Altered estradiol-dependent cellular Ca2+ homeostasis and endoplasmic reticulum stress response in Premenstrual Dysphoric Disorder

AbstractPremenstrual Dysphoric Disorder (PMDD) is characterized by debilitating mood symptoms in the luteal phase of the menstrual cycle. Prior studies of affected women have implicated a differential response to ovarian steroids. However, the molecular basis of these patients’ differential response to hormone remains poorly understood. We performed transcriptomic analyses of lymphoblastoid cell lines (LCLs) derived from women with PMDD and asymptomatic controls cultured under untreated (steroid-free), estradiol-treated (E2), and progesterone-treated (P4) conditions. Weighted gene correlation network analysis (WGCNA) of transcriptomes identified four gene modules with significant diagnosis x hormone interactions, including one enriched for neuronal functions. Next, in a gene-level analysis comparing transcriptional response to hormone across diagnoses, a generalized linear model identified 1522 genes differentially responsive to E2 (E2-DRGs). Among the top 10 E2-DRGs was a physically interacting network (NUCB1, DST, GCC2, GOLGB1) involved in endoplasmic reticulum (ER)-Golgi function. qRT-PCR validation reproduced a diagnosis x E2 interaction (F(1,24)=7.01, p = 0.014) for NUCB1, a regulator of cellular Ca2+ and ER stress. Finally, we used a thapsigargin (Tg) challenge assay to test whether E2 induces differences in Ca2+ homeostasis and ER stress response in PMDD. PMDD LCLs had a 1.36-fold decrease in Tg-induced XBP1 splicing response compared to controls, and a 1.62-fold decreased response (p = 0.005), with a diagnosis x treatment interaction (F(3,33)=3.51, p = 0.026) in the E2-exposed condition. Altered hormone-dependent in cellular Ca2+ dynamics and ER stress may contribute to the pathophysiology of PMDD.

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Activation of endoplasmic reticulum stress response during the development of ischemic heart disease

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01378.2005 ◽

2006 ◽

Vol 291 (3) ◽

pp. H1411-H1420 ◽

Cited By ~ 157

Author(s):

Asim Azfer ◽

Jianli Niu ◽

Linda M. Rogers ◽

Frances M. Adamski ◽

Pappachan E. Kolattukudy

Keyword(s):

Endoplasmic Reticulum ◽

Heart Disease ◽

Stress Response ◽

Transgenic Mice ◽

Ischemic Heart Disease ◽

Er Stress ◽

Stress Proteins ◽

Gene Array ◽

Ischemic Heart ◽

Endoplasmic Reticulum Stress Response

Endoplasmic reticulum (ER) stress has been found to be associated with neurodegenerative diseases and diabetes mellitus. Whether ER stress is involved in the development of heart disease is not known. Cardiac-specific expression of monocyte chemoattractant protein-1 (MCP-1) in mice causes the development of ischemic heart disease. Here we report that microarray analysis of gene expression changes in the heart of these transgenic mice revealed that a cluster of ER stress-related genes was transcriptionally activated in the heart during the development of ischemic heart disease. The gene array results were verified by quantitative real-time PCR that showed highly elevated transcript levels of genes involved in unfolded protein response such as ER and cytoplasmic chaperones, oxidoreductases, protein disulfide isomerase (PDI) family, and ER-associated degradation system such as ubiquitin. Immunoblot analysis confirmed the expression of chaperones, PDI, and ubiquitin. Immunohistochemical analyses showed that ER stress proteins were associated mainly with the degenerating cardiomyocytes. A novel ubiquitin fold modifier (Ufm1) that has not been previously associated with ER stress and not found to be induced under any condition was also found to be upregulated in the hearts of MCP mice (transgenic mice that express MCP-1 specifically in the heart). The present results strongly suggest that activation of ER stress response is involved in the development of ischemic heart disease in this murine model.

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Endoplasmic reticulum stress response in the roadway for the effects of non-steroidal anti-inflammatory drugs

Endoplasmic Reticulum Stress in Diseases ◽

10.1515/ersc-2015-0001 ◽

2015 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Fernanda L.B. Mügge ◽

Aristóbolo M. Silva

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Stress Responses ◽

Endoplasmic Reticulum Stress Response ◽

The Road ◽

Er Stress Response ◽

Mediated Effects ◽

Inflammatory Drugs ◽

Anti Inflammatory

AbstractOver the past decade, a handful of evidence has been provided that nonsteroidal anti-inflammatory drugs (NSAIDs) display effects on the homeostasis of the endoplasmic reticulum (ER). Their uptake into cells will eventually lead to activation or inhibition of key molecules that mediate ER stress responses, raising not only a growing interest for a pharmacological target in ER stress responses but also important questions how the ER-stress mediated effects induced by NSAIDs could be therapeutically advantageous or not. We review here the toxicity effects and therapeutic applications of NSAIDs involving the three majors ER stress arms namely PERK, IRE1, and ATF6. First, we provide brief introduction on the well-established and characterized downstream events mediated by these ER stress players, followed by presentation of the NSAIDs compounds and mode of action, and finally their effects on ER stress response. NSAIDs present promising drug agents targeting the components of ER stress in different aspects of cancer and other diseases, but a better comprehension of the mechanisms underlying their benefits and harms will certainly pave the road for several diseases’ therapy.

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Nickel Enhances Zinc-Induced Neuronal Cell Death by Priming the Endoplasmic Reticulum Stress Response

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/9693726 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Ken-ichiro Tanaka ◽

Misato Kasai ◽

Mikako Shimoda ◽

Ayane Shimizu ◽

Maho Kubota ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Stress Response ◽

Trace Metals ◽

Er Stress ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Endoplasmic Reticulum Stress Response ◽

Dependent Manner ◽

Er Stress Response

Trace metals such as zinc (Zn), copper (Cu), and nickel (Ni) play important roles in various physiological functions such as immunity, cell division, and protein synthesis in a wide variety of species. However, excessive amounts of these trace metals cause disorders in various tissues of the central nervous system, respiratory system, and other vital organs. Our previous analysis focusing on neurotoxicity resulting from interactions between Zn and Cu revealed that Cu2+ markedly enhances Zn2+-induced neuronal cell death by activating oxidative stress and the endoplasmic reticulum (ER) stress response. However, neurotoxicity arising from interactions between zinc and metals other than copper has not been examined. Thus, in the current study, we examined the effect of Ni2+ on Zn2+-induced neurotoxicity. Initially, we found that nontoxic concentrations (0–60 μM) of Ni2+ enhance Zn2+-induced neurotoxicity in an immortalized hypothalamic neuronal cell line (GT1-7) in a dose-dependent manner. Next, we analyzed the mechanism enhancing neuronal cell death, focusing on the ER stress response. Our results revealed that Ni2+ treatment significantly primed the Zn2+-induced ER stress response, especially expression of the CCAAT-enhancer-binding protein homologous protein (CHOP). Finally, we examined the effect of carnosine (an endogenous peptide) on Ni2+/Zn2+-induced neurotoxicity and found that carnosine attenuated Ni2+/Zn2+-induced neuronal cell death and ER stress occurring before cell death. Based on our results, Ni2+ treatment significantly enhances Zn2+-induced neuronal cell death by priming the ER stress response. Thus, compounds that decrease the ER stress response, such as carnosine, may be beneficial for neurological diseases.

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Ccr4 Promotes Resolution of the Endoplasmic Reticulum Stress Response during Host Temperature Adaptation in Cryptococcus neoformans

Eukaryotic Cell ◽

10.1128/ec.00006-11 ◽

2011 ◽

Vol 10 (7) ◽

pp. 895-901 ◽

Cited By ~ 20

Author(s):

Virginia E. Havel ◽

Nathan K. Wool ◽

David Ayad ◽

Kurtis M. Downey ◽

Christabel F. Wilson ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Cryptococcus Neoformans ◽

Deep Infection ◽

Temperature Adaptation ◽

Endoplasmic Reticulum Stress Response ◽

Content Type ◽

Unfolded Protein ◽

Posttranscriptional Gene Regulation

ABSTRACT Adaptation to host temperature is a prerequisite for any pathogen capable of causing deep infection in humans. Our previous studies demonstrated that a Cryptococcus neoformans ccr4 Δ mutant lacking the major deadenylase involved in regulated mRNA decay was defective in host temperature adaptation and therefore virulence. In this study, the ccr4 Δ mutant was found to exhibit characteristics of chronic unfolded-protein response (UPR) engagement in both the gene expression profile and phenotype. We demonstrate that host temperature adaptation in C. neoformans is accompanied by transient induction of the endoplasmic reticulum (ER) stress response and that Ccr4-dependent posttranscriptional gene regulation contributes to resolution of ER stress during host temperature adaptation.

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Characterization and modulation of endoplasmic reticulum stress response target genes in Kluyveromyces marxianus to improve secretory expressions of heterologous proteins

Biotechnology for Biofuels ◽

10.1186/s13068-021-02086-7 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Tianfang Shi ◽

Jungang Zhou ◽

Aijuan Xue ◽

Hong Lu ◽

Yungang He ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Kluyveromyces Marxianus ◽

Target Genes ◽

Endoplasmic Reticulum Stress Response ◽

Cell Factory ◽

Heterologous Proteins ◽

Er Stress Response ◽

Response Target

Abstract Background Kluyveromyces marxianus is a promising cell factory for producing bioethanol and that raised a demand for a high yield of heterologous proteins in this species. Expressions of heterologous proteins usually lead to the accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER) and then cause ER stress. To cope with this problem, a group of ER stress response target genes (ESRTs) are induced, mainly through a signaling network called unfolded protein response (UPR). Characterization and modulation of ESRTs direct the optimization of heterologous expressions. However, ESRTs in K. marxianus have not been identified so far. Results In this study, we characterized the ER stress response in K. marxianus for the first time, by using two ER stress-inducing reagents, dithiothreitol (DTT) and tunicamycin (TM). Results showed that the Kar2–Ire1–Hac1 pathway of UPR is well conserved in K. marxianus. About 15% and 6% of genes were upregulated during treatment of DTT and TM, respectively. A total of 115 upregulated genes were characterized as ESRTs, among which 97 genes were identified as UPR target genes and 37 UPR target genes contained UPR elements in their promoters. Genes related to carbohydrate metabolic process and actin filament organization were identified as new types of UPR target genes. A total of 102 ESRTs were overexpressed separately in plasmids and their effects on productions of two different lignocellulolytic enzymes were systematically evaluated. Overexpressing genes involved in carbohydrate metabolism, including PDC1, PGK and VID28, overexpressing a chaperone gene CAJ1 or overexpressing a reductase gene MET13 substantially improved secretion expressions of heterologous proteins. Meanwhile, overexpressing a novel gene, KLMA_50479 (named ESR1), as well as overexpressing genes involved in ER-associated protein degradation (ERAD), including HRD3, USA1 andYET3, reduced the secretory expressions. ESR1 and the aforementioned ERAD genes were deleted from the genome. Resultant mutants, except the yet3Δ mutant, substantially improved secretions of three different heterologous proteins. During the fed-batch fermentation, extracellular activities of an endoxylanase and a glucanase in hrd3Δ cells improved by 43% and 28%, respectively, compared to those in wild-type cells. Conclusions Our results unveil the transcriptional scope of the ER stress response in K. marxianus and suggest efficient ways to improve productions of heterologous proteins by manipulating expressions of ESRTs.

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The Role of Endoplasmic Reticulum Stress Response in Pollen Development and Heat Stress Tolerance

Frontiers in Plant Science ◽

10.3389/fpls.2021.661062 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mohan B. Singh ◽

Neeta Lohani ◽

Prem L. Bhalla

Keyword(s):

Endoplasmic Reticulum ◽

Protein Folding ◽

Heat Stress ◽

Stress Response ◽

Er Stress ◽

Pollen Development ◽

Gene Knockout ◽

Stress Conditions ◽

Endoplasmic Reticulum Stress Response

Endoplasmic reticulum (ER) stress is defined by a protracted disruption in protein folding and accumulation of unfolded or misfolded proteins in the ER. This accumulation of unfolded proteins can result from excessive demands on the protein folding machinery triggered by environmental and cellular stresses such as nutrient deficiencies, oxidative stress, pathogens, and heat. The cell responds to ER stress by activating a protective pathway termed unfolded protein response (UPR), which comprises cellular mechanisms targeted to maintain cellular homeostasis by increasing the ER’s protein folding capacity. The UPR is especially significant for plants as being sessile requires them to adapt to multiple environmental stresses. While multiple stresses trigger the UPR at the vegetative stage, it appears to be active constitutively in the anthers of unstressed plants. Transcriptome analysis reveals significant upregulation of ER stress-related transcripts in diploid meiocytes and haploid microspores. Interestingly, several ER stress-related genes are specifically upregulated in the sperm cells. The analysis of gene knockout mutants in Arabidopsis has revealed that defects in ER stress response lead to the failure of normal pollen development and enhanced susceptibility of male gametophyte to heat stress conditions. In this mini-review, we provide an overview of the role of ER stress and UPR in pollen development and its protective roles in maintaining male fertility under heat stress conditions.

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Abstract 454: Endoplasmic Reticulum Stress Response in Pressure-Overloaded Ischemic-Reperfused Hearts

Hypertension ◽

10.1161/hyp.60.suppl_1.a454 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Mahmood Mozaffari ◽

Jun Yao Liu ◽

Babak Baban

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Stress Response ◽

Er Stress ◽

Inflammatory Cytokine ◽

Ischemia Reperfusion ◽

Pressure Overload ◽

Annexin V ◽

Endoplasmic Reticulum Stress Response ◽

Er Stress Response

An integral component of endoplasmic reticulum (ER) stress-induced apoptosis is expression of growth arrest- and DNA damage inducible protein 153 (GADD153); this protein is normally expressed in low levels but its expression markedly increases following sustained stress to the ER. GADD153 regulates both apoptosis and inflammatory response. We previously showed that pressure overload exacerbates myocardial ischemia reperfusion (IR) injury. In this study, we tested the hypothesis that pressure overload regulates ER stress response manifested as increased GADD153 expression thereby upregulating inflammatory cytokine production and contributing to worsening of myocardial IR injury. Accordingly, Langendorff-perfused rat hearts were subjected to global IR protocol with perfusion pressure set at 80 or 160 cmH 2 O; normoxic hearts served as controls. Compared to normoxia, an IR insult increased expressions of pro-inflammatory cytokine (interleukin (IL)-17) and GADD153 in association with increased cell death. In the ischemic-reperfused hearts, pressure overload a) increased expression of GADD153, b) reduced interleukin (IL)-10 but increased IL-17 and c) increased annexin V immunostaining as well as apoptotic and necrotic cell death. Collectively, the results suggest that pressure overload exacerbates cell death in the isolated ischemic-reperfused heart involving regulation of ER stress response and inflammation.

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The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00560-8 ◽

2021 ◽

Author(s):

Kashi Raj Bhattarai ◽

Thoufiqul Alam Riaz ◽

Hyung-Ryong Kim ◽

Han-Jung Chae

Keyword(s):

Endoplasmic Reticulum ◽

Protein Folding ◽

Stress Response ◽

Er Stress ◽

Protein Modification ◽

Endoplasmic Reticulum Stress Response ◽

Unfolded Protein ◽

Er Stress Response ◽

The Unfolded Protein Response ◽

Protein Response

AbstractThe endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes.

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Metformin prevents brain injury after cardiopulmonary resuscitation by inhibiting the endoplasmic reticulum stress response and activating AMPK-mediated autophagy

Scottish Medical Journal ◽

10.1177/0036933020961543 ◽

2020 ◽

pp. 003693302096154

Author(s):

Libo Chuan ◽

Lei Zhang ◽

Hao Fu ◽

Ying Yang ◽

Quanyu Wang ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Brain Injury ◽

Stress Response ◽

Cardiopulmonary Resuscitation ◽

Er Stress ◽

Neuroprotective Effect ◽

Inhibitory Effect ◽

Spontaneous Circulation ◽

Endoplasmic Reticulum Stress Response ◽

Er Stress Response

Background and aims The neurological damage caused by cardiac arrest (CA) can seriously affect quality of life. We investigated the effect of metformin pretreatment on brain injury and survival in a rat CA/cardiopulmonary resuscitation (CPR) model. Methods and results After 14 days of pretreatment with metformin, rats underwent 9 minutes of asphyxia CA/CPR. Survival was evaluated 7 days after restoration of spontaneous circulation; neurological deficit scale (NDS) score was evaluated at days 1, 3, and 7. Proteins related to the endoplasmic reticulum (ER) stress response and autophagy were measured using immunoblotting. Seven-day survival was significantly improved and NDS score was significantly improved in rats pretreated with metformin. Metformin enhanced AMPK-induced autophagy activation. AMPK and autophagy inhibitors removed the metformin neuroprotective effect. Although metformin inhibited the ER stress response, its inhibitory effect was weaker than 4-PBA. Conclusion In a CA/CPR rat model, 14-day pretreatment with metformin has a neuroprotective effect. This effect is closely related to the activation of AMPK-induced autophagy and inhibition of the ER stress response. Long-term use of metformin can reduce brain damage following CA/CPR.

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An Integrative Network Biology Approach to Evaluate the Role of Endoplasmic Reticulum Stress Response in Obese Type 2 Diabetes

ISRN Cell Biology ◽

10.5402/2012/278636 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9

Author(s):

Anup Mammen Oommen ◽

Usha Narayanan ◽

M. R. Jagannath

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Signaling Pathways ◽

Cell Function ◽

Network Biology ◽

Endoplasmic Reticulum Stress Response ◽

Cellular Processes ◽

Integrative Network

Extracellular/intracellular stimuli can influence eukaryotic cell function through organelles that regulate critical signaling pathways. The endoplasmic reticulum (ER), for example, impacts cellular processes including protein synthesis, folding and secretion; amino acid transport; apoptosis; cell proliferation; lipid synthesis across major cell types in response to stimuli such as accumulation of misfolded proteins and glucose deprivation. Dysregulated signaling pathways underlying the ER-mediated processes mentioned above have been linked to disease conditions such as diabetes, obesity, and Alzheimer's disease. Our current understanding, however, lacks a detailed network view that integrates organelle-mediated pathway dysregulation with cellular processes and disease pathogenesis. In this report, we introduce an integrative network biology approach that combines ER-stress response pathways with basic cellular processes using data from peer-reviewed literature. As an example, we apply our systems biology approach to study the role of ER stress in pancreatic β cells under obese diabetic conditions, generate testable hypotheses, and provide novel insights into β-cell pathogenesis.

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