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Endoplasmic Reticulum Stress-Related Biomedical Implications
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Endoplasmic Reticulum Stress-Related Biomedical Implications

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

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 26970

Special Issue Editor

Prof. Dr. Chunjung Chen

E-Mail Website
Guest Editor
Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan
Interests: luteolin; brain inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Endoplasmic reticulum (ER) is a dynamic organelle, having vital roles in normal physiology and pathophysiology. Under stressful situations, the ER initiates a series of biochemical responses with an aim to the restoration and maintenance of cellular homeostasis, named unfolded protein response (UPR). Once UPR-mediated adaptive and protective responses fail, the uncontrolled ER stress turns into a signalling program substantial to cell death and inflammation. ER stress is closely linked to carcinogenesis, neurodegeneration, metabolic diseases, and inflammatory diseases. The phenomena highlight a crucial role of ER stress in disease pathogenic mechanisms and therapeutic targets.

This Special Issue invites original contributions on diverse aspects of ER stress in the number of physiological and pathological situations with aims to find ways for the elucidation of pathogenic mechanisms and development of therapeutic options.

Prof. Dr. Chunjung Chen
Guest Editor

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Keywords

  • ER stress
  • UPR signaling
  • cell death
  • inflammation

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Published Papers (7 papers)

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Research

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9 pages, 3371 KiB  
Communication
The Effect of Ketamine on Endoplasmic Reticulum Stress in Rats with Neuropathic Pain
by Eun-Hye Seo, Liyun Piao, Eun-Hwa Cho, Seung-Wan Hong and Seong-Hyop Kim
Int. J. Mol. Sci. 2023, 24(6), 5336; https://doi.org/10.3390/ijms24065336 - 10 Mar 2023
Cited by 6 | Viewed by 1473
Abstract
This study aimed to investigate the effects of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, on endoplasmic reticulum (ER) stress in rats with neuropathic pain (NP). NP was induced in rats through ligation and transection of the sciatic nerve. After confirmation of NP, the [...] Read more.
This study aimed to investigate the effects of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, on endoplasmic reticulum (ER) stress in rats with neuropathic pain (NP). NP was induced in rats through ligation and transection of the sciatic nerve. After confirmation of NP, the animals were randomly divided into ketamine and control groups. The ketamine group was administered 50 mg/kg of ketamine at 15, 18, and 21 days after surgery. The expression of NMDA receptor subtype 2B (NR2B) and ER stress markers in the spinal cord (L5) was evaluated. The ipsilateral side of the surgery in the ketamine group was less sensitive to mechanical and cold stimulations. The expression of NR2B on the ipsilateral side was significantly lower in the ketamine group than in the control group (18.93 ± 1.40% vs. 31.08 ± 0.74%, p < 0.05). All markers for ER stress on the ipsilateral side of the surgery in both groups had higher expression than those on the contralateral side. The expression of activating transcription factor-6 (ATF-6) on the ipsilateral side was significantly lower in the ketamine group than in the control group (p < 0.05). Systemic administration of ketamine inhibited the expression of NMDA receptors and improved NP symptoms. Among the markers of ER stress, the therapeutic effect of ketamine is associated with the inhibition of ATF-6 expression. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress-Related Biomedical Implications)
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13 pages, 4649 KiB  
Article
Oxidative-Stress-Mediated ER Stress Is Involved in Regulating Manoalide-Induced Antiproliferation in Oral Cancer Cells
by Sheng-Yao Peng, Jen-Yang Tang, Ting-Hsun Lan, Jun-Ping Shiau, Kuan-Liang Chen, Jiiang-Huei Jeng, Ching-Yu Yen and Hsueh-Wei Chang
Int. J. Mol. Sci. 2023, 24(4), 3987; https://doi.org/10.3390/ijms24043987 - 16 Feb 2023
Cited by 5 | Viewed by 2078
Abstract
Manoalide provides preferential antiproliferation of oral cancer but is non-cytotoxic to normal cells by modulating reactive oxygen species (ROS) and apoptosis. Although ROS interplays with endoplasmic reticulum (ER) stress and apoptosis, the influence of ER stress on manoalide-triggered apoptosis has not been reported. [...] Read more.
Manoalide provides preferential antiproliferation of oral cancer but is non-cytotoxic to normal cells by modulating reactive oxygen species (ROS) and apoptosis. Although ROS interplays with endoplasmic reticulum (ER) stress and apoptosis, the influence of ER stress on manoalide-triggered apoptosis has not been reported. The role of ER stress in manoalide-induced preferential antiproliferation and apoptosis was assessed in this study. Manoalide induces a higher ER expansion and aggresome accumulation of oral cancer than normal cells. Generally, manoalide differentially influences higher mRNA and protein expressions of ER-stress-associated genes (PERK, IRE1α, ATF6, and BIP) in oral cancer cells than in normal cells. Subsequently, the contribution of ER stress on manoalide-treated oral cancer cells was further examined. ER stress inducer, thapsigargin, enhances the manoalide-induced antiproliferation, caspase 3/7 activation, and autophagy of oral cancer cells rather than normal cells. Moreover, N-acetylcysteine, an ROS inhibitor, reverses the responses of ER stress, aggresome formation, and the antiproliferation of oral cancer cells. Consequently, the preferential ER stress of manoalide-treated oral cancer cells is crucial for its antiproliferative effect. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress-Related Biomedical Implications)
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14 pages, 3737 KiB  
Article
Endoplasmic Reticulum Stress Causing Apoptosis in a Mouse Model of an Ischemic Spinal Cord Injury
by Kiran Kumar Soni, Jinsu Hwang, Mahesh Ramalingam, Choonghyo Kim, Byeong C. Kim, Han-Seong Jeong and Sujeong Jang
Int. J. Mol. Sci. 2023, 24(2), 1307; https://doi.org/10.3390/ijms24021307 - 9 Jan 2023
Cited by 6 | Viewed by 2109
Abstract
A spinal cord injury (SCI) is the devastating trauma associated with functional deterioration due to apoptosis. Most laboratory SCI models are generated by a direct impact on an animal’s spinal cord; however, our model does not involve the direct impact on the spinal [...] Read more.
A spinal cord injury (SCI) is the devastating trauma associated with functional deterioration due to apoptosis. Most laboratory SCI models are generated by a direct impact on an animal’s spinal cord; however, our model does not involve the direct impact on the spinal cord. Instead, we use a clamp compression to create an ischemia in the descending aortas of mice. Following the success of inducing an ischemic SCI (ISCI), we hypothesized that this model may show apoptosis via an endoplasmic reticulum (ER) stress pathway. This apoptosis by the ER stress pathway is enhanced by the inducible nitric oxide synthase (iNOS). The ER is used for the protein folding in the cell. When the protein folding capacity is overloaded, the condition is termed the ER stress and is characterized by the accumulation of misfolded proteins inside the ER lumen. The unfolded protein response (UPR) signaling pathways that deal with the ER stress response then become activated. This UPR activates the three signal pathways that are regulated by the inositol-requiring enzyme 1α (IRE1α), the activating transcription factor 6 (ATF6), and the protein kinase RNA-like ER kinase (PERK). IRE1α and PERK are associated with the expression of the apoptotic proteins. Apoptosis caused by an ISCI is assessed using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) test. An ISCI also reduces synaptophysin and the neuronal nuclear protein (NeuN) in the spinal cord. In conclusion, an ISCI increases the ER stress proteins, resulting in apoptosis in neuronal cells in the spinal cord. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress-Related Biomedical Implications)
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12 pages, 1630 KiB  
Article
Mechanical Stretch-Induced NLRP3 Inflammasome Expression on Human Annulus Fibrosus Cells Modulated by Endoplasmic Reticulum Stress
by Hsin-I Chang, Cheng-Nan Chen and Kuo-Yuan Huang
Int. J. Mol. Sci. 2022, 23(14), 7951; https://doi.org/10.3390/ijms23147951 - 19 Jul 2022
Cited by 8 | Viewed by 2181
Abstract
Excessive mechanical loading is a major cause of spinal degeneration, typically originating from a tear in the annulus fibrosus (AF). Endoplasmic reticulum (ER) stress and NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome have been implicated in the pathogenesis of intervertebral disc [...] Read more.
Excessive mechanical loading is a major cause of spinal degeneration, typically originating from a tear in the annulus fibrosus (AF). Endoplasmic reticulum (ER) stress and NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome have been implicated in the pathogenesis of intervertebral disc (IVD) degeneration. However, the causal relationship between the mechanical stretching of AF cells and the NLRP3 inflammasome response associated with ER stress remains scarce. To elucidate the pathogenesis and regulatory mechanisms of mechanical stretch-induced IVD degeneration, human AF cell lines were subjected to different degrees of cyclic stretching to simulate daily spinal movements. Our results indicated that 15% high cyclic stretch (HCS) induced the expression of NLRP3 and interleukin-1 beta (IL-1β) and was also responsible for the increased expression of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 2 (NOX2) and reactive oxygen species (ROS) in human AF cells. In addition, HCS increased the expression of glucose-regulated protein 78 (GRP78), an ER stress chaperone, which was neutralized with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor. In addition, HCS was found to induce thioredoxin-interacting protein (TXNIP) expression and NLRP3 inflammasome activation, which can be suppressed by si-NOX2 or the NOX2 inhibitor GSK2795039. Consequently, HCS upregulated ER stress and ROS production, leading to increased NLRP3 and IL-1β expression in human AF cells, and may further accelerate IVD degeneration. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress-Related Biomedical Implications)
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23 pages, 3651 KiB  
Article
Ferulic Acid, Pterostilbene, and Tyrosol Protect the Heart from ER-Stress-Induced Injury by Activating SIRT1-Dependent Deacetylation of eIF2α
by Kévin Monceaux, Mélanie Gressette, Ahmed Karoui, Julie Pires Da Silva, Jérôme Piquereau, Renée Ventura-Clapier, Anne Garnier, Mathias Mericskay and Christophe Lemaire
Int. J. Mol. Sci. 2022, 23(12), 6628; https://doi.org/10.3390/ijms23126628 - 14 Jun 2022
Cited by 18 | Viewed by 3095
Abstract
Disturbances in Endoplasmic Reticulum (ER) homeostasis induce ER stress, which has been involved in the development and progression of various heart diseases, including arrhythmias, cardiac hypertrophy, ischemic heart diseases, dilated cardiomyopathy, and heart failure. A mild-to-moderate ER stress is considered beneficial and adaptative [...] Read more.
Disturbances in Endoplasmic Reticulum (ER) homeostasis induce ER stress, which has been involved in the development and progression of various heart diseases, including arrhythmias, cardiac hypertrophy, ischemic heart diseases, dilated cardiomyopathy, and heart failure. A mild-to-moderate ER stress is considered beneficial and adaptative for heart functioning by engaging the pro-survival unfolded protein response (UPR) to restore normal ER function. By contrast, a severe or prolonged ER stress is detrimental by promoting cardiomyocyte apoptosis through hyperactivation of the UPR pathways. Previously, we have demonstrated that the NAD+-dependent deacetylase SIRT1 is cardioprotective in response to severe ER stress by regulating the PERK pathway of the UPR, suggesting that activation of SIRT1 could protect against ER-stress-induced cardiac damage. The purpose of this study was to identify natural molecules able to alleviate ER stress and inhibit cardiomyocyte cell death through SIRT1 activation. Several phenolic compounds, abundant in vegetables, fruits, cereals, wine, and tea, were reported to stimulate the deacetylase activity of SIRT1. Here, we evaluated the cardioprotective effect of ten of these phenolic compounds against severe ER stress using cardiomyoblast cells and mice. Among the molecules tested, we showed that ferulic acid, pterostilbene, and tyrosol significantly protect cardiomyocytes and mice heart from cardiac alterations induced by severe ER stress. By studying the mechanisms involved, we showed that the activation of the PERK/eIF2α/ATF4/CHOP pathway of the UPR was reduced by ferulic acid, pterostilbene, and tyrosol under ER stress conditions, leading to a reduction in cardiomyocyte apoptosis. The protection afforded by these phenolic compounds was not directly related to their antioxidant activity but rather to their ability to increase SIRT1-mediated deacetylation of eIF2α. Taken together, our results suggest that ferulic acid, pterostilbene, and tyrosol are promising molecules to activate SIRT1 to protect the heart from the adverse effects of ER stress. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress-Related Biomedical Implications)
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Review

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33 pages, 11747 KiB  
Review
The Common Cellular Events in the Neurodegenerative Diseases and the Associated Role of Endoplasmic Reticulum Stress
by Soojeong Kim, Doo Kyung Kim, Seho Jeong and Jaemin Lee
Int. J. Mol. Sci. 2022, 23(11), 5894; https://doi.org/10.3390/ijms23115894 - 24 May 2022
Cited by 26 | Viewed by 5490
Abstract
Neurodegenerative diseases are inseparably linked with aging and increase as life expectancy extends. There are common dysfunctions in various cellular events shared among neurogenerative diseases, such as calcium dyshomeostasis, neuroinflammation, and age-associated decline in the autophagy-lysosome system. However, most of all, the prominent [...] Read more.
Neurodegenerative diseases are inseparably linked with aging and increase as life expectancy extends. There are common dysfunctions in various cellular events shared among neurogenerative diseases, such as calcium dyshomeostasis, neuroinflammation, and age-associated decline in the autophagy-lysosome system. However, most of all, the prominent pathological feature of neurodegenerative diseases is the toxic buildup of misfolded protein aggregates and inclusion bodies accompanied by an impairment in proteostasis. Recent studies have suggested a close association between endoplasmic reticulum (ER) stress and neurodegenerative pathology in cellular and animal models as well as in human patients. The contribution of mutant or misfolded protein-triggered ER stress and its associated signaling events, such as unfolded protein response (UPR), to the pathophysiology of various neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and Huntington’s disease, amyotrophic lateral sclerosis, and prion disease, is described here. Impaired UPR action is commonly attributed to exacerbated ER stress, pathogenic protein aggregate accumulation, and deteriorating neurodegenerative pathologies. Thus, activating certain UPR components has been shown to alleviate ER stress and its associated neurodegeneration. However, uncontrolled activation of some UPR factors has also been demonstrated to worsen neurodegenerative phenotypes, suggesting that detailed molecular mechanisms around ER stress and its related neurodegenerations should be understood to develop effective therapeutics against aging-associated neurological syndromes. We also discuss current therapeutic endeavors, such as the development of small molecules that selectively target individual UPR components and address ER stress in general. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress-Related Biomedical Implications)
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22 pages, 1349 KiB  
Review
Endoplasmic Reticulum (ER) Stress and Its Role in Pancreatic β-Cell Dysfunction and Senescence in Type 2 Diabetes
by Ji-Hye Lee and Jaemin Lee
Int. J. Mol. Sci. 2022, 23(9), 4843; https://doi.org/10.3390/ijms23094843 - 27 Apr 2022
Cited by 48 | Viewed by 9692
Abstract
An increased life span and accompanying nutritional affluency have led to a rapid increase in diseases associated with aging, such as obesity and type 2 diabetes, imposing a tremendous economic and health burden on society. Pancreatic β-cells are crucial for controlling glucose homeostasis [...] Read more.
An increased life span and accompanying nutritional affluency have led to a rapid increase in diseases associated with aging, such as obesity and type 2 diabetes, imposing a tremendous economic and health burden on society. Pancreatic β-cells are crucial for controlling glucose homeostasis by properly producing and secreting the glucose-lowering hormone insulin, and the dysfunction of β-cells determines the outcomes for both type 1 and type 2 diabetes. As the native structure of insulin is formed within the endoplasmic reticulum (ER), ER homeostasis should be appropriately maintained to allow for the proper metabolic homeostasis and functioning of β-cells. Recent studies have found that cellular senescence is critically linked with cellular stresses, including ER stress, oxidative stress, and mitochondrial stress. These studies implied that β-cell senescence is caused by ER stress and other cellular stresses and contributes to β-cells’ dysfunction and the impairment of glucose homeostasis. This review documents and discusses the current understanding of cellular senescence, β-cell function, ER stress, its associated signaling mechanism (unfolded protein response), and the effect of ER stress on β-cell senescence and dysfunction. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress-Related Biomedical Implications)
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