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Douglas J Cattie, Claire E Richardson, Kirthi C Reddy, Elan M Ness-Cohn, Rita Droste, Mary K Thompson, Wendy V Gilbert, Dennis H Kim
The translation initiation factor eIF3 is a multi-subunit protein complex that coordinates the assembly of the 43S pre-initiation complex in eukaryotes. Prior studies have demonstrated that not all subunits of eIF3 are essential for the initiation of translation, suggesting that some subunits may serve regulatory roles. Here, we show that loss-of-function mutations in the genes encoding the conserved eIF3k and eIF3l subunits of the translation initiation complex eIF3 result in a 40% extension in lifespan and enhanced resistance to endoplasmic reticulum (ER) stress in Caenorhabditis elegans...
September 2016: PLoS Genetics
Yuan Zhang, Ting Wang, Ke Yang, Ji Xu, Lijie Ren, Weiping Li, Wenlan Liu
Enolase-phosphatase 1 (ENOPH1), a newly discovered enzyme of the methionine salvage pathway, is emerging as an important molecule regulating stress responses. In this study, we investigated the role of ENOPH1 in blood brain barrier (BBB) injury under ischemic conditions. Focal cerebral ischemia induced ENOPH1 mRNA and protein expression in ischemic hemispheric microvessels in rats. Exposure of cultured brain microvascular endothelial cells (bEND3 cells) to oxygen-glucose deprivation (OGD) also induced ENOPH1 upregulation, which was accompanied by increased cell death and apoptosis reflected by increased 3-(4, 5-Dimethylthiazol-2-yl)-2, 5- diphenyltetrazolium bromide formation, lactate dehydrogenase release and TUNEL staining...
2016: Frontiers in Molecular Neuroscience
Jean-Christophe Simard, Isabelle Durocher, Denis Girard
Nowadays, silver nanoparticles (AgNP) are widely used in the medical field mainly for their antibacterial properties. Although some studies report a cytotoxic activity of the particles, the mechanisms involved in AgNP-induced cell death remain to be determined. Herein, we report that AgNP of 2 (AgNP2) and 15 nm (AgNP15) induce apoptosis in human MCF-7 and T-47D breast cancer cells. Treatment with AgNP2 and AgNP15 led to accumulation and aggregation of misfolded proteins causing an endoplasmic reticulum (ER) stress and activating the unfolded protein response (UPR)...
November 2016: Apoptosis: An International Journal on Programmed Cell Death
John M Hourihan, Lorenza E Moronetti Mazzeo, L Paulette Fernández-Cárdenas, T Keith Blackwell
Emerging evidence suggests that many proteins may be regulated through cysteine modification, but the extent and functions of this signaling remain largely unclear. The endoplasmic reticulum (ER) transmembrane protein IRE-1 maintains ER homeostasis by initiating the unfolded protein response (UPR(ER)). Here we show in C. elegans and human cells that IRE-1 has a distinct redox-regulated function in cytoplasmic homeostasis. Reactive oxygen species (ROS) that are generated at the ER or by mitochondria sulfenylate a cysteine within the IRE-1 kinase activation loop...
August 18, 2016: Molecular Cell
Amber C Howard, Jarod Rollins, Santina Snow, Sarah Castor, Aric N Rogers
Although certain methods of lowering and/or altering mRNA translation are associated with increased lifespan, the mechanisms underlying this effect remain largely unknown. We previously showed that the increased lifespan conferred by reducing expression of eukaryotic translation initiation factor 4G (eIF4G/IFG-1) enhances survival under starvation conditions while shifting protein expression toward factors involved with maintaining ER-dependent protein and lipid balance. In this study, we investigated changes in ER homeostasis and found that lower eIF4G/IFG-1 increased survival under conditions of ER stress...
August 18, 2016: Aging Cell
Ling He, Jing Yuan, Qingyun Xu, Ruixue Chen, Liguo Chen, Meixia Fang
BACKGROUND: In our previous study, we found significant differences in the mRNA and microRNA (miRNA) levels among hypertensive patients with different degrees of vascular endothelial cells damage. These differences were closely associated with endoplasmic reticulum stress (ERS)-related proteins. Moreover, compared to the control group, the expression of transcription factor activating factor 4 (ATF4) was also found to be significantly different in the hypertensive patients with different degrees of vascular endothelial cells damage groups...
2016: PloS One
K L Dias-Teixeira, R M Pereira, J S Silva, N Fasel, B H Aktas, U G Lopes
The integrated endoplasmic reticulum stress response (IERSR) is an evolutionarily conserved adaptive mechanism that ensures endoplasmic reticulum (ER) homeostasis and cellular survival in the presence of stress including nutrient deprivation, hypoxia, and imbalance of Ca(+) homeostasis, toxins, and microbial infection. Three transmembrane proteins regulate integrated signaling pathways that comprise the IERSR, namely, IRE-1 that activates XBP-1, the pancreatic ER kinase (PERK) that phosphorylates the eukaryotic translation initiation factor 2 and transcription factor 6 (ATF6)...
2016: Frontiers in Immunology
Kensuke Miyake, Takuma Shibata, Umeharu Ohto, Toshiyuki Shimizu
Nucleic acid (NA) is continuously degraded in lysosomes, cytoplasm, and nucleus. NA degradation has a key role in preventing hazardous activation of NA sensors. DNA degradation by lysosomal and cytoplasmic DNases prevents homeostatic activation of cytoplasmic DNA sensing pathways. Crude NA, however, is not sufficient for stimulating NA sensors. mRNAs and rRNAs need to be processed by inositol-requiring enzyme 1 (IRE-1) or RNase L before stimulating cytoplasmic RNA sensors. Activation of cytoplasmic RNA sensors by processed RNAs is tightly controlled by their degradation through the machineries, such as RNA editing, by adenosine (A) deaminases that act on RNA 1 (ADAR1) and the RNA exosome...
June 22, 2016: Journal of Leukocyte Biology
Antoine E Roux, Kelley Langhans, Walter Huynh, Cynthia Kenyon
Cells can enter quiescent states in which cell cycling and growth are suspended. We find that during a long developmental arrest (quiescence) induced by starvation, newly hatched C. elegans acquire features associated with impaired proteostasis and aging: mitochondrial fission, ROS production, protein aggregation, decreased proteotoxic-stress resistance, and at the organismal level, decline of mobility and high mortality. All signs of aging but one, the presence of protein aggregates, were reversed upon return to development induced by feeding...
June 14, 2016: Cell Metabolism
Fu-Shun Yu, Meng-Liang Lin, Shu-Chun Hsu, Chien-Chih Yu, Yi-Ping Huang, Yueh-Hsiung Kuo, Jing-Gung Chung
4-Hydroxybutenolide (K87), a synthetic compound from furfuryl alcohol via photooxidation, was used to investigate whether it can inhibit mobility, migration and invasion of SCC-4 human oral cancer cells in vitro. Cell viability was measured by flow cytometric assay, the enzymatic activities of MMP-2/9 were assayed by gelatin zymography analysis, the protein levels were assayed by western blotting, confocal laser microscopy and EMSA assay, and the gene expression of MMP-2/-7, FAK and ROCK1 mRNA were assayed by PCR...
August 2016: International Journal of Oncology
Graeme W Carlile, Renaud Robert, Elizabeth Matthes, Qi Yang, Roberto Solari, Richard Hatley, Colin M Edge, John W Hanrahan, Raymond Andersen, David Y Thomas, Véronique Birault
Cystic fibrosis (CF) is a major lethal genetic disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR). This encodes a chloride ion channel on the apical surface of epithelial cells. The most common mutation in CFTR (F508del-CFTR) generates a protein that is misfolded and retained in the endoplasmic reticulum. Identifying small molecules that correct this CFTR trafficking defect is a promising approach in CF therapy. However, to date only modest efficacy has been reported for correctors in clinical trials...
August 2016: Molecular Pharmacology
Benedict Seo, Dawn E Coates, Gregory J Seymour, Alison M Rich
OBJECTIVE: To examine the expression of unfolded protein response (UPR) genes, a set of genes that are activated to assist in protein trafficking and cellular homeostasis when endoplasmic reticulum (ER) stress occurs, in inflamed and uninflamed periodontal tissues, with or without Russell bodies (RB). RB are a histologically apparent extension of the ER that represents an accumulation of abnormal proteins that cannot be secreted or degraded and may serve as a marker of ER stress. DESIGN: Periodontal tissue specimens were collected and categorised histologically based on the presence of inflammation and the quantity of RB...
September 2016: Archives of Oral Biology
Xiaomin Yao, Yue Li, Xiaoyan Cheng, Hongwei Li
Endoplasmic reticulum (ER) stress is involved in the development of several liver diseases and tumors. This study investigated the underlying mechanisms of α-naphthyl isothiocyanate (ANIT)-induced liver injury with cholestasis in mice and found ER stress contributes to the injury. All animals were randomly divided into three groups. In the ANIT-intoxicated group, mice were intragastrically given 100mg/kg ANIT (dissolved in corn oil), while the other groups received an equal volume of vehicle as control. After 24 and 48h of ANIT administration, blood samples and liver tissues of all animals were collected for serum biochemistry and hepatic histopathological examinations to evaluate liver injuries with cholestasis...
June 2016: Pathology, Research and Practice
Aditi Banerjee, Hafiz Ahmed, Peixin Yang, Steven J Czinn, Thomas G Blanchard
The plant metabolite andrographolide induces cell cycle arrest and apoptosis in cancer cells. The mechanism(s) by which andrographolide induces apoptosis however, have not been elucidated. The present study was performed to determine the molecular events that promote apoptosis in andrographolide treated cells using T84, HCT116 and COLO 205 colon cancer cell lines. Andrographolide was determined to limit colony formation and Ki67 expression, alter nuclear morphology, increase cytoplasmic histone-associated-DNA-fragments, and increase cleaved caspase-3 levels...
May 5, 2016: Oncotarget
Ryan G Snodgrass, Shurong Huang, Dmitry Namgaladze, Ola Jandali, Tiffany Shao, Spandana Sama, Bernhard Brüne, Daniel H Hwang
Palmitic acid (C16:0) and TLR2 ligand induce, but docosahexaenoic acid (DHA) inhibits monocyte activation. C16:0 and TLR2 or TLR4 ligand induce certain ER stress markers; thus, we determined whether ER stress induced by these agonists is sufficient to induce monocyte activation, and whether the ER stress is inhibited by DHA which is known to inhibit C16:0- or ligand-induced TLR activation. Monocyte activation and ER stress were assessed by TLR/inflammasome-induced IL-1β production, and phosphorylation of IRE-1 and eIF2 and expression of CHOP, respectively in THP-1 cells...
June 2016: Journal of Nutritional Biochemistry
Xiaolei Li, Yu Sun, Hui Chen, Gengyao Zhu, Yuan Liang, Qiang Wang, Jingcheng Wang, Lianqi Yan
Hydroxycamptothecin (HCPT) has been proven to prevent intraarticular scar adhesion, but the mechanism is still unclear. ER stress is known to participate in many diseases, and the IRE-1 signal pathway has been reported in fibrotic diseases. The aim of this study was to illustrate the mechanism of HCPT-induced apoptosis in fibroblasts and the prevention of intraarticular scar adhesion. The effects of HCPT on fibroblasts were determined by CCK-8 assay, Hoechst staining and Western blot. The effect of HCPT on intraarticular scar adhesion was detected by macroscopic evaluation, hydroxyproline content, histological evaluation, fibroblast counting and immunohistochemical analysis...
June 15, 2016: European Journal of Pharmacology
Xiaole Li, Jia Li, Lulu Wang, Aiyun Li, Zhixia Qiu, Lian-Wen Qi, Junping Kou, Kang Liu, Baolin Liu, Fang Huang
BACKGROUND AND PURPOSE: Hypoxic activation of hypoxia-inducible factor 1α (HIF-1α) and fibrosis in adipose tissue contribute to adipose dysfunction. This study was designed to investigate the effects of metformin and resveratrol on the regulation of HIF-1α and fibrosis in hypoxic adipose tissue. EXPERIMENTAL APPROACH: Mice were fed a high-fat diet to induce hypoxia and fibrosis in adipose tissue; adipose tissue incubated in vitro in 1% O2 showed a similar change...
June 2016: British Journal of Pharmacology
Dorothé Jenni Eisermann, Uwe Wenzel, Elena Fitzenberger
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes an imbalance of proteostasis and is related to many pathological conditions. In answer to this ER stress cells activate a network of three integrated signaling pathways consolidated as the unfolded protein response of the ER (UPR(ER)), which is also present in the stress-sensitive Caenorhabditis elegans mutant mev-1. Whereas inhibition of one of those pathways by RNA-interference (RNAi) versus xbp-1 results in reduced survival of mev-1 nematodes under heat stress, additional knockdown of the xbp-1 splicing activator ire-1 results in a PEK-1-dependent hormetic response...
May 13, 2016: Biochemical and Biophysical Research Communications
Scott J Bultman, Darcy Wood Holley, Gustaaf G de Ridder, Salvatore V Pizzo, Tatiana N Sidorova, Katherine T Murray, Brian C Jensen, Zhongjing Wang, Ariana Bevilacqua, Xin Chen, Megan T Quintana, Manasi Tannu, Gary B Rosson, Kumar Pandya, Monte S Willis
There has been an increasing recognition that mitochondrial perturbations play a central role in human heart failure. Mitochondrial networks, whose function is to maintain the regulation of mitochondrial biogenesis, autophagy ('mitophagy') and mitochondrial fusion/fission, are new potential therapeutic targets. Yet our understanding of the molecular underpinning of these processes is just emerging. We recently identified a role of the SWI/SNF ATP-dependent chromatin remodeling complexes in the metabolic homeostasis of the adult cardiomyocyte using cardiomyocyte-specific and inducible deletion of the SWI/SNF ATPases BRG1 and BRM in adult mice (Brg1/Brm double mutant mice)...
May 2016: Cardiovascular Pathology: the Official Journal of the Society for Cardiovascular Pathology
Yu-Feng Song, Chao Huang, Xi Shi, Ya-Xiong Pan, Xu Liu, Zhi Luo
The present study was conducted to investigate the effect of Cu exposure on endoplasmic reticulum (ER) stress and Ca(2+) homeostasis, and also explore the underlying mechanism of the ER stress and Ca(2+) homeostasis in the Cu-induced change of hepatic lipid metabolism in javelin goby Synechogobius hasta. To this end, four experiments were conducted. In experiment 1, the full-length cDNA sequences of two ER molecular chaperones [glucose-regulated protein 78 (GRP78) and calreticulin (CRT)] and three ER stress sensors [PKR-like ER kinase (PERK), inositol requiring enzyme (IRE)-1α, and activating transcription factor (ATF)-6α] cDNAs were firstly characterized from S...
June 2016: Aquatic Toxicology
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