the organs which are vulnerable to ER stress.

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