scholarly journals Activation of ER Stress-Dependent miR-216b Has a Critical Role in Salvia miltiorrhiza Ethanol-Extract-Induced Apoptosis in U266 and U937 Cells

2018 ◽  
Vol 19 (4) ◽  
pp. 1240 ◽  
Author(s):  
Changmin Kim ◽  
Hyo-Sook Song ◽  
Hojung Park ◽  
Bonglee Kim
Keyword(s):  
Er Stress ◽  
Salvia Miltiorrhiza ◽  
Critical Role ◽  
Ethanol Extract ◽  
U937 Cells ◽  
Induced Apoptosis ◽  
Stress Dependent

scholarly journals MiR-657/ATF2 Signaling Pathway Has a Critical Role in Spatholobus suberectus Dunn Extract-Induced Apoptosis in U266 and U937 Cells

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 150 ◽  
Author(s):  
Hyun Lim ◽  
Moon Park ◽  
Changmin Kim ◽  
Beomku Kang ◽  
Hyo-Sook Song ◽  
...  
Keyword(s):  
Er Stress ◽  
Critical Role ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Parp Cleavage ◽  
Dependent Manner ◽  
U937 Cells ◽  
Anti Cancer ◽  
Spatholobus Suberectus ◽  
Induced Apoptosis ◽  
Related Proteins

Though Spatholobus suberectus Dunn (SSD) has been reported to have anti-virus, anti-osteoclastogenesis, and anti-inflammation activities, its underlying anti-cancer mechanism has never been elucidated in association with the role of miR-657 in endoplasmic reticulum (ER) stress-related apoptosis to date. SSD treatment exerted cytotoxicity in U266 and U937 cells in a dose-dependent manner. Also, apoptosis-related proteins such as PARP, procaspase-3, and Bax were regulated by SSD treatment. Furthermore, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed that a number of apoptotic bodies were increased by SSD. Interestingly, the ER stress-related proteins such as p-ATF2 and CHOP were elevated by SSD. Interestingly, reactive oxygen species (ROS) generation and cytotoxicity by SSD treatment were significantly reduced by N-Acetyl-L-cysteine (NAC). Among the microRNAs (miRNAs) regulated by SSD treatment, miR-657 was most significantly reduced by SSD treatment. However, an miR-657 mimic reversed SSD-induced apoptosis by the attenuation of the expression of p-ATF2, CHOP, and PARP cleavage. Overall, these findings provide scientific evidence that miR657 is an onco-miRNA targeting the ER stress signal pathway and SSD induces apoptosis via the inhibition of miR-657, ROS, and the activation of p-ATF2 and CHOP as a potent anti-cancer agent for myeloid-originated hematological cancer.

scholarly journals 15,16-Dihydrotanshinone I, a Compound ofSalvia miltiorrhizaBunge, Induces Apoptosis through Inducing Endoplasmic Reticular Stress in Human Prostate Carcinoma Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Mao-Te Chuang ◽  
Feng-Ming Ho ◽  
Chien-Chih Wu ◽  
Shao-Yu Zhuang ◽  
Shyr-Yi Lin ◽  
...  
Keyword(s):  
Er Stress ◽  
Prostate Carcinoma ◽  
Therapeutic Potential ◽  
Binding Protein ◽  
Salvia Miltiorrhiza ◽  
Carcinoma Cells ◽  
Initiation Factor ◽  
Human Prostate ◽  
Induced Apoptosis ◽  
Stress Dependent

5,16-dihydrotanshinone I (DHTS) is extracted fromSalvia miltiorrhizaBunge (tanshen root) and was found to be the most effective compound of tanshen extracts against breast cancer cells in our previous studies. However, whether DHTS can induce apoptosis through an endoplasmic reticular (ER) stress pathway was examined herein. In this study, we found that DHTS significantly inhibited the proliferation of human prostate DU145 carcinoma cells and induced apoptosis. DHTS was able to induce ER stress as evidenced by the upregulation of glucose regulation protein 78 (GRP78/Bip) and CAAT/enhancer binding protein homologous protein/growth arrest- and DNA damage-inducible gene 153 (CHOP/GADD153), as well as increases in phosphorylated eukaryotic initiation factor 2α (eIF2α), c-jun N-terminal kinase (JNK), and X-box-binding protein 1 (XBP1) mRNA splicing forms. DHTS treatment also caused significant accumulation of polyubiquitinated proteins and hypoxia-inducible factor (HIF)-1α, indicating that DHTS might be a proteasome inhibitor that is known to induce ER stress or enhance apoptosis caused by the classic ER stress-dependent mechanism. Moreover, DHTS-induced apoptosis was reversed by salubrinal, an ER stress inhibitor. Results suggest that DHTS can induce apoptosis of prostate carcinoma cells via induction of ER stress and/or inhibition of proteasome activity, and may have therapeutic potential for prostate cancer patients.

Abstract 590: Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Masafumi Myoishi ◽  
Testuo Minamino ◽  
Masafumi Kitakaze
Keyword(s):  
Endoplasmic Reticulum ◽  
Coronary Artery ◽  
Er Stress ◽  
Atherosclerotic Plaques ◽  
Coronary Syndrome ◽  
Er Chaperone ◽  
Unstable Plaques ◽  
Induced Apoptosis ◽  
Stress Dependent ◽  
Dependent Pathway

Background Endoplasmic reticulum (ER) responds to various stresses by up-regulation of ER chaperones, and prolonged ER stress eventually causes apoptosis. Although apoptosis is considered to be essential for the progression and rupture of atherosclerotic plaques, the influence of ER stress and apoptosis on rupture of unstable coronary plaques remains unclear. Methods and Results We obtained 152 coronary artery segments at autopsy and 40 atherectomy specimens from 71 and 40 patients, respectively . Smooth muscle cells (SMCs) and macrophages in the fibrous caps of thin cap atheroma and ruptured plaques, but not in the fibrous caps of thick cap atheroma and fibrous plaques, showed a marked increase in the expression of ER chaperone and numbers of apoptotic cells. ER chaperones also expressed higher in atherectomy specimens from patients with unstable angina pectoris than with stable angina. To explore the plausible molecular mechanism of activation of ER stress and the mechanistic link to apoptosis, we investigated plaque lipids such as oxysterols. Among oxysterols, expression of 7-ketocholesterol was increased in the fibrous caps of thin cap atheroma compared with thick cap atheroma. Treatment of either cultured coronary artery SMCs or THP-1 cells with 7-ketocholesterol induced upregulation of ER chaperones and apoptosis, while these changes were prevented by antioxidants. We also investigated possible signaling pathways for ER-initiated apoptosis and found that the CHOP (a transcription factor induced by ER stress)-dependent pathway was activated in unstable plaques. In addition, knockdown of CHOP expression by siRNA decreased ER stress-dependent death of cultured coronary artery SMCs and THP-1 cells. Conclusions Increased ER stress occurs in unstable plaques. Our findings suggest that ER stress-induced apoptosis of SMCs and macrophages may contribute to plaque vulnerability.

scholarly journals Explore the Molecular Mechanism of Apoptosis Induced by Tanshinone IIA on Activated Rat Hepatic Stellate Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Tai-Long Pan ◽  
Pei-Wen Wang
Keyword(s):  
Stellate Cell ◽  
Salvia Miltiorrhiza ◽  
Ethanol Extract ◽  
Stellate Cells ◽  
Tanshinone Iia ◽  
Cycle Arrest ◽  
Erk Phosphorylation ◽  
Liver Fibrogenesis ◽  
Potential Strategy ◽  
Induced Apoptosis

Since the activated hepatic stellate cell (HSC) is the predominant event in the progression of liver fibrosis, selective clearance of HSC should be a potential strategy in therapy.Salvia miltiorrhizaroots ethanol extract (SMEE) remarkably ameliorates liver fibrogenesis in DMN-administrated rat model. Next, tanshinone IIA (Tan IIA), the major compound of SMEE, significantly inhibited rat HSC viability and led to cell apoptosis. Proteome tools elucidated that increased prohibitin is involved in cell cycle arrest under Tan IIA is the treatment while knockdown of prohibitin could attenuate Tan IIA-induced apoptosis. In addition, Tan IIA mediated translocation of C-Raf which interacted with prohibitin activating MAPK and inhibiting AKT signaling in HSC. MAPK antagonist suppressed ERK phosphorylation which was necessary for Tan IIA-induced expression of Bax and cytochrome c. PD98059 also abolished Tan IIA-modulated cleavage of PARP. Our findings suggested that Tan IIA could contribute to apoptosis of HSC by promoting ERK-Bax-caspase pathways through C-Raf/prohibitin complex.

scholarly journals Endoplasmic Reticulum Stress and Lipid Metabolism: Mechanisms and Therapeutic Potential

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Sana Basseri ◽  
Richard C. Austin
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Lipid Metabolism ◽  
Er Stress ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Signal Transduction Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent

The endoplasmic reticulum (ER) plays a crucial role in protein folding, assembly, and secretion. Disruption of ER homeostasis may lead to accumulation of misfolded or unfolded proteins in the ER lumen, a condition referred to as ER stress. In response to ER stress, a signal transduction pathway known as the unfolded protein response (UPR) is activated. UPR activation allows the cell to cope with an increased protein-folding demand on the ER. Recent studies have shown that ER stress/UPR activation plays a critical role in lipid metabolism and homeostasis. ER-stress-dependent dysregulation of lipid metabolism may lead to dyslipidemia, insulin resistance, cardiovascular disease, type 2 diabetes, and obesity. In this paper, we examine recent findings illustrating the important role ER stress/UPR signalling pathways play in regulation of lipid metabolism, and how they may lead to dysregulation of lipid homeostasis.

scholarly journals Imiquimod‐induced apoptosis of melanoma cells is mediated by ER stress‐dependent Noxa induction and enhanced by NF ‐κB inhibition

2016 ◽  
Vol 20 (2) ◽  
pp. 266-286 ◽  
Author(s):  
Abdelouahid El‐Khattouti ◽  
Denis Selimovic ◽  
Matthias Hannig ◽  
Erin B. Taylor ◽  
Zakaria Y. Abd Elmageed ◽  
...  
Keyword(s):  
Er Stress ◽  
Melanoma Cells ◽  
Induced Apoptosis ◽  
Stress Dependent

scholarly journals FBXO6-Mediated Ubiquitination and Degradation of Ero1L Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis

2016 ◽  
Vol 39 (6) ◽  
pp. 2501-2508 ◽  
Author(s):  
Xi Chen ◽  
Lang-Huan Duan ◽  
Peng-cheng Luo ◽  
Gang Hu ◽  
Xin Yu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Critical Role ◽  
Dependent Manner ◽  
Ubiquitin E3 Ligase ◽  
The Stability ◽  
Induced Apoptosis ◽  
F Box Protein ◽  
Protein Disulfide

Background/Aims: FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex, recognizing the chitobiose in unfolded N-glycoprotein to target glycoproteins for polyubiquitination and degradation. Although how FBXO6 recognizes glycoprotein has been fully investigated, the ubiquitination substrates of FBXO6 remain largely unknown. Previously, we have systematically identified the glycoproteins that interact with FBXO6 in an N-glycan dependent manner by LC/MS spectrum and confirmed the interaction between FBXO6 and glycosylated Ero1L, a protein disulfide oxidase in endoplasmic reticulum (ER). Methods: The relationship between endogenous Ero1L and exogenous Flag-FBXO6 were determined by Western blot. In vivo ubiquitination assay was used to detect the direct effect of FBXO6 in the regulation of Ero1L. Both CCK8 and FACS assays were used to determine the apoptosis ratio of cells after treatments. Results: Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. Functionally, we show that FBXO6 inhibits ER stress-induced apoptosis by modulating the protein level of Ero1L. Conclusion: Collectively, our results demonstrate FBXO6 as a functional E3 ubiquitin ligase for Ero1L that plays a critical role in inhibiting ER stress-induced apoptosis.

Apelin-13 protects the heart against ischemia-reperfusion injury through inhibition of ER-dependent apoptotic pathways in a time-dependent fashion

2011 ◽  
Vol 301 (4) ◽  
pp. H1471-H1486 ◽  
Author(s):  
Jianping Tao ◽  
Wei Zhu ◽  
Yapeng Li ◽  
Ping Xin ◽  
Jing Li ◽  
...  
Keyword(s):  
Er Stress ◽  
Signaling Pathways ◽  
Time Course ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Fold Increase ◽  
Erk Activation ◽  
Caspase 12 ◽  
Induced Apoptosis ◽  
Stress Dependent

Endoplasmic reticulum (ER) stress is activated during and contributes to ischemia-reperfusion (I/R) injury. Attenuation of ER stress-induced apoptosis protects the heart against I/R injury. Using apelin, a ligand used to activate the apelin APJ receptor, which is known to be cardioprotective, this study was designed to investigate 1) the time course of changes in I/R injury after ER stress; 2) whether apelin infusion protects the heart against I/R injury via modulation of ER stress-dependent apoptosis signaling pathways; and 3) how phosphatidylinositol 3-kinase (PI3K)/Akt, endothelial nitric oxide synthase (eNOS), AMP-activated protein kinase (AMPK), and ERK activation are involved in the protection offered by apelin treatment. The results showed that, using an in vivo rat I/R model induced by 30 min of ischemia followed by reperfusion, infarct size (IS) increased from 2 h of reperfusion (34.85 ± 2.14%) to 12 h of reperfusion (48.98 ± 3.35, P < 0.05), which was associated with an abrupt increase in ER stress-dependent apoptosis activation, as evidenced by increased CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and JNK activation (CHOP: 2.49-fold increase, caspase-12: 2.09-fold increase, and JNK: 3.38-fold increase, P < 0.05, respectively). Administration of apelin at 1 μg/kg not only completely abolished the activation of ER stress-induced apoptosis signaling pathways at 2 h of reperfusion but also significantly attenuated time-related changes at 24 h of reperfusion. Using pharmacological inhibition, we also demonstrated that PI3K/Akt, AMPK, and ERK activation were involved in the protection against I/R injury via inhibition of ER stress-dependent apoptosis activation. In contrast, although eNOS activation played a role in decreasing IS at 2 h of reperfusion, it failed to modify either IS or ER stress-induced apoptosis signaling pathways at 24 h after reperfusion.

scholarly journals A miR-494 dependent feedback loop regulates ER stress

2020 ◽  
Author(s):  
Namita Chatterjee ◽  
Cristina Espinosa-Diez ◽  
Sudarshan Anand
Keyword(s):  
Er Stress ◽  
Stress Responses ◽  
De Novo ◽  
Critical Role ◽  
Dependent Manner ◽  
Inflammatory Chemokines ◽  
Stress Dependent ◽  
And Control

AbstractDefects in stress responses are important contributors in many chronic conditions including cancer, cardiovascular disease, diabetes, and obesity-driven pathologies like non-alcoholic steatohepatitis (NASH). Specifically, endoplasmic reticulum (ER) stress is linked with these pathologies and control of ER stress can ameliorate tissue damage. MicroRNAs have a critical role in regulating diverse stress responses including ER stress. Here we show that miR-494 plays a functional role during ER stress. ER stress inducers (tunicamycin & thapsigargin) robustly increase the expression of miR-494 in vitro in an ATF6 dependent manner. Surprisingly, miR-494 pretreatment dampens the induction and magnitude of ER stress in response to tunicamycin in endothelial cells. Conversely, inhibition of miR-494 increases ER stress de novo and amplifies the effects of ER stress inducers. Using Mass Spectrometry (TMT-MS) we identified 23 proteins that are downregulated by both tunicamycin and miR-494. Among these, we found 6 transcripts which harbor a putative miR-494 binding site. We validated the anti-apoptotic gene BIRC5 (survivin) as one of the targets of miR-494 during ER stress. Finally, induction of ER stress in vivo increases miR-494 expression in the liver. Pretreatment of mice with a miR-494 plasmid via hydrodynamic injection decreased ER stress in response to tunicamycin in part by decreasing inflammatory chemokines and cytokines. In summary, our data indicates that ER stress driven miR-494 may act in a feedback inhibitory loop to dampen downstream ER stress signaling. We propose that RNA-based approaches targeting miR-494 or its targets may be attractive candidates for inhibiting ER stress dependent pathologies in human disease.

scholarly journals Programming of Fetal Insulin Resistance in Pregnancies with Maternal Obesity by ER Stress and Inflammation

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Francisco Westermeier ◽  
Pablo J. Sáez ◽  
Roberto Villalobos-Labra ◽  
Luis Sobrevia ◽  
Marcelo Farías-Jofré
Keyword(s):  
Insulin Resistance ◽  
Er Stress ◽  
Maternal Obesity ◽  
Critical Role ◽  
Cellular Processes ◽  
Unfolded Protein ◽  
Complex Interactions ◽  
Fetal Complications ◽  
Stress Dependent ◽  
Protein Response

The global epidemics of obesity during pregnancy and excessive gestational weight gain (GWG) are major public health problems worldwide. Obesity and excessive GWG are related to several maternal and fetal complications, including diabetes (pregestational and gestational diabetes) and intrauterine programming of insulin resistance (IR). Maternal obesity (MO) and neonatal IR are associated with long-term development of obesity, diabetes mellitus, and increased global cardiovascular risk in the offspring. Multiple mechanisms of insulin signaling pathway impairment have been described in obese individuals, involving complex interactions of chronically elevated inflammatory mediators, adipokines, and the critical role of the endoplasmic reticulum (ER) stress-dependent unfolded protein response (UPR). However, the underlying cellular processes linking MO and IR in the offspring have not been fully elucidated. Here, we summarize the state-of-the-art evidence supporting the possibility that adverse metabolic postnatal outcomes such as IR in the offspring of pregnancies with MO and/or excessive GWG may be related to intrauterine activation of ER stress response.

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