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Marc-André Déry, Andréa C LeBlanc
The cellular prion protein (PrP) is essential for transmissible prion diseases, but its exact physiological function remains unclear. Better understanding the regulation of the human prion protein gene (PRNP) expression can provide insight into this elusive function. Spliced XBP1 (sXBP1) was recently shown to mediate endoplasmic reticulum (ER) stress-induced PRNP expression. In this manuscript, we identify Luman, a ubiquitous, non-canonical unfolded protein response (UPR), as a novel regulator of ER stress-induced PRNP expression...
February 13, 2017: Scientific Reports
Mohammad Moshahid Khan, Weng-Lang Yang, Max Brenner, Alexandra Cerutti Bolognese, Ping Wang
Cold-inducible RNA-binding protein (CIRP), released into the circulation during sepsis, causes lung injury via an as yet unknown mechanism. Since endoplasmic reticulum (ER) stress is associated with acute lung injury (ALI), we hypothesized that CIRP causes ALI via induction of ER stress. To test this hypothesis, we studied the lungs of wild-type (WT) and CIRP knockout (KO) mice at 20 h after induction of sepsis by cecal ligation and puncture (CLP). WT mice had significantly more severe ALI than CIRP KO mice...
January 27, 2017: Scientific Reports
Takuya Akiyama, Kenji Oishi, Andy Wullaert
Endoplasmic reticulum (ER) stress is caused by accumulation of unfolded and misfolded proteins in the ER, thereby compromising its vital cellular functions in protein production and secretion. Genome wide association studies in humans as well as experimental animal models linked ER stress in intestinal epithelial cells (IECs) with intestinal disorders including inflammatory bowel diseases. However, the mechanisms linking the outcomes of ER stress in IECs to intestinal disease have not been clarified. In this study, we investigated the impact of ER stress on intestinal epithelial barrier function using human colon carcinoma-derived Caco-2 monolayers...
2016: PloS One
Quentin Tavernier, Iadh Mami, Marion Rabant, Alexandre Karras, Pierre Laurent-Puig, Eric Chevet, Eric Thervet, Dany Anglicheau, Nicolas Pallet
The ribonuclease angiogenin is a component of the mammalian stress response that is secreted by renal epithelial cells on activation of the inositol-requiring enzyme 1α (IRE1α)-active spliced X-box binding protein 1 (sXBP1) axis and instrumental to the adaptation to AKI associated with endoplasmic reticulum stress. To determine whether the amount of angiogenin in urine of individuals with a kidney injury reflects the magnitude of the lesions and provides information on the risk of organ failure, we examined individuals referred for a kidney injury and determined the biochemical characteristics of urinary angiogenin and its diagnostic and prognostic values...
February 2017: Journal of the American Society of Nephrology: JASN
Terry G Coursey, Johanna Tukler Henriksson, Flavia L Barbosa, Cintia S de Paiva, Stephen C Pflugfelder
Goblet cells (GCs) are specialized secretory cells that produce mucins and a variety of other proteins. Significant conjunctival GC loss occurs in both experimental dry eye models and patients with keratoconjunctivitis sicca due to the induction of interferon (IFN)-γ. With the use of a primary murine culture model, we found that GCs are highly sensitive to IFN-γ with significantly reduced proliferation and altered structure with low concentrations. GC cultures treated with IFN-γ have increased gene expression of Muc2 and Muc5AC but do not express these mucin glycoproteins...
June 2016: American Journal of Pathology
Lindsey Phillipson-Weiner, Emily T Mirek, Yongping Wang, W Geoffrey McAuliffe, Ronald C Wek, Tracy G Anthony
Treatment with the antileukemic agent asparaginase can induce acute pancreatitis, but the pathophysiology remains obscure. In the liver of mice, eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2) is essential for mitigating metabolic stress caused by asparaginase. We determined the consequences of asparaginase treatment on the pancreata of wild-type (WT, GCN2-intact) and GCN2-deleted (ΔGcn2) mice. Mean pancreas weights in ΔGcn2 mice treated with asparaginase for 8 days were increased (P < 0...
June 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
JunYuan Zheng, JiangHong Wu, Jing Chen, Jie Liu, YingYing Lu, ChunLan Huang, GuoYong Hu, XingPeng Wang, Yue Zeng
OBJECTIVE: To investigate the therapeutic effects of quercetin on early-stage inflammation in hypertriglyceridemia (HTG)-related acute pancreatitis (AP) both in vivo and in vitro, and its possible mechanism. METHODS: In vivo, rats were fed a high-fat diet to induce HTG, and AP was induced by intraperitoneal injection of cerulein (50 μg/kg × 2). Quercetin (100, 150 and 200 mg/kg) was administered by intraperitoneal injection after AP induction. In vitro, rat exocrine acinar cells were preincubated with palmitic acid (PA, 0...
March 2016: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
Takahiro Hikiji, Junpei Norisada, Yoko Hirata, Kensuke Okuda, Hideko Nagasawa, Shinsuke Ishigaki, Gen Sobue, Kazutoshi Kiuchi, Kentaro Oh-hashi
Activation of inositol-requiring enzyme 1 (IRE1) due to abnormal conditions of the endoplasmic reticulum (ER) is responsible for the cleavage of an unspliced form of X-box binding protein 1 (uXBP1), producing its spliced form (sXBP1). To estimate IRE1 activation, several analytical procedures using green fluorescence protein and firefly luciferase have been developed and applied to clarify the roles of IRE1-XBP1 signaling pathways during development and disease progression. In this study, we established a highly sensitive assay of IRE1 activity using a small luciferase, NanoLuc, which has approximately 100-fold higher activity than firefly luciferase...
August 7, 2015: Biochemical and Biophysical Research Communications
Thati Madhusudhan, Hongjie Wang, Wei Dong, Sanchita Ghosh, Fabian Bock, Veera Raghavan Thangapandi, Satish Ranjan, Juliane Wolter, Shrey Kohli, Khurrum Shahzad, Florian Heidel, Martin Krueger, Vedat Schwenger, Marcus J Moeller, Thomas Kalinski, Jochen Reiser, Triantafyllos Chavakis, Berend Isermann
Endoplasmic reticulum (ER) stress is associated with diabetic nephropathy (DN), but its pathophysiological relevance and the mechanisms that compromise adaptive ER signalling in podocytes remain unknown. Here we show that nuclear translocation of the transcription factor spliced X-box binding protein-1 (sXBP1) is selectively impaired in DN, inducing activating transcription factor-6 (ATF6) and C/EBP homology protein (CHOP). Podocyte-specific genetic ablation of XBP1 or inducible expression of ATF6 in mice aggravates DN...
March 10, 2015: Nature Communications
Ahmed Bettaieb, Diana A Averill-Bates
Hyperthermia (39-45°C) has emerged as an alternate prospect for cancer therapy in combination with radiation and chemotherapy. Despite promising progress in the clinic, molecular mechanisms involved in hyperthermia-induced cell death are not clear. Hyperthermia causes protein denaturation/aggregation, which results in cell death by apoptosis and/or necrosis. Hyperthermia also induces thermotolerance, which renders cells resistant to subsequent exposure to lethal heat shock. This study investigates the role of both lethal (42-43°C) and mild (40°C) hyperthermia in regulating ER stress and ER stress-induced apoptosis in HeLa cells...
January 2015: Biochimica et Biophysica Acta
Oriol A Rangel-Zuñiga, Carmen Haro, Pablo Perez-Martinez, Javier Delgado-Lista, Carmen Marin, Gracia M Quintana-Navarro, Francisco J Tinahones, María M Malagón, Fernando Lopez-Segura, Jose López-Miranda, Francisco Perez-Jimenez, Antonio Camargo
The addition of antioxidants to frying oil reduces postprandial oxidative stress and the inflammatory response. ER stress may trigger both inflammation and oxidative stress processes. We aimed to determine the biological effects of the intake of four models of frying oils on postprandial ER stress in peripheral blood mononuclear cells. Twenty obese people received four breakfasts following a randomized crossover design, consisting of muffins made with different oils (virgin olive oil (VOO), sunflower oil (SFO), and a mixture of seed oils (SFO/canola oil) with either dimethylpolysiloxane (SOD) or natural antioxidants from olives (SOP) added), which were previously subjected to 20 heating cycles...
November 2014: Molecular Nutrition & Food Research
Hyo-Jin Park, Sun-Ji Park, Deog-Bon Koo, Sang-Rae Lee, Il-Keun Kong, Jae-Woong Ryoo, Young-Il Park, Kyu-Tae Chang, Dong-Seok Lee
AIMS: We examined whether the three unfolded protein response (UPR) signaling pathways, which are activated in response to endoplasmic reticulum (ER)-stress, are involved in progesterone production in the luteal cells of the corpus luteum (CL) during the mouse estrous cycle. MAIN METHODS: The luteal phase of C57BL/6 female mice (8 weeks old) was divided into two stages: the functional stage (16, 24, and 48 h) and the regression stage (72 and 96 h). Western blotting and reverse transcription (RT)-PCR were performed to analyze UPR protein/gene expression levels in each stage...
September 15, 2014: Life Sciences
Susana Rovira-Llopis, Celia Bañuls, Nadezda Apostolova, Carlos Morillas, Antonio Hernandez-Mijares, Milagros Rocha, Victor M Victor
Oxidative and endoplasmic reticulum (ER) stress is related to type 2 diabetes (T2D), but the influence of glycemic control on these parameters and its relationship with leukocyte-endothelial interactions is not known. In our study population consisting of 164 diabetic patients, (102 with glycated hemoglobin [HbA1c] <7% and 62 with HbA1c >7%) and 84 nondiabetic controls, we have verified a common anthropometric and metabolic pattern of T2D with dyslipidemia. Inflammatory parameters (high-sensitive C-reactive protein [hs-CRP] and tumor necrosis factor alpha [TNFα]) and E-selectin levels were enhanced in the HbA1c >7% group with regard to controls...
October 20, 2014: Antioxidants & Redox Signaling
Marzia Scortegagna, Hyungsoo Kim, Jian-Liang Li, Hang Yao, Laurence M Brill, Jaeseok Han, Eric Lau, David Bowtell, Gabriel Haddad, Randal J Kaufman, Ze'ev A Ronai
The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output...
May 2014: PLoS Genetics
Xavier Palomer, Eva Capdevila-Busquets, Gerard Garreta, Mercy M Davidson, Manuel Vázquez-Carrera
INTRODUCTION: Endoplasmic reticulum (ER) stress has been linked to several cardiovascular diseases, such as atherosclerosis, heart failure and cardiac hypertrophy. ER stress impairs insulin signalling, thus contributing to the development of insulin resistance and diabetes. Since several studies have reported that PPARα may inhibit ER stress, the main aim of this study consisted in investigating whether activation of this nuclear receptor is able to prevent lipid-induced ER stress in cardiac cells, as well as studying the mechanisms involved...
November 2014: Clínica e Investigación en Arteriosclerosis
Masayuki Koyama, Masato Furuhashi, Shutaro Ishimura, Tomohiro Mita, Takahiro Fuseya, Yusuke Okazaki, Hideaki Yoshida, Kazufumi Tsuchihashi, Tetsuji Miura
Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling of the pulmonary artery (PA). Recently, endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) have been disclosed in various types of diseases. Here we examined whether ER stress is involved in the pathogenesis of PAH. Four weeks of chronic normobaric hypoxia increased right ventricular (RV) systolic pressure by 63% compared with that in normoxic controls and induced RV hypertrophy and medial thickening of the PA in C57BL/6J mice...
May 2014: American Journal of Physiology. Heart and Circulatory Physiology
Feyza Engin, Truc Nguyen, Alena Yermalovich, Gökhan S Hotamisligil
The endoplasmic reticulum adapts to fluctuations in demand and copes with stress through an adaptive signaling cascade called the unfolded protein response (UPR). Accumulating evidence indicates that the canonical UPR is critical to the survival and function of insulin-producing pancreatic β-cells, and alterations in the UPR may contribute to the pathogenesis of type 2 diabetes. However, the dynamic regulation of UPR molecules in the islets of animal models and humans with type 2 diabetes remains to be elucidated...
February 11, 2014: Scientific Reports
Sinisa Savic, Lylia Ouboussad, Laura J Dickie, Janina Geiler, Chi Wong, Gina M Doody, Sarah M Churchman, Frederique Ponchel, Paul Emery, Graham P Cook, Maya H Buch, Reuben M Tooze, Michael F McDermott
X-box binding protein 1 (XBP1) is a central regulator of the endoplasmic reticulum (ER) stress response. It is induced via activation of the IRE1 stress sensor as part of the unfolded protein response (UPR) and has been implicated in several diseases processes. XBP1 can also be activated in direct response to Toll-like receptor (TLR) ligation independently of the UPR but the pathogenic significance of this mode of XBP1 activation is not well understood. Here we show that TLR-dependent XBP1 activation is operative in the synovial fibroblasts (SF) of patients with active rheumatoid arthritis (RA)...
May 2014: Journal of Autoimmunity
Ying I Wang, Ahmed Bettaieb, Chongxiu Sun, J Sherrod DeVerse, Christopher E Radecke, Steven Mathew, Christina M Edwards, Fawaz G Haj, Anthony G Passerini, Scott I Simon
Circulating triglyceride-rich lipoproteins (TGRL) from hypertriglyceridemic subjects exacerbate endothelial inflammation and promote monocyte infiltration into the arterial wall. We have recently reported that TGRL isolated from human blood after a high-fat meal can elicit a pro- or anti-atherogenic state in human aortic endothelial cells (HAEC), defined as up- or down-regulation of VCAM-1 expression in response to tumor necrosis factor alpha (TNFα) stimulation, respectively. A direct correlation was found between subjects categorized at higher risk for cardiovascular disease based upon serum triglycerides and postprandial production of TGRL particles that increased VCAM-1-dependent monocyte adhesion to inflamed endothelium...
2013: PloS One
Chao Yu, Katharina Achazi, Matthias Niedrig
Tick-borne encephalitis (TBE) is a serious human neurological disease caused by TBE virus (TBEV). However, the mechanisms of TBEV-caused pathogenesis remain unclear. The endoplasmic reticulum (ER) stress response, also defined as the unfolded protein response (UPR), is an important conserved molecular signaling pathway that modulates many biological functions including innate immunity and viral pathogenesis. Here, we investigated the effects of the two UPR signaling pathways upon TBEV infection in Vero E6 cells...
December 26, 2013: Virus Research
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