Deltamethrin Induces Apoptosis in Cerebrum Neurons of Quail via Promoting Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

Abstract Deltamethrin (DLM) is a widely used and highly effective insecticide. DLM exposure is harmful to animal and human. Quail, as a bird model, has been widely used in the toxicology field. However, there is little information available in the literature about quail cerebrum damage caused by DLM. Here, we investigated the effect of DLM on quail cerebrum neurons. Four groups of healthy quails were assigned (10 quails in each group), respectively given 0, 15, 30, and 45 mg/kg DLM by gavage for 12 weeks. Through the measurements of quail cerebrum, it was found that DLM exposure induced obvious histological changes, oxidative stress, and neurons apoptosis. To further explore the possible molecular mechanisms, we performed real-time quantitative PCR to detect the expression of endoplasmic reticulum (ER) stress-related mRNA. In addition, we detected ATP content in quail cerebrum to evaluate the functional status of mitochondria. The study showed that DLM exposure significantly increased the expression of ER stress-related mRNA and decreased ATP content in quail cerebrum. These results suggest that chronic exposure to DLM induces apoptosis of quail cerebrum neurons via promoting ER stress and mitochondrial dysfunction. Furthermore, our results provide a novel explanation for DLM-induced apoptosis of avian cerebrum neurons.

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Emodin Alleviates Hydrogen Peroxide-Induced Inflammation and Oxidative Stress via Mitochondrial Dysfunction by Inhibiting the PI3K/mTOR/GSK3β Pathway in Neuroblastoma SH-SY5Y Cells

BioMed Research International ◽

10.1155/2020/1562915 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Rui Li ◽

Wenzhou Liu ◽

Li Ou ◽

Feng Gao ◽

Min Li ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Cell Damage ◽

Neuroblastoma Cells ◽

Inflammatory Factors ◽

Protective Mechanism ◽

Human Neuroblastoma ◽

Induced Apoptosis

Emodin is an active monomer extracted from rhubarb root, which has many biological functions, including anti-inflammation, antioxidation, anticancer, and neuroprotection. However, the protective effect of emodin on nerve injury needs to be further elucidated. The purpose of this study is to investigate the effect of emodin on the neuroprotection and the special molecular mechanism. Here, the protective activity of emodin inhibiting H2O2-induced apoptosis and neuroinflammation as well as its molecular mechanisms was examined using human neuroblastoma cells (SH-SY5Y cells). The results showed that emodin significantly enhanced cell viability, reduced cell apoptosis and LDH release. Simultaneously, emodin downregulated H2O2-induced inflammatory factors, including IL-6, NO, and TNF-α, and alleviated H2O2-induced oxidative stress and mitochondrial dysfunction in SH-SY5Y cells. In addition, emodin inhibited the activation of the PI3K/mTOR/GSK3β signaling pathway. What is more, the PI3K/mTOR/GSK3β pathway participated in the protective mechanism of emodin on H2O2-induced cell damage. Collectively, it suggests that emodin alleviates H2O2-induced apoptosis and neuroinflammation potentially by regulating the PI3K/mTOR/GSK3β signaling pathway.

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Activation of endoplasmic reticulum stress mediates oxidative stress–induced apoptosis of granulosa cells in ovaries affected by endometrioma

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaz066 ◽

2019 ◽

Vol 26 (1) ◽

pp. 40-52 ◽

Cited By ~ 2

Author(s):

Chisato Kunitomi ◽

Miyuki Harada ◽

Nozomi Takahashi ◽

Jerilee M K Azhary ◽

Akari Kusamoto ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Granulosa Cells ◽

Ovarian Function ◽

Stress Sensor ◽

Local Factor ◽

High Oxidative Stress ◽

Induced Apoptosis ◽

Sensor Proteins

Abstract Endometriosis exerts detrimental effects on ovarian physiology and compromises follicular health. Granulosa cells from patients with endometriosis are characterized by increased apoptosis, as well as high oxidative stress. Endoplasmic reticulum (ER) stress, a local factor closely associated with oxidative stress, has emerged as a critical regulator of ovarian function. We hypothesized that ER stress is activated by high oxidative stress in granulosa cells in ovaries with endometrioma and that this mediates oxidative stress–induced apoptosis. Human granulosa-lutein cells (GLCs) from patients with endometrioma expressed high levels of mRNAs associated with the unfolded protein response (UPR). In addition, the levels of phosphorylated ER stress sensor proteins, inositol-requiring enzyme 1 (IRE1) and double-stranded RNA-activated protein kinase-like ER kinase (PERK), were elevated in granulosa cells from patients with endometrioma. Given that ER stress results in phosphorylation of ER stress sensor proteins and induces UPR factors, these findings indicate that these cells were under ER stress. H2O2, an inducer of oxidative stress, increased expression of UPR-associated mRNAs in cultured human GLCs, and this effect was abrogated by pretreatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor in clinical use. Treatment with H2O2 increased apoptosis and the activity of the pro-apoptotic factors caspase-8 and caspase-3, both of which were attenuated by TUDCA. Our findings suggest that activated ER stress induced by high oxidative stress in granulosa cells in ovaries with endometrioma mediates apoptosis of these cells, leading to ovarian dysfunction in patients with endometriosis.

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Sustained Endoplasmic Reticulum Stress as a Cofactor of Oxidative Stress in Decidual Cells from Patients with Early Pregnancy Loss

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-2192 ◽

2011 ◽

Vol 96 (3) ◽

pp. E493-E497 ◽

Cited By ~ 39

Author(s):

Ai-Xia Liu ◽

Wei-Hua He ◽

Li-Jun Yin ◽

Ping-Ping Lv ◽

Yu Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Early Pregnancy ◽

Pregnancy Loss ◽

Redox Status ◽

Early Pregnancy Loss ◽

Decidual Cells ◽

Failed Induction ◽

Induced Apoptosis

Background: Oxidative stress is a common pathological background for different etiologies of early pregnancy loss (EPL). It has been suggested that elevated reactive oxygen species trigger endoplasmic reticulum (ER) stress by influencing ER function. However, it is unclear whether ER stress is associated with EPL. Objectives: The aim of the study was to determine whether and how ER stress occurs during the development of EPL. Approaches: Proteomic analysis was performed on decidua from women with EPL, and then ER stress markers, redox status, apoptotic features, and cell viability were analyzed in EPL decidual cells (DCs). Results: EPL decidua were characterized by decreased levels of glucose-regulated protein 78 (GPR78) and valosin-containing protein and burdened with ubiquitinated proteins. Evidence of ER stress-induced apoptosis in EPL DCs was demonstrated by extensive dilation of ER, morphological features of apoptosis, and activation of caspase-4 and caspase-12. Furthermore, H2O2 reduced the viabilities in both EPL and control DCs, whereas EPL DCs were more vulnerable to additional OS challenge than the controls as a result of failed induction of GRP78 expression. The cell survival percentages of DCs were dose-dependently reduced by H2O2 and could be reversed in the presence of vitamin E. This effect was partly mediated by reducing the amount of misfolded proteins rather than regulating GRP78 expression. Conclusions: The sum of these observations demonstrate for the first time that sustained ER stress occurs in EPL DCs and the potentially vicious relationship between ER stress and oxidative stress is likely to play an important role in the development of EPL.

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Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-κB regulation

AJP Cell Physiology ◽

10.1152/ajpcell.00345.2012 ◽

2013 ◽

Vol 304 (7) ◽

pp. C636-C655 ◽

Cited By ~ 50

Author(s):

Bhavana Chhunchha ◽

Nigar Fatma ◽

Eri Kubo ◽

Prerana Rai ◽

Sanjay P. Singh ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Er Stress ◽

Molecular Mechanisms ◽

Stress Proteins ◽

Ht22 Cells ◽

Peroxiredoxin 6 ◽

Homologous Protein ◽

Survival Signaling ◽

Induced Apoptosis

Oxidative stress and endoplasmic reticulum (ER) stress are emerging as crucial events in the etiopathology of many neurodegenerative diseases. While the neuroprotective contributions of the dietary compound curcumin has been recognized, the molecular mechanisms underlying curcumin's neuroprotection under oxidative and ER stresses remains elusive. Herein, we show that curcumin protects HT22 from oxidative and ER stresses evoked by the hypoxia (1% O2 or CoCl2 treatment) by enhancing peroxiredoxin 6 (Prdx6) expression. Cells exposed to CoCl2 displayed reduced expression of Prdx6 with higher reactive oxygen species (ROS) expression and activation of NF-κB with IκB phosphorylation. When NF-κB activity was blocked by using SN50, an inhibitor of NF-κB, or cells treated with curcumin, the repression of Prdx6 expression was restored, suggesting the involvement of NF-κB in modulating Prdx6 expression. These cells were enriched with an accumulation of ER stress proteins, C/EBP homologous protein (CHOP), GRP/78, and calreticulin, and had activated states of caspases 12, 9, and 3. Reinforced expression of Prdx6 in HT22 cells by curcumin reestablished survival signaling by reducing propagation of ROS and blunting ER stress signaling. Intriguingly, knockdown of Prdx6 by antisense revealed that loss of Prdx6 contributed to cell death by sustaining enhanced levels of ER stress-responsive proapoptotic proteins, which was due to elevated ROS production, suggesting that Prdx6 deficiency is a cause of initiation of ROS-mediated ER stress-induced apoptosis. We propose that using curcumin to reinforce the naturally occurring Prdx6 expression and attenuate ROS-based ER stress and NF-κB-mediated aberrant signaling improves cell survival and may provide an avenue to treat and/or postpone diseases associated with ROS or ER stress.

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Sustained Endoplasmic Reticulum Stress as a Cofactor of Oxidative Stress in Decidual Cells from Patients with Early Pregnancy Loss

Endocrinology ◽

10.1210/endo.152.1.9994 ◽

2011 ◽

Vol 152 (1) ◽

pp. 333-333

Author(s):

Ai-Xia Liu ◽

Wei-Hua He ◽

Li-Jun Yin ◽

Ping-Ping Lv ◽

Yu Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Early Pregnancy ◽

Pregnancy Loss ◽

Redox Status ◽

Early Pregnancy Loss ◽

Decidual Cells ◽

Failed Induction ◽

Induced Apoptosis

Background: Oxidative stress (OS) is a common pathological background for different etiologies of early pregnancy loss (EPL). It has been suggested that elevated reactive oxygen species trigger endoplasmic reticulum (ER) stress by influencing ER function. However, it is unclear whether ER stress is associated with EPL. Objectives: The aim of the study was to determine whether and how ER stress occurs during the development of EPL. Approaches: Proteomic analysis was performed on decidua from women with EPL, and then ER stress markers, redox status, apoptotic features, and cell viability were analyzed in EPL decidual cells (DCs). Results: EPL decidua were characterized by decreased levels of glucose-regulated protein 78 (GPR78) and valosin-containing protein and burdened with ubiquitinated proteins. Evidence of ER stress-induced apoptosis in EPL DCs was demonstrated by extensive dilation of ER, morphological features of apoptosis, and activation of caspase-4 and caspase-12. Furthermore, H2O2 reduced the viabilities in both EPL and control DCs, whereas EPL DCs were more vulnerable to additional OS challenge than the controls as a result of failed induction of GRP78 expression. The cell survival percentages of DCs were dose-dependently reduced by H2O2 and could be reversed in the presence of vitamin E. This effect was partly mediated by reducing the amount of misfolded proteins rather than regulating GRP78 expression. Conclusions: The sum of these observations demonstrate for the first time that sustained ER stress occurs in EPL DCs and the potentially vicious relationship between ER stress and OS is likely to play an important role in the development of EPL.

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Capsaicin mediates apoptosis in human nasopharyngeal carcinoma NPC-TW 039 cells through mitochondrial depolarization and endoplasmic reticulum stress

Human & Experimental Toxicology ◽

10.1177/0960327111417269 ◽

2011 ◽

Vol 31 (6) ◽

pp. 539-549 ◽

Cited By ~ 37

Author(s):

S-W Ip ◽

S-H Lan ◽

H-F Lu ◽

A-C Huang ◽

J-S Yang ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Nasopharyngeal Carcinoma ◽

Er Stress ◽

Molecular Mechanisms ◽

Human Cancer ◽

Dependent Manner ◽

Mitochondrial Depolarization ◽

Human Nasopharyngeal Carcinoma ◽

Induced Apoptosis

Capsaicin, a pungent compound found in hot chili peppers, has been reported to have antitumor activities in many human cancer cell lines, but the induction of precise apoptosis signaling pathway in human nasopharyngeal carcinoma (NPC) cells is unclear. Here, we investigated the molecular mechanisms of capsaicin-induced apoptosis in human NPC, NPC-TW 039, cells. Effects of capsaicin involved endoplasmic reticulum (ER) stress, caspase-3 activation and mitochondrial depolarization. Capsaicin-induced cytotoxic effects (cell death) through G0/G1 phase arrest and induction of apoptosis of NPC-TW 039 cells in a dose-dependent manner. Capsaicin treatment triggered ER stress by promoting the production of reactive oxygen species (ROS), increasing levels of inositol-requiring 1 enzyme (IRE1), growth arrest and DNA-damage-inducible 153 (GADD153) and glucose-regulated protein 78 (GRP78). Other effects included an increase in cytosolic Ca2+, loss of the mitochondrial transmembrane potential (ΔΨ m), releases of cytochrome c and apoptosis-inducing factor (AIF), and activation of caspase-9 and -3. Furthermore, capsaicin induced increases in the ratio of Bax/Bcl-2 and abundance of apoptosis-related protein levels. These results suggest that ER stress- and mitochondria-mediated cell death is involved in capsaicin-induced apoptosis in NPC-TW 039 cells.

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Apatinib induces endoplasmic reticulum stress-mediated apoptosis and autophagy and potentiates cell sensitivity to paclitaxel via the IRE-1α–AKT–mTOR pathway in esophageal squamous cell carcinoma

Cell & Bioscience ◽

10.1186/s13578-021-00640-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yu-Ming Wang ◽

Xin Xu ◽

Jian Tang ◽

Zhi-Yong Sun ◽

Yu-Jie Fu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Endoplasmic Reticulum ◽

Esophageal Squamous Cell Carcinoma ◽

Er Stress ◽

Cell Carcinoma ◽

Cancer Cells ◽

Squamous Cell ◽

Molecular Mechanisms ◽

Mtor Pathway ◽

Induced Apoptosis

Abstract Background Apatinib, a novel vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, has been approved for the treatment of metastatic gastric cancer and other tumors. Apatinib exerts antiproliferative and proapoptotic effects in different kinds of cancer cells. However, the molecular mechanisms by which apatinib effective against esophageal squamous cell carcinoma (ESCC) have only been partially researched and whether it has a sensitizing effect on paclitaxel remains unclear. Materials and methods The effects of apatinib or paclitaxel on endoplasmic reticulum (ER) stress, autophagy, apoptosis and proliferation of ESCC cell lines were evaluated. Western blot and immunohistochemistry analyses were performed to detect the expression of related genes. The weight and volume of xenograft tumors in mice were measured. Results In the current study, we elucidated the antiproliferative and ER-stress-mediated autophagy-inducing effects of apatinib on ECA-109 and KYSE-150 esophageal squamous cancer cells and identified the underlying mechanisms of its action. We demonstrated that apatinib not only inhibited the proliferation and induced the apoptosis of ESCC cells, but also activated ER stress and triggered protective autophagy. Moreover, inhibiting autophagy by chloroquine (CQ) enhanced the apatinib-induced apoptosis of ESCC cells through the IRE-1α–AKT–mTOR pathway. In addition, we showed, for the first time, the paclitaxel combined with apatinib and CQ exhibited the best antitumor effect on ESCC both in vivo and in vitro via the IRE-1α–AKT–mTOR pathway. Conclusions Our data showed that apatinib induced ER stress, autophagy and apoptosis in ESCC. Inhibiting autophagy by CQ enhanced apatinib-induced apoptosis. The combination of apatinib and CQ sensitized ESCC cells to paclitaxel to induce apoptosis through the IRE-1α–AKT–mTOR signaling pathway, thus providing the basis for its use in innovative anticancer therapeutic strategies. Graphic abstract

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NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis

The Journal of Cell Biology ◽

10.1083/jcb.201006121 ◽

2010 ◽

Vol 191 (6) ◽

pp. 1113-1125 ◽

Cited By ~ 187

Author(s):

Gang Li ◽

Christopher Scull ◽

Lale Ozcan ◽

Ira Tabas

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Cellular Mechanisms ◽

Apoptosis Pathway ◽

Stress Oxidative ◽

Induced Apoptosis ◽

And Oxidative Stress

Endoplasmic reticulum (ER)–induced apoptosis and oxidative stress contribute to several chronic disease processes, yet molecular and cellular mechanisms linking ER stress and oxidative stress in the setting of apoptosis are poorly understood and infrequently explored in vivo. In this paper, we focus on a previously elucidated ER stress–apoptosis pathway whose molecular components have been identified and documented to cause apoptosis in vivo. We now show that nicotinamide adenine dinucleotide phosphate reduced oxidase (NOX) and NOX-mediated oxidative stress are induced by this pathway and that apoptosis is blocked by both genetic deletion of the NOX subunit NOX2 and by the antioxidant N-acetylcysteine. Unexpectedly, NOX and oxidative stress further amplify CCAAT/enhancer binding protein homologous protein (CHOP) induction through activation of the double-stranded RNA–dependent protein kinase (PKR). In vivo, NOX2 deficiency protects ER-stressed mice from renal cell CHOP induction and apoptosis and prevents renal dysfunction. These data provide new insight into how ER stress, oxidative stress, and PKR activation can be integrated to induce apoptosis in a pathophysiologically relevant manner.

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Abstract P085: Microrna Profiling Of Vascular Smooth Muscle Cells In Human Hypertension Potential Regulators Of Endoplasmic Reticulum And Oxidative Stress

Hypertension ◽

10.1161/hyp.76.suppl_1.p085 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

YU WANG ◽

Livia Camargo ◽

Wendy Beatie ◽

Martin McBride ◽

Augusto C Montezano ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Molecular Mechanisms ◽

Stress Proteins ◽

Target Prediction ◽

Fold Change ◽

Ros Generation ◽

Human Hypertension ◽

Mirna Array

Numerous molecular mechanisms have been implicated in processes underlying vascular phenotypic changes and alterations in hypertension, including microRNAs (miRNAs), oxidative stress and perturbed endoplasmic reticulum (ER) function. The interplay between these elements is unclear. We assessed the VSMC miRNAs profile in hypertension focusing on oxidative and ER stress pathways. VSMCs from small arteries from normotensive (NT) and hypertensive (HT) subjects were used. miRNA profiling of 758 miRNAs was performed using TaqMan advanced miRNA assay (TaqMan Low Density Array Human microRNA). Ingenuity Pathway Analysis (IPA) was used for miRNA target prediction. Expression of vascular genes and proteins was detected by RT-PCR and immunoblotting. ROS generation (chemiluminescence) was assessed in the absence and presence of ER stress inducer tunicamycin (5μg/ml, 24h). miRNA array identified 25 miRNAs uniquely expressed in HT and 21 miRNAs uniquely expressed in NT (CT<30). Of the 332 miRNAs present in both groups, 60 miRNAs were significantly upregulated in HT (fold change >1.5), while 136 miRNAs were significantly downregulated in HT (fold change >1.5). miRNAs that were altered in hypertension, targeted genes involved in oxidative and ER stress. Pro-oxidant [Nox1 mRNA (1.71 fold), Nox4 (1.59 fold), Nox5 (2.04 fold)] and antioxidant [SOD2 mRNA (4.43 fold), GPx1 (1.97 fold)] enzymes protein levels upregulated in HT (p<0.05 vs NT). ER stress proteins, such as PERK (1.57 fold) and elF2α (2.31 fold) were also upregulated in HT (p<0.05 vs NT). IPA analysis of our miRNA library, revealed that miR-505-5p (-2.13 fold), miR-324-5p (-1.51 fold), miR-185-5p (-1.742 fold) and miR-491-5p (-1.667 fold) may regulate Nox5 levels. Moreover, miR-200b-3p (-28.57 fold) targets multiple ER stress pathways including elF2α. Treatment with tunicamycin increased ROS generation (2.29 fold) and Nox5 protein expression (1.69 fold) while downregulating SOD2 mRNA (-8.02 fold) in HT (p<0.05 vs NT). Our findings unveil the differentially expressed miRNAs and their predicted redox targets, highlighting potential interplay between VSMC ER stress, oxidative stress and miRNAs in human hypertension.

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Hyperglycemia Induces Endoplasmic Reticulum Stress in Atrial Cardiomyocytes, and Mitofusin-2 Downregulation Prevents Mitochondrial Dysfunction and Subsequent Cell Death

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/6569728 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Ming Yuan ◽

Mengqi Gong ◽

Zhiwei Zhang ◽

Lei Meng ◽

Gary Tse ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

High Glucose ◽

Atrial Remodeling ◽

Mitofusin 2 ◽

Mitochondrial Oxidative Stress ◽

Atrial Cardiomyocytes

Mitochondrial oxidative stress and dysfunction play an important role of atrial remodeling and atrial fibrillation (AF) in diabetes mellitus. Endoplasmic reticulum (ER) stress has been linked to both physiological and pathological states including diabetes. The aim of this project is to explore the roles of ER stress in hyperglycemia-induced mitochondrial dysfunction and cell death of atrial cardiomyocytes. High glucose upregulated ER stress, mitochondrial oxidative stress, and mitochondria-associated ER membrane (MAM)- enriched proteins (such as glucose-regulated protein 75 (GRP75) and mitofusin-2 (Mfn2)) of primary cardiomyocytes in vitro. Sodium phenylbutyrate (4-PBA) prevented the above changes. Silencing of Mfn2 in HL-1 cells decreased the Ca2+ transfer from ER to mitochondria under ER stress conditions, which were induced by the ER stress agonist, tunicamycin (TM). Electron microscopy data suggested that Mfn2 siRNA significantly disrupted ER-mitochondria tethering in ER stress-injured HL-1 cells. Mfn2 silencing attenuated mitochondrial oxidative stress and Ca2+ overload, increased mitochondrial membrane potential and mitochondrial oxygen consumption, and protected cells from TM-induced apoptosis. In summary, Mfn2 plays an important role in high glucose-induced ER stress in atrial cardiomyocytes, and Mfn2 silencing prevents mitochondrial Ca2+ overload-mediated mitochondrial dysfunction, thereby decreasing ER stress-mediated cardiomyocyte cell death.

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