47 Inhibition of endoplasmic reticulum stress during invitro maturation improves the developmental competence of bovine cumulus-oocyte complexes

2020 ◽  
Vol 32 (2) ◽  
pp. 149
Author(s):  
H. Khatun ◽  
Y. Ihara ◽  
K. Takakura ◽  
Y. Wada ◽  
K.-I. Yamanaka
Keyword(s):  
Reactive Oxygen Species ◽  
Endoplasmic Reticulum ◽  
Embryonic Development ◽  
Er Stress ◽  
Mrna Expression ◽  
Reactive Oxygen ◽  
Developmental Competence ◽  
Apoptotic Cells ◽  
Oxygen Species ◽  
Maturation Rate

Endoplasmic reticulum (ER) stress, a dysfunction in protein-folding capacity of ER, is involved in many physiological responses including embryonic development. Evidence shows that the ER stress-induced unfolded protein response signaling pathway is associated with impairment of oocyte maturation and pre-implantation embryonic development; supplementation of culture medium with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, improved the developmental process of oocytes and embryos by attenuating ER stress. However, no reports are available on the role of TUDCA in reducing ER stress during IVM of bovine oocytes. Therefore, the aim of this study was to examine the mechanism of TUDCA on reducing ER stress in maturation of bovine cumulus-oocyte complexes (COCs) and whether inhibition of ER stress during maturation can promote subsequent embryonic development. Bovine ovaries were collected from a local slaughterhouse, and after aspiration COCs were matured with/without TUDCA (50, 100, and 200 µM) for 22h at 38.5°C in a humidified atmosphere of 5% CO2. After IVM, we examined the maturation rate, reactive oxygen species, apoptosis, protein/mRNA expression levels, and subsequent embryonic development after IVF. The data were analysed using analysis of variance followed by the Tukey-Kramer multiple comparison test. As a result, the dose-dependent experiment shows that a 100μM concentration of TUDCA significantly increased the maturation rate and decreased the percentage of apoptotic cells in COCs and reactive oxygen species levels in denuded oocytes. Subsequently, the expression of ER stress inducible protein GRP78/BIP significantly decreased in COCs treated with 100 µM TUDCA compared with the control COCs. In addition, the mRNA expression of ER stress and pro-apoptotic markers (GRP78/BIP, PERK, IER1, ATF4, XBP1, CHOP, and BAX) in COCs were significantly decreased by TUDCA (100 µM) treatment, whereas it increased anti-apoptotic BCL2 expression. Moreover, we show that TUDCA (100 µM) supplementation enhances embryonic development by significantly increasing the blastocyst formation rate (43.6±1.8% vs. 49.7±1.3%) and decreasing the number of apoptotic cells (7.7±1.1% vs. 5.03±0.6%) in blastocysts. These findings suggest that existence of ER stress during maturation alters the developmental competence of bovine COCs. Therefore, for the first time, we demonstrate that application of TUDCA during IVM plays a crucial role in reducing ER stress and improves the meiotic maturation, oocyte quality, and subsequent embryonic development invitro.

scholarly journals Selective Activation of Endoplasmic Reticulum Stress by Reactive-Oxygen-Species-Mediated Ochratoxin A-Induced Apoptosis in Tubular Epithelial Cells

2021 ◽  
Vol 22 (20) ◽  
pp. 10951
Author(s):  
Chong-Sun Khoi ◽  
Yu-Wen Lin ◽  
Jia-Huang Chen ◽  
Biing-Hui Liu ◽  
Tzu-Yu Lin ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Ochratoxin A ◽  
Reactive Oxygen ◽  
Underlying Mechanism ◽  
Oxygen Species ◽  
Food And Feed ◽  
Renal Proximal Tubular Cells ◽  
Induced Apoptosis

Ochratoxin A (OTA), one of the major food-borne mycotoxins, impacts the health of humans and livestock by contaminating food and feed. However, the underlying mechanism of OTA nephrotoxicity remains unknown. This study demonstrated that OTA induced apoptosis through selective endoplasmic reticulum (ER) stress activation in human renal proximal tubular cells (HK-2). OTA increased ER-stress-related JNK and precursor caspase-4 cleavage apoptotic pathways. Further study revealed that OTA increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) could reduce OTA-induced JNK-related apoptosis and ROS levels in HK-2 cells. Our results demonstrate that OTA induced ER stress-related apoptosis through an ROS-mediated pathway. This study provides new evidence to clarify the mechanism of OTA-induced nephrotoxicity.

scholarly journals Reactive oxygen species mediate anlotinib-induced apoptosis via activation of endoplasmic reticulum stress in pancreatic cancer

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Liguo Yang ◽  
Xiaoshu Zhou ◽  
Jinrui Sun ◽  
Qianghui Lei ◽  
Qi Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Pancreatic Cancer ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Lines ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Antitumour Effect ◽  
Apoptotic Effect

Abstract Anlotinib (AL3818), a novel multi-targeted receptor tyrosine kinase inhibitor, has recently been proven to be an antitumour drug. This study aimed to explore the antitumour effect of anlotinib and its underlying molecular mechanisms in human pancreatic cancer (PC) cells. The anti-proliferative effect of anlotinib for three PC cell lines was validated using CCK-8, colony formation and EdU detection assays. Cell cycle, cell apoptosis, and reactive oxygen species (ROS) detection assays, a PC xenograft model and immunohistochemistry were performed to elucidate the mechanisms by which anlotinib induced tumour lethality in vitro and in vivo. These results demonstrated that anlotinib inhibited proliferation, induced G2/M phase arrest and triggered apoptosis in PC cell lines. Anlotinib induced PC’s apoptosis through the accumulation of ROS which activated the endoplasmic reticulum (ER) stress via PERK/p-eIF2α/ATF4 pathway. Furthermore, we demonstrated that the expression level of Nrf2, an antioxidant protein, increased with anlotinib treatment. Nrf2 knockdown enhanced the pro-apoptotic effect of anlotinib and the expression of the PERK/p-eIF2α/ATF4 pathway. The in vivo results suggested that suppressing Nrf2 improved the antitumour effect of anlotinib on PC cells. These data indicated that the apoptotic effect of anlotinib on PC cells was induced by ER stress via the accumulation of ROS. In the future, anlotinib combined with an Nrf2 inhibitor may provide a new therapeutic strategy for the treatment of human PC.

scholarly journals 3β-Hydroxysteroid-Δ24 Reductase (DHCR24) Protects Pancreatic β Cells from Endoplasmic Reticulum Stress-Induced Apoptosis by Scavenging Excessive Intracellular Reactive Oxygen Species

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yang Li ◽  
Xude Wang ◽  
Baoyu Yang ◽  
Haozhen Wang ◽  
Zhenzhong Ma ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Reactive Oxygen ◽  
Intracellular Reactive Oxygen Species ◽  
Control Group ◽  
Oxygen Species ◽  
Protein Levels ◽  
Cell Dysfunction ◽  
Induced Apoptosis

There is accumulating evidence showing that apoptosis induced by endoplasmic reticulum (ER) stress plays a key role in pancreatic β cell dysfunction and insulin resistance. 3β-Hydroxysteroid-Δ24 Reductase (DHCR24) is a multifunctional enzyme located in the endoplasmic reticulum (ER), which has been previously shown to protect neuronal cells from ER stress-induced apoptosis. However, the role of DHCR24 in type 2 diabetes is only incompletely understood so far. In the present study, we induced ER stress by tunicamycin (TM) treatment and showed that infection of MIN6 cells with Ad-DHCR24-myc rendered these cells resistant to caspase-3-mediated apoptosis induced by TM, while cells transfected with siRNAs targeting DHCR24 were more sensitive to TM. Western blot analysis showed that TM treatment induced upregulation of Bip protein levels in both cells infected with Ad-LacZ (the control group) and Ad-DHCR24-myc, indicating substantial ER stress. Cells infected with Ad-LacZ exhibited a rapid and strong activation of ATF6 and p38, peaking at 3 h after TM exposure. Conversely, cells infected with Ad-DHCR24-myc showed a higher and more sustained activation of ATF6 and Bip than control cells. DHCR24 overexpression also inhibited the generation of intracellular reactive oxygen species (ROS) induced by ER stress and protected cells from apoptosis caused by treatment with both cholesterol and hydrogen peroxide. In summary, these data demonstrate, for the first time, that DHCR24 protects pancreatic β cells from apoptosis induced by ER stress.

scholarly journals Endoplasmic reticulum (ER) stress–induced reactive oxygen species (ROS) are detrimental for the fitness of a thioredoxin reductase mutant

2018 ◽  
Vol 293 (31) ◽  
pp. 11984-11995 ◽  
Author(s):  
Paraskevi Kritsiligkou ◽  
Jonathan D. Rand ◽  
Alan J. Weids ◽  
Ximeng Wang ◽  
Chris J. Kershaw ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Thioredoxin Reductase ◽  
Reactive Oxygen ◽  
Oxygen Species

scholarly journals ATF4-Dependent NRF2 Transcriptional Regulation Promotes Antioxidant Protection during Endoplasmic Reticulum Stress

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 569 ◽  
Author(s):  
Carmen Sarcinelli ◽  
Helena Dragic ◽  
Marie Piecyk ◽  
Virginie Barbet ◽  
Cédric Duret ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Reactive Oxygen ◽  
Related Factor ◽  
Alternative Mechanism ◽  
Oxygen Species ◽  
Activating Transcription Factor 4 ◽  
Nrf2 Activation ◽  
Activating Transcription Factor

Endoplasmic reticulum (ER) stress generates reactive oxygen species (ROS) that induce apoptosis if left unabated. To limit oxidative insults, the ER stress PKR-like endoplasmic reticulum Kinase (PERK) has been reported to phosphorylate and activate nuclear factor erythroid 2-related factor 2 (NRF2). Here, we uncover an alternative mechanism for PERK-mediated NRF2 regulation in human cells that does not require direct phosphorylation. We show that the activation of the PERK pathway rapidly stimulates the expression of NRF2 through activating transcription factor 4 (ATF4). In addition, NRF2 activation is late and largely driven by reactive oxygen species (ROS) generated during late protein synthesis recovery, contributing to protecting against cell death. Thus, PERK-mediated NRF2 activation encompasses a PERK-ATF4-dependent control of NRF2 expression that contributes to the NRF2 protective response engaged during ER stress-induced ROS production.

scholarly journals Proteasome Inhibitor PS-341 Induces Apoptosis through Induction of Endoplasmic Reticulum Stress-Reactive Oxygen Species in Head and Neck Squamous Cell Carcinoma Cells

2004 ◽  
Vol 24 (22) ◽  
pp. 9695-9704 ◽  
Author(s):  
Andrew Fribley ◽  
Qinghua Zeng ◽  
Cun-Yu Wang
Keyword(s):  
Reactive Oxygen Species ◽  
Squamous Cell Carcinoma ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Reactive Oxygen ◽  
Neck Squamous Cell Carcinoma ◽  
Oxygen Species

ABSTRACT PS-341, also known as Velcade or Bortezomib, represents a new class of anticancer drugs which has been shown to potently inhibit the growth and/or progression of human cancers, including head and neck squamous cell carcinoma (HNSCC). Although it has been logically hypothesized that NF-κB is a major target of PS-341, the underlying mechanism by which PS-341 inhibits tumor cell growth is unclear. Here we found that PS-341 potently activated the caspase cascade and induced apoptosis in human HNSCC cell lines. Although PS-341 could inhibit NF-κB activation, the inhibition of NF-κB was not sufficient to initiate apoptosis in HNSCC cells. Using biochemical and microarray approaches, we found that proteasome inhibition by PS-341 induced endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in HNSCC cells. The inhibition of ROS significantly suppressed caspase activation and apoptosis induced by PS-341. Consistently, PS-341 could not induce the ER stress-ROS in PS-341-resistant HNSCC cells. Taken together, our results suggest that in addition to the abolishment of the prosurvival NF-κB, PS-341 might directly induce apoptosis by activating proapoptotic ER stress-ROS signaling cascades in HNSCC cells, providing novel insights into the PS-341-mediated antitumor activity.

scholarly journals Gadd153 Sensitizes Cells to Endoplasmic Reticulum Stress by Down-Regulating Bcl2 and Perturbing the Cellular Redox State

2001 ◽  
Vol 21 (4) ◽  
pp. 1249-1259 ◽  
Author(s):  
Karen D. McCullough ◽  
Jennifer L. Martindale ◽  
Lars-Oliver Klotz ◽  
Tak-Yee Aw ◽  
Nikki J. Holbrook
Keyword(s):  
Reactive Oxygen Species ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cell Lines ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Down Regulation ◽  
Gadd153 Expression ◽  
Bcl2 Expression

ABSTRACT gadd153, also known as chop, is a highly stress-inducible gene that is robustly expressed following disruption of homeostasis in the endoplasmic reticulum (ER) (so-called ER stress). Although all reported types of ER stress induce expression of Gadd153, its role in the stress response has remained largely undefined. Several studies have correlated Gadd153 expression with cell death, but a mechanistic link between Gadd153 and apoptosis has never been demonstrated. To address this issue we employed a cell model system in which Gadd153 is constitutively overexpressed, as well as two cell lines in which Gadd153 expression is conditional. In all cell lines, overexpression of Gadd153 sensitized cells to ER stress. Investigation of the mechanisms contributing to this effect revealed that elevated Gadd153 expression results in the down-regulation of Bcl2 expression, depletion of cellular glutathione, and exaggerated production of reactive oxygen species. Restoration of Bcl2 expression in Gadd153-overexpressing cells led to replenishment of glutathione and a reduction in levels of reactive oxygen species, and it protected cells from ER stress-induced cell death. We conclude that Gadd153 sensitizes cells to ER stress through mechanisms that involve down-regulation of Bcl2 and enhanced oxidant injury.

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