Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin

2007 ◽  
Vol 292 (1) ◽  
pp. C353-C361 ◽  
Author(s):  
Katsura Takano ◽  
Yoshiyuki Tabata ◽  
Yasuko Kitao ◽  
Rika Murakami ◽  
Hiroto Suzuki ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cultured Cells ◽  
Initiation Factor ◽  
Substantia Nigra Pars Compacta ◽  
Intracellular Camp ◽  
Related Factor ◽  
Renal Tubular Epithelium ◽  
Enhanced Expression

Enhanced endoplasmic reticulum (ER) stress leads to cell death in various pathophysiological situations. During a search for compounds that regulate ER stress, we identified methoxyflavones, a group of flavonoids, as strong protective agents against ER stress. Analysis in mouse insulinoma MIN6 cells revealed that methoxyflavones mildly activated the eukaryotic initiation factor 2α and nuclear factor erythroid 2-related factor pathways, but not the XBP1 pathway, and induced downstream genes, including glucose-regulated protein (GRP) 78, a molecular chaperone in the ER. The protective effect of methoxyflavones was enhanced by agents that increase intracellular cAMP levels such as forskolin, dibutyryl-cAMP and IBMX, but suppressed by the protein kinase A (PKA) inhibitor H-89, suggesting involvement of the PKA pathway in the regulation of ER stress by methoxyflavones. Consistent with the results in cultured cells, pretreatment of mice with tangeretin, a methoxyflavone, enhanced expression of GRP78 and HO-1 without causing ER stress in renal tubular epithelium and prevented tunicamycin-induced cell death. Furthermore, preadministration of tangeretin in mice enhanced expression of GRP78 in the substantia nigra pars compacta and protected dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin that induces both oxidative and ER stress. These results suggest that methoxyflavones play an important role in the regulation of ER stress and could be a therapeutic target for the ER stress-related diseases.

scholarly journals Oxidative Damage to the Endoplasmic Reticulum is Implicated in Ischemic Neuronal Cell Death

2003 ◽  
Vol 23 (10) ◽  
pp. 1117-1128 ◽  
Author(s):  
Takeshi Hayashi ◽  
Atsushi Saito ◽  
Shuzo Okuno ◽  
Michel Ferrand-Drake ◽  
Robert L Dodd ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Protein Modification ◽  
Neuronal Degeneration ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Transgenic Animals ◽  
Initiation Factor

The endoplasmic reticulum (ER), which plays important roles in apoptosis, is susceptible to oxidative stress. Because reactive oxygen species (ROS) are robustly produced in the ischemic brain, ER damage by ROS may be implicated in ischemic neuronal cell death. We induced global brain ischemia on wild-type and copper/zinc superoxide dismutase (SOD1) transgenic rats and compared ER stress and neuronal damage. Phosphorylated forms of eukaryotic initiation factor 2α (eIF2α) and RNA-dependent protein kinase-like ER eIF2α kinase (PERK), both of which play active roles in apoptosis, were increased in hippocampal CA1 neurons after ischemia but to a lesser degree in the transgenic animals. This finding, together with the finding that the transgenic animals showed decreased neuronal degeneration, indicates that oxidative ER damage is involved in ischemic neuronal cell death. To elucidate the mechanisms of ER damage by ROS, we analyzed glucose-regulated protein 78 (GRP78) binding with PERK and oxidative ER protein modification. The proteins were oxidatively modified and stagnated in the ER lumen, and GRP78 was detached from PERK by ischemia, all of which were attenuated by SOD1 overexpression. We propose that ROS attack and modify ER proteins and elicit ER stress response, which results in neuronal cell death.

scholarly journals Human Cytomegalovirus Protein pUL38 Induces ATF4 Expression, Inhibits Persistent JNK Phosphorylation, and Suppresses Endoplasmic Reticulum Stress-Induced Cell Death

2009 ◽  
Vol 83 (8) ◽  
pp. 3463-3474 ◽  
Author(s):  
Baoqin Xuan ◽  
Zhikang Qian ◽  
Emi Torigoi ◽  
Dong Yu
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Human Cytomegalovirus ◽  
Initiation Factor ◽  
Α Subunit ◽  
Unfolded Protein ◽  
Initiation Factor 2 ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT The endoplasmic reticulum (ER) is a key organelle involved in sensing and responding to stressful conditions, including those resulting from infection of viruses, such as human cytomegalovirus (HCMV). Three signaling pathways collectively termed the unfolded protein response (UPR) are activated to resolve ER stress, but they will also lead to cell death if the stress cannot be alleviated. HCMV is able to modulate the UPR to promote its infection. The specific viral factors involved in such HCMV-mediated modulation, however, were unknown. We previously showed that HCMV protein pUL38 was required to maintain the viability of infected cells, and it blocked cell death induced by thapsigargin. Here, we report that pUL38 is an HCMV-encoded regulator to modulate the UPR. In infection, pUL38 allowed HCMV to upregulate phosphorylation of PKR-like ER kinase (PERK) and the α subunit of eukaryotic initiation factor 2 (eIF-2α), as well as induce robust accumulation of activating transcriptional factor 4 (ATF4), key components of the PERK pathway. pUL38 also allowed the virus to suppress persistent phosphorylation of c-Jun N-terminal kinase (JNK), which was induced by the inositol-requiring enzyme 1 pathway. In isolation, pUL38 overexpression elevated eIF-2α phosphorylation, induced ATF4 accumulation, limited JNK phosphorylation, and suppressed cell death induced by both thapsigargin and tunicamycin, two drugs that induce ER stress by different mechanisms. Importantly, ATF4 overexpression and JNK inhibition significantly reduced cell death in pUL38-deficient virus infection. Thus, pUL38 targets ATF4 expression and JNK activation, and this activity appears to be critical for protecting cells from ER stress induced by HCMV infection.

scholarly journals Eukaryotic translation initiation factor 2A protects pancreatic beta cells during endoplasmic reticulum stress while rescuing translation inhibition

2021 ◽  
Author(s):  
Evgeniy Panzhinskiy ◽  
Søs Skovsø ◽  
Haoning Cen ◽  
Kwan Chu ◽  
Kate MacDonald ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Translation ◽  
Human Islets ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Related Factor ◽  
Min6 Cells ◽  
Primary Mouse ◽  
Mouse Islets

Abstract The endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) helps decide cell survival in diabetes. The alternative eukaryotic initiation factor 2A (EIF2A) has been proposed to mediate EIF2S1-independent translation during cellular stress and viral infection, but its role in cells is unknown. EIF2A abundance is high in human and mouse islets relative to other tissues, and both thapsigargin and palmitate significantly increased EIF2A mRNA and EIF2A protein levels in MIN6 cells, mouse islets and human islets. Knockdowns of EIF2A, the related factor EIF2D, or both EIF2A and EIF2D, were not sufficient to cause apoptosis. On the other hand, transient or stable EIF2A over-expression protected MIN6 cells, primary mouse islets, and human islets from ER stress-induced, caspase-3-dependent apoptosis. Mechanistically, EIF2A overexpression decreased ERN1 (also known as IRE1) expression in thapsigargin-treated MIN6 cells or human islets. In vivo, cell specific EIF2A viral overexpression reduced ER stress, improved insulin secretion, and abrogated hyperglycemia in Ins2Akita/WT mice. EIF2A overexpression significantly increased expression of genes involved in protein translation and reduced expression of pro-apoptotic genes (e.g. ALDH1A3). Remarkably, the decrease in global protein synthesis during UPR was prevented by EIF2A, despite ER stress-induced EIF2S1 phosphorylation. The protective effects of EIF2A were additive to those of ISRIB, a drug that counteracts the effects of EIF2S1 phosphorylation. Cells overexpressing EIF2A showed higher expression of translation factor EIF2B5, which may contribute to the lack of translational inhibition in these cells. We conclude that EIF2A is a novel target for cell protection and the circumvention of EIF2S1-mediated translational repression.

2,4,6-Trichlorophenol Cytotoxicity Involves Oxidative Stress, Endoplasmic Reticulum Stress, and Apoptosis

2014 ◽  
Vol 33 (6) ◽  
pp. 532-541 ◽  
Author(s):  
Xiaoning Zhang ◽  
Xiaona Zhang ◽  
Zhidan Niu ◽  
Yongmei Qi ◽  
Dejun Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Messenger Rna ◽  
Nuclear Translocation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Α Subunit

This study aims to evaluate the cytotoxicity and potential mechanisms of 2,4,6-trichlorophenol (2,4,6-TCP) in mouse embryonic fibroblasts. Our results show that 2,4,6-TCP causes morphological changes and reduces cell viability. The overproduction of reactive oxygen species, the upregulation of nuclear factor-E2-related factor 2 (Nrf2) and heme oxygenase 1 (HMOX1) messenger RNA (mRNA) expressions, and the nuclear translocation of Nrf2 protein demonstrate that 2,4,6-TCP induces oxidative stress, and the Nrf2/HMOX1 pathway might be involved in 2,4,6-TCP-induced antioxidative response. Simultaneously, our data also demonstrate that 2,4,6-TCP upregulates the expressions of binding immunoglobulin protein, inositol-requiring enzyme/endonuclease 1α, and C/EBP homologous protein; stimulates α subunit of eukaryotic translation initiation factor 2 phosphorylation; and induces the splicing of Xbp1 mRNA, suggesting that endoplasmic reticulum (ER) stress is triggered. Moreover, 2,4,6-TCP alters the mitochondrial membrane potential and increases the apoptosis rate, the caspase 3 activity, and the Bax/Bcl-2 ratio, demonstrating that the mitochondrial pathway is involved in the 2,4,6-TCP-induced apoptosis. Thus, these results show that 2,4,6-TCP induces oxidative stress, ER stress, and apoptosis, which together contribute to its cytotoxicity in vitro.

scholarly journals The Kinase Inhibitor Sorafenib Induces Cell Death through a Process Involving Induction of Endoplasmic Reticulum Stress

2007 ◽  
Vol 27 (15) ◽  
pp. 5499-5513 ◽  
Author(s):  
Mohamed Rahmani ◽  
Eric Maynard Davis ◽  
Timothy Ryan Crabtree ◽  
Joseph Reza Habibi ◽  
Tri K. Nguyen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Kinase Inhibitor ◽  
Cytosolic Calcium ◽  
Calcium Mobilization ◽  
Initiation Factor ◽  
Central Component ◽  
Human Leukemia ◽  
Eif2α Phosphorylation

ABSTRACT Sorafenib is a multikinase inhibitor that induces apoptosis in human leukemia and other malignant cells. Recently, we demonstrated that sorafenib diminishes Mcl-1 protein expression by inhibiting translation through a MEK1/2-ERK1/2 signaling-independent mechanism and that this phenomenon plays a key functional role in sorafenib-mediated lethality. Here, we report that inducible expression of constitutively active MEK1 fails to protect cells from sorafenib-mediated lethality, indicating that sorafenib-induced cell death is unrelated to MEK1/2-ERK1/2 pathway inactivation. Notably, treatment with sorafenib induced endoplasmic reticulum (ER) stress in human leukemia cells (U937) manifested by immediate cytosolic-calcium mobilization, GADD153 and GADD34 protein induction, PKR-like ER kinase (PERK) and eukaryotic initiation factor 2α (eIF2α) phosphorylation, XBP1 splicing, and a general reduction in protein synthesis as assessed by [35S]methionine incorporation. These events were accompanied by pronounced generation of reactive oxygen species through a mechanism dependent upon cytosolic-calcium mobilization and a significant decline in GRP78/Bip protein levels. Interestingly, enforced expression of IRE1α markedly reduced sorafenib-mediated apoptosis, whereas knockdown of IRE1α or XBP1, disruption of PERK activity, or inhibition of eIF2α phosphorylation enhanced sorafenib-mediated lethality. Finally, downregulation of caspase-2 or caspase-4 by small interfering RNA significantly diminished apoptosis induced by sorafenib. Together, these findings demonstrate that ER stress represents a central component of a MEK1/2-ERK1/2-independent cell death program triggered by sorafenib.

scholarly journals Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues

2010 ◽  
Vol 299 (4) ◽  
pp. C736-C749 ◽  
Author(s):  
Suzette Laing ◽  
Guohui Wang ◽  
Tamara Briazova ◽  
Chunbin Zhang ◽  
Aixia Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Particulate Matter ◽  
Er Stress ◽  
Cultured Cells ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Endoplasmic Reticulum Stress Response ◽  
Induced Apoptosis ◽  
The Impact ◽  
Liver Tissues

Recent studies have suggested a link between inhaled particulate matter (PM) exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases. However, a precise understanding of the biological mechanism underlying PM-associated toxicity and pathogenesis remains elusive. Here, we investigated the impact of PM exposure in intracellular stress signaling pathways with animal models and cultured cells. Inhalation exposure of the mice to environmentally relevant fine particulate matter (aerodynamic diameter < 2.5 μm, PM2.5) induces endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR) in the lung and liver tissues as well as in the mouse macrophage cell line RAW264.7. Ambient PM2.5 exposure activates double-strand RNA-activated protein kinase-like ER kinase (PERK), leading to phosphorylation of translation initiation factor eIF2α and induction of C/EBP homologous transcription factor CHOP/GADD153. Activation of PERK-mediated UPR pathway relies on the production of reactive oxygen species (ROS) and is critical for PM2.5-induced apoptosis. Furthermore, PM2.5 exposure can activate ER stress sensor IRE1α, but it decreases the activity of IRE1α in splicing the mRNA encoding the UPR trans-activator X-box binding protein 1 (XBP1). Together, our study suggests that PM2.5 exposure differentially activates the UPR branches, leading to ER stress-induced apoptosis through the PERK-eIF2α-CHOP UPR branch. This work provides novel insights into the cellular and molecular basis by which ambient PM2.5 exposure elicits its cytotoxic effects that may be related to air pollution-associated pathogenesis.

scholarly journals Induction of GRP78 by Ischemic Preconditioning Reduces Endoplasmic Reticulum Stress and Prevents Delayed Neuronal Cell Death

2003 ◽  
Vol 23 (8) ◽  
pp. 949-961 ◽  
Author(s):  
Takeshi Hayashi ◽  
Atsushi Saito ◽  
Shuzo Okuno ◽  
Michel Ferrand-Drake ◽  
Pak H Chan
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Ischemic Preconditioning ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ischemic Tolerance ◽  
Initiation Factor ◽  
Tolerance Time ◽  
Delayed Neuronal Cell Death

Although the endoplasmic reticulum (ER) is implicated in neuronal degeneration in some situations, its role in delayed neuronal cell death (DND) after ischemia remains uncertain. The authors speculated that ER stress is involved in DND, that it is reduced by ischemic preconditioning, and that ER stress reduction by preconditioning is due to ER molecular chaperone induction. The phosphorylation status of eukaryotic initiation factor 2α (eIF2α) and RNA-dependent protein kinase–like ER eIF2α kinase (PERK) was investigated in the rat hippocampus after ischemia with and without preconditioning. PERK is phosphorylated by ER stress, which phosphorylates eIF2α. To investigate the role of ER molecular chaperones in preconditioning, the authors examined GRP78 and GRP94 expression, both of which are ER chaperones that inhibit PERK phosphorylation, and compared their induction and ischemic tolerance time windows. Phosphorylation of eIF2α and PERK was confirmed after severe ischemia but was inhibited by preconditioning. After preconditioning, GRP78 was increased in the brain with a peak at 2 days, which corresponded with the ischemic tolerance time window. Immunoprecipitation and double staining demonstrated involvement of GRP78 in prevention of PERK phosphorylation. These results suggest that GRP78 induced by preconditioning may reduce ER stress and eventual DND after ischemia.

scholarly journals Endoplasmic Reticulum Stress Contributed to Dipyridamole-Induced Impaired Autophagic Flux and Glioma Apoptosis

2022 ◽  
Vol 23 (2) ◽  
pp. 579
Author(s):  
Cheng-Yi Chang ◽  
Chih-Cheng Wu ◽  
Jiaan-Der Wang ◽  
Su-Lan Liao ◽  
Wen-Ying Chen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Apoptotic Cell ◽  
Glioma Cells ◽  
Apoptotic Cell Death ◽  
Autophagic Flux ◽  
Intracellular Camp ◽  
Cell Proliferation Inhibition ◽  
Camp Levels

Elevation of intracellular cAMP levels has been implicated in glioma cell proliferation inhibition, differentiation, and apoptosis. Inhibition of phosphodiesterase is a way to elevate intracellular cAMP levels. The present study aimed to investigate the anti-glioma potential of dipyridamole, an inhibitor of phosphodiesterase. Upon treatment with dipyridamole, human U87 glioma cells decreased cell viability, clonogenic colonization, migration, and invasion, along with Noxa upregulation, Endoplasmic Reticulum (ER) stress, impaired autophagic flux, Yes-associated Protein 1 (YAP1) phosphorylation, and YAP1 reduction. Pharmacological and genetic studies revealed the ability of dipyridamole to initiate Noxa-guided apoptosis through ER stress. Additionally, the current study further identified the biochemical role of YAP1 in communicating with ER stress and autophagy under situations of dipyridamole treatment. YAP1 promoted autophagy and protected glioma cells from dipyridamole-induced apoptotic cell death. Dipyridamole impaired autophagic flux and rendered glioma cells more vulnerable to apoptotic cell death through ER stress-inhibitable YAP1/autophagy axis. The overall cellular changes caused by dipyridamole appeared to ensure a successful completion of apoptosis. Dipyridamole also duplicated the biochemical changes and apoptosis in glioma T98G cells. Since dipyridamole has additional biochemical and pharmacological properties, further research centered on the anti-glioma mechanisms of dipyridamole is still needed.

Inhibition of Autophagy Potentiated Hippocampal Cell Death Induced by Endoplasmic Reticulum Stress and its Activation by Trehalose Failed to be Neuroprotective

2019 ◽  
Vol 16 (1) ◽  
pp. 3-11
Author(s):  
Luisa Halbe ◽  
Abdelhaq Rami
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cell Damage ◽  
Protective Mechanism ◽  
Unfolded Proteins ◽  
Neuronal Viability ◽  
Hippocampal Cell ◽  
Trigger Cell Death ◽  
Autophagy Inhibition

Introduction: Endoplasmic reticulum (ER) stress induced the mobilization of two protein breakdown routes, the proteasomal- and autophagy-associated degradation. During ERassociated degradation, unfolded ER proteins are translocated to the cytosol where they are cleaved by the proteasome. When the accumulation of misfolded or unfolded proteins excels the ER capacity, autophagy can be activated in order to undertake the degradative machinery and to attenuate the ER stress. Autophagy is a mechanism by which macromolecules and defective organelles are included in autophagosomes and delivered to lysosomes for degradation and recycling of bioenergetics substrate. Materials and Methods: Autophagy upon ER stress serves initially as a protective mechanism, however when the stress is more pronounced the autophagic response will trigger cell death. Because autophagy could function as a double edged sword in cell viability, we examined the effects autophagy modulation on ER stress-induced cell death in HT22 murine hippocampal neuronal cells. We investigated the effects of both autophagy-inhibition by 3-methyladenine (3-MA) and autophagy-activation by trehalose on ER-stress induced damage in hippocampal HT22 neurons. We evaluated the expression of ER stress- and autophagy-sensors as well as the neuronal viability. Results and Conclusion: Based on our findings, we conclude that under ER-stress conditions, inhibition of autophagy exacerbates cell damage and induction of autophagy by trehalose failed to be neuroprotective.

scholarly journals Polyhexamethylene Guanidine Phosphate Induces Apoptosis through Endoplasmic Reticulum Stress in Lung Epithelial Cells

2021 ◽  
Vol 22 (3) ◽  
pp. 1215
Author(s):  
Mi Ho Jeong ◽  
Mi Seon Jeon ◽  
Ga Eun Kim ◽  
Ha Ryong Kim
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Epithelial Cell ◽  
Er Stress ◽  
Lung Fibrosis ◽  
A549 Cells ◽  
Polyhexamethylene Guanidine ◽  
Lung Epithelial ◽  
Epithelial Cell Death ◽  
Guanidine Phosphate

Airway epithelial cell death contributes to the pathogenesis of lung fibrosis. Polyhexamethylene guanidine phosphate (PHMG-p), commonly used as a disinfectant, has been shown to be strongly associated with lung fibrosis in epidemiological and toxicological studies. However, the molecular mechanism underlying PHMG-p-induced epithelial cell death is currently unclear. We synthesized a PHMG-p–fluorescein isothiocyanate (FITC) conjugate and assessed its uptake into lung epithelial A549 cells. To examine intracellular localization, the cells were treated with PHMG-p–FITC; then, the cytoplasmic organelles were counterstained and observed with confocal microscopy. Additionally, the organelle-specific cell death pathway was investigated in cells treated with PHMG-p. PHMG-p–FITC co-localized with the endoplasmic reticulum (ER), and PHMG-p induced ER stress in A549 cells and mice. The ER stress inhibitor tauroursodeoxycholic acid (TUDCA) was used as a pre-treatment to verify the role of ER stress in PHMG-p-induced cytotoxicity. The cells treated with PHMG-p showed apoptosis, which was inhibited by TUDCA. Our results indicate that PHMG-p is rapidly located in the ER and causes ER-stress-mediated apoptosis, which is an initial step in PHMG-p-induced lung fibrosis.

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