scholarly journals Effect of Endoplasmic Reticulum Stress on Human Trophoblast Cells: Survival Triggering or Catastrophe Resulting in Death

2021 ◽  
Author(s):  
Gurur Garip ◽  
Berrin Ozdil ◽  
Duygu Calik-Kocaturk ◽  
Fatih Oltulu ◽  
Fatma Zuhal Eroglu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Calcium Homeostasis ◽  
Cell Dynamics ◽  
Human Trophoblast ◽  
Endometrial Cells ◽  
Cell Death Pathways ◽  
Stress Studies

ABSTRACTAlthough in vitro endoplasmic reticulum (ER) stress studies have been carried out using Tunicamycin in human trophoblast cell lines in recent years, the effect of calcium homeostasis impaired by the effect of Thapsigargin on cell survival - death pathways have not been clearly demonstrated.Here, the effects of ER stress and impaired calcium homeostasis on cell death pathways such as apoptosis and autophagy in 2-dimensional and 3-dimensional cell cultures were investigated using the HTR8 / SVneo cell line representing human trophoectoderm cells and the ER stressor Thapsigargin. By using Real Time PCR, gene and immunofluorescence analyzes were studied at the protein level.In this study, it has been established that the Thapsigargin creates ER stress by increasing the level of GRP78 gene and protein in 2 and 3 dimensions of human trophoectoderm cells and that cells show different characterization properties in 2 and 3 dimensions. It has been determined that while it moves in the direction of EIF2A and IRE1A mechanisms in 2 dimensions, it proceeds in the direction of EIF2A and ATF6 mechanisms in 3 dimensions and creates different responses in survival and programmed cell death mechanisms such as apoptosis and autophagy.With forthcoming studies, it is thought that the effects of Thapsigargin on the intrinsic pathway of apoptosis and the linkage of the autophagy mechanism, the examination of the survival-death pathways in the co-culture model with endometrial cells, therapeutic target molecules that will contribute to the elucidation of intracellular cell dynamics may increase the success of implantation.

scholarly journals A Novel Transcription Factor, ERD15 (Early Responsive to Dehydration 15), Connects Endoplasmic Reticulum Stress with an Osmotic Stress-induced Cell Death Signal

2011 ◽  
Vol 286 (22) ◽  
pp. 20020-20030 ◽  
Author(s):  
Murilo S. Alves ◽  
Pedro A. B. Reis ◽  
Silvana P. Dadalto ◽  
Jerusa A. Q. A. Faria ◽  
Elizabeth P. B. Fontes ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Osmotic Stress ◽  
Er Stress ◽  
Unfolded Protein ◽  
Eukaryotic Organisms ◽  
Protein Response

As in all other eukaryotic organisms, endoplasmic reticulum (ER) stress triggers the evolutionarily conserved unfolded protein response in soybean, but it also communicates with other adaptive signaling responses, such as osmotic stress-induced and ER stress-induced programmed cell death. These two signaling pathways converge at the level of gene transcription to activate an integrated cascade that is mediated by N-rich proteins (NRPs). Here, we describe a novel transcription factor, GmERD15 (Glycine max Early Responsive to Dehydration 15), which is induced by ER stress and osmotic stress to activate the expression of NRP genes. GmERD15 was isolated because of its capacity to stably associate with the NRP-B promoter in yeast. It specifically binds to a 187-bp fragment of the NRP-B promoter in vitro and activates the transcription of a reporter gene in yeast. Furthermore, GmERD15 was found in both the cytoplasm and the nucleus, and a ChIP assay revealed that it binds to the NRP-B promoter in vivo. Expression of GmERD15 in soybean protoplasts activated the NRP-B promoter and induced expression of the NRP-B gene. Collectively, these results support the interpretation that GmERD15 functions as an upstream component of stress-induced NRP-B-mediated signaling to connect stress in the ER to an osmotic stress-induced cell death signal.

scholarly journals Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

2007 ◽  
Vol 193 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Shin Tsunekawa ◽  
Naoki Yamamoto ◽  
Katsura Tsukamoto ◽  
Yuji Itoh ◽  
Yukiko Kaneko ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Islet Cells ◽  
Binding Protein ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic β-cells against their cell death. In in vivo experiments, we used β-cell-specific calmodulin-overexpressing mice where massive apoptosis takes place in their β-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1α, X-box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in β-cell-specific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess of ER stress occurs in the transgenic β-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.

scholarly journals Lactogens reduce endoplasmic reticulum stress-induced rodent and human β-cell death and diabetes incidence in Akita mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Rosemary Li ◽  
Nagesha Guthalu Kondegowda ◽  
Joanna Filipowska ◽  
Rollie F. Hampton ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Placental Lactogen ◽  
Diabetes Incidence ◽  
Β Cells ◽  
Β Cell ◽  
Akita Mice ◽  
Stress Pathway

Diabetes occurs due to a loss of functional β-cells, resulting from β-cell death and dysfunction. Lactogens protect rodent and human β-cells <i>in vitro</i> and<i> in vivo</i> against triggers of β-cell cytotoxicity relevant to diabetes, many of which converge onto a common pathway, endoplasmic reticulum (ER) stress. However, whether lactogens modulate the ER stress pathway is unknown. This study examines if lactogens can protect β-cells against ER stress and mitigate diabetes incidence in Akita mice, a rodent model of ER stress-induced diabetes, akin to neonatal diabetes in humans. We show that lactogens protect INS1 cells, primary rodent and human β-cells <i>in vitro</i> against two distinct ER stressors, tunicamycin and thapsigargin, through activation of the JAK2/STAT5 pathway. Lactogens mitigate expression of pro-apoptotic molecules in the ER stress pathway that are induced by chronic ER stress in INS1 cells and rodent islets. Transgenic expression of placental lactogen in β-cells of Akita mice drastically reduces the severe hyperglycemia, diabetes incidence, hypoinsulinemia, β-cell death, and loss of β-cell mass observed in Akita littermates. These are the first studies in any cell type demonstrating lactogens modulate the ER stress pathway, causing enhanced β-cell survival and reduced diabetes incidence in the face of chronic ER stress.

scholarly journals The Cardiotoxicity Induced by Arsenic Trioxide is Alleviated by Salvianolic Acid A via Maintaining Calcium Homeostasis and Inhibiting Endoplasmic Reticulum Stress

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 543 ◽  
Author(s):  
Ruiying Wang ◽  
Jingyi Zhang ◽  
Shan Wang ◽  
Min Wang ◽  
Tianyuan Ye ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Arsenic Trioxide ◽  
Calcium Homeostasis ◽  
In Vitro Study ◽  
Protective Effects ◽  
Salvianolic Acid ◽  
Salvianolic Acid A

Arsenic trioxide (ATO) has been verified as a breakthrough with respect to the management of acute promyelocytic leukemia (APL) in recent decades but associated with some serious adverse phenomena, particularly cardiac functional abnormalities. Salvianolic acid A (Sal A) is a major effective component in treating ATO-induced cardiotoxicity. Therefore, the objective of our study was to assess whether Sal A had protective effects by the regulation of calcium homeostasis and endoplasmic reticulum (ER) stress. For the in vivo study, BALB/c mice were treated with ATO and/or Sal A via daily tail vein injections for two weeks. For the in vitro study, we detected the effects of ATO and/or Sal A in real time using adult rat ventricular myocytes (ARVMs) and an IonOptix MyoCam system. Our results showed that Sal A pretreatment alleviated cardiac dysfunction and Ca2+ overload induced by ATO in vivo and vitro. Moreover, Sal A increased sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) activity and expression, alleviated [Ca2+]ER depletion, and decreased ER stress-related protein expression. Sal A protects the heart from ATO-induced injury and its administration correlates with the modulation of SERCA, the recovery of Ca2+ homeostasis, and the down-regulation of ER stress-mediated apoptosis.

scholarly journals Lactogens reduce endoplasmic reticulum stress-induced rodent and human β-cell death and diabetes incidence in Akita mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Rosemary Li ◽  
Nagesha Guthalu Kondegowda ◽  
Joanna Filipowska ◽  
Rollie F. Hampton ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Placental Lactogen ◽  
Diabetes Incidence ◽  
Β Cells ◽  
Β Cell ◽  
Akita Mice ◽  
Stress Pathway

Diabetes occurs due to a loss of functional β-cells, resulting from β-cell death and dysfunction. Lactogens protect rodent and human β-cells <i>in vitro</i> and<i> in vivo</i> against triggers of β-cell cytotoxicity relevant to diabetes, many of which converge onto a common pathway, endoplasmic reticulum (ER) stress. However, whether lactogens modulate the ER stress pathway is unknown. This study examines if lactogens can protect β-cells against ER stress and mitigate diabetes incidence in Akita mice, a rodent model of ER stress-induced diabetes, akin to neonatal diabetes in humans. We show that lactogens protect INS1 cells, primary rodent and human β-cells <i>in vitro</i> against two distinct ER stressors, tunicamycin and thapsigargin, through activation of the JAK2/STAT5 pathway. Lactogens mitigate expression of pro-apoptotic molecules in the ER stress pathway that are induced by chronic ER stress in INS1 cells and rodent islets. Transgenic expression of placental lactogen in β-cells of Akita mice drastically reduces the severe hyperglycemia, diabetes incidence, hypoinsulinemia, β-cell death, and loss of β-cell mass observed in Akita littermates. These are the first studies in any cell type demonstrating lactogens modulate the ER stress pathway, causing enhanced β-cell survival and reduced diabetes incidence in the face of chronic ER stress.

Xanthohumol Induces Apoptosis in B-CLL In Vitro by Sustained Endoplasmic Reticulum Stress and Inhibition of NFκ-B.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4979-4979
Author(s):  
Sofie Lust ◽  
Barbara Vanhoecke ◽  
Mireille Van Gele ◽  
Mary Kaileh ◽  
Jerina Boelens ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Caspase 3 ◽  
Protein Translation ◽  
Mrna Levels ◽  
Induced Apoptosis ◽  
Sustained Phosphorylation

Abstract Introduction Correct folding of new proteins is supervised in the endoplasic reticulum (ER) unfolded protein response (UPR). Misfolded proteins recruit the chaperone Grp78 that is thereby released from the transcription factors ATF6, IRE-1 leading to compensatory increase in Grp78, and PERK, leading to phosphorylation of eIF2α and block of further protein translation. UPR overload leads to ER stress and cell death. Targeting the endoplasmic reticulum (ER) is a new strategy explored in B-CLL. The hop-derived chalcone Xanthohumol (X) has been characterized as a ‘broad-spectrum’ cancer chemopreventive agent. Recently, we demonstrated that X induces dose- and time-dependent cell death of MCF7/6 breast cancer cells accompanied by ER stress. X induces apoptosis and cleavage of poly(ADP)-ribose-polymerase (PARP) in B-CLL in vitro. The present study investigates the branches of the UPR in relation to X induced apoptosis of B-CLL cells. Materials and methods. Lymphocytes were isolated by Lymphoprep from 15 patients with B-CLL after informed consent. CD19 positive cells were selected by EasySep positive selection kit. Apoptosis was assessed by flow-cytometry (AnnexinV-PI). Western Blotting was used for Grp78, ATF6, XBP1, phospho-eIF2a, eIF2a, ATF4, CHOP, phospho-IKK, IKK, PARP, caspase-9, -8, -7, -4, cleaved caspase-3, mcl-1, bcl-xL, bax, bak, and bid. NF-kB activity was assessed by EMSA. Quantitative RT-PCR was performed to analyze Grp78 mRNA levels. Bcl-2 protein level was detected by flow cytometry and reactive oxygen species (ROS) by fluorescence microscopy. Results and conclusion X induced an upregulation of Grp78 mRNA levels which was not translated in an increase in protein. X treatment stimulated a rapid and sustained phosphorylation of eIF2a, suggesting the involvement of PERK. In contrast, the ER-stress transducers ATF6 and IRE1 were not activated. X-induced ER stress was associated with strong induction of the pro-apoptotic protein CHOP and inhibition of the NF-kB pathway. Furthermore, the pro-apoptotic effect of X was accompanied by an accumulation of ROS, a downregulation of the anti-apoptotic proteins mcl-1, bcl-xL, bcl-2 and processing of caspase-3, -7 and -9.In conclusion, the chalcone X is capable of inducing cell death with down-regulation of bcl-2, mcl-1, bcl-xL, and activation of the caspase cascade. This is accompanied by ER-stress as evidenced by the upregulation of Grp78 mRNA levels, induction of a rapid and sustained phosphorylation of eIF2a, upregulation of CHOP, and inhibition of the NF-kB signaling.

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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