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Tian Xia, Song Tong, Kai Fan, Wei Zhai, Bin Fang, Si-Hua Wang, Jian-Jun Wang
X-box binding protein 1 (XBP1) was found to be overexpressed in glioma and breast cancers, suggesting that XBP1 might act as a potent oncogenic protein. However, the clinical significance and biological role of XBP1 in esophageal squamous cell carcinoma (ESCC) remain unknown. In this study, we report that XBP1 is markedly overexpressed in ESCC cell lines and clinical samples. XBP1 overexpression was significantly correlated with ESCC tumor stage, lymph node metastasis and poor outcome. A functional study demonstrated that XBP1 promoted cell growth and cell invasion both in vitro and in vivo...
2016: American Journal of Cancer Research
Chengjian Mao, Mara Livezey, Ji Eun Kim, David J Shapiro
Outgrowth of metastases expressing ERα mutations Y537S and D538G is common after endocrine therapy for estrogen receptor α (ERα) positive breast cancer. The effect of replacing wild type ERα in breast cancer cells with these mutations was unclear. We used the CRISPR-Cas9 genome editing system and homology directed repair to isolate and characterize 14 T47D cell lines in which ERαY537S or ERαD538G replace one or both wild-type ERα genes. In 2-dimensional, and in quantitative anchorage-independent 3-dimensional cell culture, ERαY537S and ERαD538G cells exhibited estrogen-independent growth...
October 7, 2016: Scientific Reports
Jacey H Ma, Joshua J Wang, Junhua Li, Bruce A Pfeffer, Yiming Zhong, Sarah X Zhang
Purpose: The retinal pigment epithelium (RPE) tight junctions play a pivotal role in maintaining the homeostatic environment of the neural retina. Herein, we investigated the role of X-box binding protein 1 (XBP1), an endoplasmic reticulum (ER) stress-responsive transcription factor, in regulation of RPE tight junctions. Methods: Human RPE cell line (ARPE-19) and primary primate RPE cells were used for in vitro experiments and RPE-specific XBP1 knockout (KO) mice were used for in vivo study...
October 1, 2016: Investigative Ophthalmology & Visual Science
Luisa Pozzo, Andrea Vornoli, Ilaria Coppola, Clara Maria Della Croce, Lucia Giorgetti, Pier Giovanni Gervasi, Vincenzo Longo
AIMS: The aim of the study was to evaluate lipid, cholesterol and glucose metabolism in a novel rat model of non-alcoholic fatty liver disease (NAFLD). MAIN METHODS: Rats (Wistar) were fed high fat/cholesterol diet (HFD) and a single low dose (35mg/kg) of streptozotocin (STZ). Collagen and glycogen content, oxidative stress and glucokinase activity were measured using biochemical assays. Other metabolic pathway were assessed by qRT-PCR. KEY FINDINGS: HFD/STZ treated rats, compared to control ones, showed an increase in expression of biomarkers of inflammation (TNFα, IL6), fibrosis (TGFβ), mitochondrial stress (UCP2) and oxidative stress (GSH and carbonylated proteins) but not of ER stress (CHOP, XBP1)...
September 28, 2016: Life Sciences
Christian von Loeffelholz, Stephanie Döcke, Johan F Lock, Steffi Lieske, Paul Horn, Jennifer Kriebel, Simone Wahl, Paula Singmann, Tonia de Las Heras Gala, Harald Grallert, Nathaniel Raschzok, Igor M Sauer, Regine Heller, Gerhard Jahreis, Ralf A Claus, Michael Bauer, Martin Stockmann, Andreas L Birkenfeld, Andreas F H Pfeiffer
BACKGROUND & AIMS: Molecular adaptations in human nonalcoholic fatty liver disease (NAFLD) are incompletely understood. This study investigated main gene categories related to hepatic de novo lipogenesis (DNL) and lipid oxidation capacity. METHODS: Liver specimens of 48 subjects were histologically classified according to steatosis severity. In depth analyses were performed using real-time polymerase chain reaction (RT-PCR), immunoblotting and immunohistochemistry...
September 30, 2016: Hepatology Research: the Official Journal of the Japan Society of Hepatology
Kai Liao, Jing Yan, Songlin Li, Tianjiao Wang, Wei Xu, Kangsen Mai, Qinghui Ai
The unfolded protein response (UPR) is a mechanism to cope with perturbed endoplasmic reticulum (ER) functions or accumulation of unfolded protein in the ER in eukaryotic cells. Furthermore, the UPR also participates in a number of physiological and pathological processes, such as nutrient sensing, lipid synthesis, and inflammatory response. In this study, four UPR-related genes (GRP78/BiP, ATF6α, XBP1 and CHO) were isolated characterized from large yellow croaker (Larimichthys crocea), and their expression in response to dietary lipid sources (various fatty acids) such as fish oil (FO), palmic acid (PA), olive oil (OO), sunflower oil (SO), and perilla oil (PO), were examined following feeding...
September 21, 2016: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
Yuan Lu, Jian-Ya Xu, Xiao-Hua Zhang, Xia Zhao
ETHNOPHARMACOLOGICAL RELEVANCE: In recent years, asthma has increased dramatically in prevalence with a considerable economic burden all over the world. Long-term remission should be regarded as the promising and meaningful therapeutic goal in asthma management. However, the precise definition criteria and rational therapies for asthma remission have not been well-established. In academia, there is a consensus that even in those who develop asymptomatic remission of asthma, persistent airway inflammation is ubiquitous...
November 4, 2016: Journal of Ethnopharmacology
David A Hess, Katherine M Strelau, Anju Karki, Mei Jiang, Ana C Azevedo-Pouly, Ann-Hwee Lee, Tye G Deering, Chinh Q Hoang, Raymond J MacDonald, Stephen F Konieczny
Transcriptional networks that govern secretory cell specialization, including instructing cells to develop a unique cytoarchitecture, amass extensive protein synthesis machinery, and be embodied to respond to endoplasmic reticulum (ER) stress, remain largely uncharacterized. In this study, we discovered that the secretory cell transcription factor MIST1 (Bhlha15), previously shown to be essential for cytoskeletal organization and secretory activity, also functions as a potent ER stress-inducible transcriptional regulator...
September 19, 2016: Molecular and Cellular Biology
Hang Nguyen, Bruce D Uhal
Recent work from this laboratory showed that endoplasmic reticulum (ER) stress-induced apoptosis of alveolar epithelial cells (AECs) is regulated by the autocrine angiotensin (ANG)II/ANG1-7 system. The proteasome inhibitor MG132 or surfactant protein C (SP-C) BRICHOS domain mutation G100S induced apoptosis in human AECs by activating the pro-apoptotic cathepsin D and reducing anti-apoptotic angiotensin converting enzyme-2 (ACE-2). This study tested the hypothesis that ER stress-induced apoptosis of human AECs might be mediated by influence of the unfolded protein response (UPR) on the autocrine ANGII/ANG1-7 system...
September 16, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Prashiela Manga, Nada Elbuluk, Seth J Orlow
Vitiligo, an acquired depigmentation disorder, manifests as white macules on the skin and can cause significant psychological stress and stigmatization. Recent advances have shed light on key components that drive disease onset and progression as well as therapeutic approaches. Vitiligo can be triggered by stress to the melanin pigment-producing cells of the skin, the melanocytes. The triggers, which range from sunburn to mechanical trauma and chemical exposures, ultimately cause an autoimmune response that targets melanocytes, driving progressive skin depigmentation...
2016: F1000Research
Dadi Jiang, Connor Lynch, Bruno C Medeiros, Michaela Liedtke, Rakesh Bam, Arvin B Tam, Zhifen Yang, Muthuraman Alagappan, Parveen Abidi, Quynh-Thu Le, Amato J Giaccia, Nicholas C Denko, Maho Niwa, Albert C Koong
Activation of the IRE1α-XBP1 branch of the unfolded protein response (UPR) has been implicated in multiple types of human cancers, including multiple myeloma (MM). Through an in silico drug discovery approach based on protein-compound virtual docking, we identified the anthracycline antibiotic doxorubicin as an in vitro and in vivo inhibitor of XBP1 activation, a previously unknown activity for this widely utilized cancer chemotherapeutic drug. Through a series of mechanistic and phenotypic studies, we showed that this novel activity of doxorubicin was not due to inhibition of topoisomerase II (Topo II)...
2016: Scientific Reports
Jie-Mei Wang, Yining Qiu, Zeng-Quan Yang, Li Li, Kezhong Zhang
Diabetic skin ulcers represent a challenging clinical problem with mechanisms not fully understood. In this study, we investigated the role and mechanism for the primary Unfolded Protein Response (UPR) transducer inositol requiring enzyme 1 (IRE1α) in diabetic wound healing. Bone marrow-derived progenitor cells (BMPCs) were isolated from adult male type-2 diabetic and their littermate control mice. In diabetic BMPCs, IRE1α protein expression and phosphorylation were repressed. The impaired diabetic BMPC angiogenic function was rescued by adenovirus-mediated expression of IRE1α, but not by the RNase-inactive IRE1á or the activated X-box binding protein 1 (XBP1), the canonical IRE1á target...
September 15, 2016: Diabetes
Juan Manuel Chao de la Barca, Gilles Simard, Patrizia Amati-Bonneau, Zainab Safiedeen, Delphine Prunier-Mirebeau, Stéphanie Chupin, Cédric Gadras, Lydie Tessier, Naïg Gueguen, Arnaud Chevrollier, Valérie Desquiret-Dumas, Marc Ferré, Céline Bris, Judith Kouassi Nzoughet, Cinzia Bocca, Stéphanie Leruez, Christophe Verny, Dan Miléa, Dominique Bonneau, Guy Lenaers, M Carmen Martinez, Vincent Procaccio, Pascal Reynier
Leber's hereditary optic neuropathy (MIM#535000), the commonest mitochondrial DNA-related disease, is caused by mutations affecting mitochondrial complex I. The clinical expression of the disorder, usually occurring in young adults, is typically characterized by subacute, usually sequential, bilateral visual loss, resulting from the degeneration of retinal ganglion cells. As the precise action of mitochondrial DNA mutations on the overall cell metabolism in Leber's hereditary optic neuropathy is unknown, we investigated the metabolomic profile of the disease...
September 15, 2016: Brain: a Journal of Neurology
Matthias Kroiss, Silviu Sbiera, Sabine Kendl, Max Kurlbaum, Martin Fassnacht
Mitotane is the only drug approved for treatment of the orphan disease adrenocortical carcinoma (ACC) and was recently shown to be the first clinically used drug acting through endoplasmic reticulum (ER)-stress induced by toxic lipids. Since mitotane has limited clinical activity as monotherapy, we here study the potential of activating ER-stress through alternative pathways. The single reliable NCI-H295 cell culture model for ACC was used to study the impact MG132, bortezomib (BTZ) and carfilzomib (CFZ) on mRNA and protein expression of ER-stress markers, cell viability and steroid hormone secretion...
September 8, 2016: Hormones & Cancer
Stephan Löser, Lisa G Gregory, Youming Zhang, Katrein Schaefer, Simone A Walker, James Buckley, Laura Denney, Charlotte H Dean, William O C Cookson, Miriam F Moffatt, Clare M Lloyd
BACKGROUND: Genome-wide association studies have identified the ORMDL3 (ORM (yeast)-like protein isoform 3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. OBJECTIVE: We sought to investigate in vivo the functional role of ORMDL3 in disease inception. METHODS: An Ormdl3 deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata determined...
September 10, 2016: Journal of Allergy and Clinical Immunology
Zheng Mou, Yu-He Yuan, Yu-Xia Lou, Yang Heng, Ju-Yang Huang, Cong-Yuan Xia, Yan Gao, Cheng-Gen Zhu, Shi-Feng Chu, Piao Luo, Jian-Gong Shi, Nai-Hong Chen
AIM: Accumulation of α-synuclein (α-syn) in the brain is a characteristic of Parkinson's disease (PD). In this study, we investigated whether treatment with tunicamycin, an endoplasmic reticulum (ER) stress inducer, led to the accumulation of α-syn in PC12 cells, and where α-syn protein was accumulated, and, finally, whether bibenzyl compound 20c, a novel compound isolated from Gastrodia elata (Tian ma), could alleviate the accumulation of α-syn and ER stress activation in tunicamycin-treated PC12 cells...
September 12, 2016: Acta Pharmacologica Sinica
Aarthi V Maganti, Sarah A Tersey, Farooq Syed, Jennifer B Nelson, Stephanie C Colvin, Bernhard Maier, Raghavendra G Mirmira
Type 1 diabetes is an autoimmune disorder that is characterized by a failure of the unfolded protein response in islet β cells with subsequent endoplasmic reticulum stress and cellular death. Thiazolidinediones are insulin sensitizers that activate the nuclear receptor PPAR-γ and have been shown to partially ameliorate autoimmune type 1 diabetes in humans and non-obese diabetic (NOD) mice. We hypothesized that thiazolidinediones reduce β cell stress and death independently of insulin sensitivity. To test this hypothesis, female NOD mice were administered pioglitazone during the pre-diabetic phase and assessed for insulin sensitivity and β cell function relative to controls...
September 9, 2016: Journal of Biological Chemistry
Zhen Ren, Si Chen, Jie Zhang, Utkarsh Doshi, Albert P Li, Lei Guo
Nefazodone, an antagonist for the 5-hydroxytryptanine receptor, has been used for the treatment of depression. Acute liver injury has been documented to be associated with the use of nefazodone; however, the mechanisms of nefazodone-induced liver toxicity are not well defined. In this report, using biochemical and molecular analyses, we characterized the molecular mechanisms underlying the hepatotoxicity of nefazodone. We found that nefazodone induced endoplasmic reticulum (ER) stress in HepG2 cells, as the expression of typical ER stress markers, including CHOP, ATF-4, and p-eIF2α, was significantly increased, and splicing of XBP1 was observed...
September 9, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Sarah E Kobylewski, Kimberly A Henderson, Kristin E Yamada, Curtis D Eckhert
Fruits, nuts, legumes, and vegetables are rich sources of boron (B), an essential plant nutrient with chemopreventive properties. Blood boric acid (BA) levels reflect recent B intake, and men at the US mean intake have a reported non-fasting level of 10 μM. Treatment of DU-145 prostate cancer cells with physiological concentrations of BA inhibits cell proliferation without causing apoptosis and activates eukaryotic initiation factor 2 (eIF2α). EIF2α induces cell differentiation and protects cells by redirecting gene expression to manage endoplasmic reticulum stress...
September 1, 2016: Biological Trace Element Research
Katarzyna K Krawczyk, Mari Ekman, Catarina Rippe, Mario Grossi, Bengt-Olof Nilsson, Sebastian Albinsson, Bengt Uvelius, Karl Swärd
Phenotypic modulation of smooth muscle cells is a hallmark of disease. The associated expansion of endoplasmic reticulum (ER) volume remains unexplained. Thrombospondin-4 was recently found to promote ATF6α activation leading to ER expansion. Using bladder outlet obstruction as a paradigm for phenotypic modulation, we tested if thrombospondin-4 is induced in association with ATF6α activation and ER expansion. Thrombospondin-4 was induced and ATF6α was activated after outlet obstruction in rodents. Increased abundance of spliced of Xbp1, another ER-stress sensor, and induction of Atf4 and Creb3l2 was also seen...
2016: Scientific Reports
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