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Shantel Olivares, Anne S Henkel
OBJECTIVE: Fibroblast growth factor 21 (FGF21), a key regulator of the metabolic response to fasting, is highly induced by endoplasmic reticulum (ER) stress. The X-box binding protein 1 (Xbp1) is one of several ER stress proteins that has been shown to directly activate the FGF21 promoter. We aimed to determine whether hepatic Xbp1 is required for induction of hepatic FGF21 in vivo. METHODS: Mice bearing a hepatocyte-specific deletion of Xbp1 (Xbp1(LKO)) were subjected to fasting, pharmacologic ER stress, or a ketogenic diet, all potent stimuli of Fgf21 expression...
December 2017: Molecular Metabolism
Elizabeth A Mazzio, Charles A Lewis, Karam F A Soliman
BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is characterized by the absence of hormone receptors (estrogen, progesterone and human epidermal growth factor receptor-2) and a relatively poor prognosis due to inefficacy of hormone receptor-based chemotherapies. It is imperative that we continue to explore natural products with potential to impede growth and metastasis of TNBC. In this study, we screened over 1,000 natural products for capacity to induce cell death in TNBC (MDA-MB -231) cells...
November 2017: Cancer Genomics & Proteomics
Tien-Huang Chen, Yi-Hsuan Chiang, Jiun-Nan Hou, Chih-Chieh Cheng, Eny Sofiyatun, Cheng-Hsun Chiu, Wei-June Chen
Dengue viruses (DENVs) cause dengue fever which is an important mosquito-borne disease in tropical areas. Generally, DENV does not cause cellular damage in mosquito cells. However, alterations in cytosolic calcium ions ([Ca(2+)]cyt) and the mitochondrial membrane potential (MMP), as well as accumulated reactive oxygen species (ROS), including superoxide anions (O2(∙-)) and hydrogen peroxide (H2O2), can be detected in C6/36 cells with DENV2 infection. Evident upregulation of BiP/GRP78 also appeared at 24 h postinfection in DENV2-infected C6/36 cells...
2017: BioMed Research International
J Bae, T Hideshima, G L Zhang, J Zhou, D B Keskin, N C Munshi, K C Anderson
XBP1 (X-box binding protein 1), CD138 (Syndecan-1), and CS1 (SLAMF7) are highly expressed antigens in cancers including multiple myeloma (MM). Here we identify and characterize immunogenic HLA-A24 peptides derived from these antigens for potential vaccination therapy of HLA-A24+ patients with MM. The identified immunogenic HLA-A24-specific XBP1 unspliced (UN)185-193 (I S P W I L A V L), XBP1 spliced (SP)223-231 (V Y P E G P S S L), CD138265-273 (I F A V C L V G F) and CS1240-248 (L F V L G L F L W) peptides induced antigen-specific CTL with anti-MM activity in an HLA-A24 restricted manner...
November 1, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Guizhen Zhao, Yi Fu, Zeyu Cai, Fang Yu, Ze Gong, Rongbo Dai, Yanhua Hu, Lingfang Zeng, Qingbo Xu, Wei Kong
Rationale: Although not fully understood, the phenotypic transition of vascular smooth muscle cells exhibits at the early onset of the pathology of aortic aneurysms. Exploring the key regulators that are responsible for maintaining the contractile phenotype of VSMCs may confer vascular homeostasis and prevent aneurysmal disease. X-box binding protein 1, which exists in a transcriptionally inactive unspliced form (XBP1u) and a spliced active form (XBP1s), is a key component in response to endoplasmic reticular (ER) stress...
October 31, 2017: Circulation Research
Saeid Ghavami, Behzad Yeganeh, Amir A Zeki, Shahla Shojaei, Nicholas J Kenyon, Sean Ott, Afshin Samali, John Patterson, Javad Alizadeh, Adel Rezaei Moghadam, Ian M C Dixon, Helmut Unruh, Darryl A Knight, Martin Post, Thomas Klonisch, Andrew John Halayko
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease in adults with limited treatment options. Autophagy and the unfolded protein response (UPR), fundamental processes induced by cell stress, are dysregulated in lung fibroblasts and epithelial cells from humans with IPF. METHODS: Human primary cultured lung parenchymal and airway fibroblasts from non-IPF and IPF donors were stimulated with TGFβ1 with or without the inhibitors of autophagy or UPR (IRE1α inhibitor)...
October 26, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
Nirav R Bhakta, Stephanie A Christenson, Srilaxmi Nerella, Owen D Solberg, Christine P Nguyen, David F Choy, Kyle L Jung, Suresh Garudadri, Luke R Bonser, Joshua L Pollack, Lorna T Zlock, David J Erle, Charles Langelier, Joseph L Derisi, Joseph R Arron, John V Fahy, Prescott G Woodruff
RATIONALE: Quantification of type-2 inflammation provided a molecular basis for heterogeneity in asthma. Non-type-2 pathways that contribute to asthma pathogenesis are not well understood. OBJECTIVES: To identify dysregulated pathways beyond type-2 inflammation. METHODS: We applied RNA sequencing to airway epithelial brushings obtained from stable mild asthmatics not on corticosteroids (n=19) and healthy controls (n=16). Sequencing reads were mapped to human and viral genomes...
October 24, 2017: American Journal of Respiratory and Critical Care Medicine
Fiona Chalmers, Marcel van Lith, Bernadette Sweeney, Katharine Cain, Neil J Bulleid
Background: The mammalian endoplasmic reticulum (ER) continuously adapts to the cellular secretory load by the activation of an unfolded protein response (UPR).  This stress response results in expansion of the ER, upregulation of proteins involved in protein folding and degradation, and attenuation of protein synthesis.  The response is orchestrated by three signalling pathways each activated by a specific signal transducer, either inositol requiring enzyme α (IRE1α), double-stranded RNA-activated protein kinase-like ER kinase (PERK) or activating transcription factor 6 (ATF6)...
2017: Wellcome Open Research
Noelia Diaz-Morales, Francesca Iannantuoni, Irene Escribano-Lopez, Celia Bañuls, Susana Rovira-Llopis, Eva Sola, Milagros Rocha, Antonio Hernandez-Mijares, Victor M Victor
Since type 2 diabetes (T2D) is closely associated with enhanced oxidative stress and metformin has been shown to exert a protective role against said stress, we posed the question of whether metformin treatment might also modulate endoplasmic reticulum (ER) stress and autophagy in leukocytes of T2D patients. We studied 53 T2D patients (37 of whom had been treated with metformin 1700mg for at least 1 year) and 30 healthy volunteers. Whereas leukocytes from both groups of T2D patients exhibited increased protein levels of GRP78 with respect to controls, ATF6 was enhanced specifically in non-metformin-treated T2D, while <i>s-xbp1</i> and p-eIF2α increased only in the metformin-treated group...
October 23, 2017: Antioxidants & Redox Signaling
Jing Guo, Ying-Jie Niu, Kyung-Tae Shin, Jeong-Woo Kwon, Nam-Hyung Kim, Xiang-Shu Cui
Fatty acid synthase (FAS) is an important enzyme involved in the de novo synthesis of long-chain fatty acids. During development, the function of FAS in growth is greater than that in energy storage pathways; therefore, we hypothesized that knockout of FAS would affect early embryonic development owing to the induction of endoplasmic reticulum (ER) stress. In the present study, the function of FAS was studied using the CRISPR (clustered regularly interspaced short palindromic repeats)/ CRISPR-associated protein 9 (Cas9) system...
October 23, 2017: Journal of Cellular Physiology
Can Huang, Shourong Wu, Hong Ji, Xuesong Yan, Yudan Xie, Saomi Murai, Hezhao Zhao, Makoto Miyagishi, Vivi Kasim
Cell cycle progression is a tightly controlled fundamental process in living cells, with any defects being closely linked to various abnormalities. The tumor suppressor p53/p21 axis is a core pathway controlling cell cycle progression; however, its regulatory mechanism has not been fully elucidated. In an effort to unravel this crucial network, we screened a short hairpin RNA expression vector library and identified unspliced X-box binding protein 1 (XBP1-u) as a novel and critical regulator of the p53/p21 axis...
October 2017: Science Advances
Xiuduan Xu, Aodeng Qimuge, Hongli Wang, Chen Xing, Ye Gu, Shasha Liu, Huan Xu, Meiru Hu, Lun Song
Short- and long-term exposure to particulate matter (PM) 2.5 instigates adverse health effect upon the cardiovascular (CV) system. Disclosing the molecular events by which PM2.5 evokes CV injuries is essential in developing effective risk-reduction strategy. Here we found that rats after intratracheally instillation with PM2.5 displayed increased circulating level of ANGII, the major bioactive peptide in renin-angiotensin-system (RAS), which resulted from the elevation of ANGII production in the vascular endothelium...
October 18, 2017: Scientific Reports
Yannis Gerakis, Claudio Hetz
Alterations in the buffering capacity of the proteostasis network are a salient feature of Alzheimer's disease, associated with the occurrence of chronic endoplasmic reticulum (ER) stress. To cope with ER stress, cells activate the unfolded protein response (UPR), a signal transduction pathway that enforces adaptive programs through the induction of transcription factors such as X-box binding protein 1 (XBP1). A new study by Marcora et al used a fly model to study amyloid β pathogenesis in the secretory pathway of neurons...
September 22, 2017: Neurobiology of Aging
Azmeraw T Amare, Klaus Oliver Schubert, Bernhard T Baune
Personalized medicine (personalized psychiatry in a specific setting) is a new model towards individualized care, in which knowledge from genomics and other omic pillars (microbiome, epigenomes, proteome, and metabolome) will be combined with clinical data to guide efforts to new drug development and targeted prescription of the existing treatment options. In this review, we summarize pharmacogenomic studies in mood disorders that may lay the foundation towards personalized psychiatry. In addition, we have discussed the possible strategies to integrate data from omic pillars as a future path to personalized psychiatry...
September 2017: EPMA Journal
Jing Yan, Feng Jiang, Rong Zhang, Tongfu Xu, Zhou Zhou, Wei Ren, Danfeng Peng, Yong Liu, Cheng Hu, Weiping Jia
Monogenic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms. Whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes. One novel heterozygous mutation (p.Ala2Thr) in INS was identified. It was further genotyped in an additional case-control population (6523 cases and 4635 controls), and this variant was observed in 0...
August 23, 2017: Journal of Molecular Cell Biology
Gábor J Szebeni, Árpád Balázs, Ildikó Madarász, Gábor Pócz, Ferhan Ayaydin, Iván Kanizsai, Roberta Fajka-Boja, Róbert Alföldi, László Hackler, László G Puskás
Achiral Mannich-type curcumin analogs have been synthetized and assayed for their cytotoxic activity. The anti-proliferative and cytotoxic activity of curcuminoids has been tested on human non-small-cell lung carcinoma (A549), hepatocellular carcinoma (HepG2) and pancreatic cancer cell line (PANC-1). Based on the highest anti-proliferative activity nine drug candidates were further tested and proved to cause phosphatidylserine exposure as an early sign of apoptosis. Curcumin analogs with the highest apoptotic activity were selected for mechanistic studies in the most sensitive PANC-1 cells...
October 7, 2017: International Journal of Molecular Sciences
Zhen Ren, Si Chen, Tao Qing, Jiekun Xuan, Letha Couch, Dianke Yu, Baitang Ning, Leming Shi, Lei Guo
Leflunomide, used for the treatment of rheumatoid arthritis, has been reported to cause severe liver problems and liver failure; however, the underlying mechanisms are not clear. In this study, we used multiple approaches including genomic analysis to investigate and characterize the possible molecular mechanisms of the cytotoxicity of leflunomide in hepatic cells. We found that leflunomide caused endoplasmic reticulum (ER) stress and activated an unfolded protein response, as evidenced by increased expression of related genes including CHOP and GADD34; and elevated protein levels of typical ER stress markers including CHOP, ATF-4, p-eIF2α, and spliced XBP1...
October 5, 2017: Toxicology
Sabrina M Heman-Ackah, Raquel Manzano, Jeroen J M Hoozemans, Wiep Scheper, Rowan Flynn, Wilfried Haerty, Sally A Cowley, Andrew R Bassett, Matthew J A Wood
The recent generation of induced pluripotent stem cells (iPSCs) from a patient with Parkinson's disease (PD) resulting from triplication of the α-synuclein (SNCA) gene locus allows unprecedented opportunities to explore its contribution to the molecular pathogenesis of PD. We used the double-nicking CRISPR/Cas9 system to conduct site-specific mutagenesis of SNCA in these cells, generating an isogenic iPSC line with normalized SNCA gene dosage. Comparative gene expression analysis of neuronal derivatives from these iPSCs revealed an ER stress phenotype, marked by induction of the IRE1α/XBP1 axis of the unfolded protein response (UPR) and culminating in terminal UPR activation...
November 15, 2017: Human Molecular Genetics
A Altperery, S Raud, S Sütt, R Reimets, T Visnapuu, M Toots, E Vasar
In this work, the effect of mild stress (elevated plus maze test, EPM) on the expression of endoplasmic reticulum (ER) stress markers in different brain areas of wild type (WT) and Wfs1-deficient (Wfs1KO) mice was investigated. The following ER stress markers were studied: activating transcription factor 6α (Atf6α), protein kinase-like ER kinase (Perk), X-box binding protein 1 (Xbp1) and its spliced form (Xbp1s), 78-kilodalton glucose regulated protein (Grp78), 94-kilodalton glucose regulated protein (Grp94), C/EBP homologous protein (Chop)...
September 26, 2017: Behavioural Brain Research
Tokiro Ishikawa, Makoto Kashima, Atsushi J Nagano, Tomoko Ishikawa-Fujiwara, Yasuhiro Kamei, Takeshi Todo, Kazutoshi Mori
When activated by the accumulation of unfolded proteins in the endoplasmic reticulum, metazoan IRE1, the most evolutionarily conserved unfolded protein response (UPR) transducer, initiates unconventional splicing of XBP1 mRNA. Unspliced and spliced mRNA are translated to produce pXBP1(U) and pXBP1(S), respectively. pXBP1(S) functions as a potent transcription factor, whereas pXBP1(U) targets pXBP1(S) to degradation. In addition, activated IRE1 transmits two signaling outputs independent of XBP1, namely activation of the JNK pathway, which is initiated by binding of the adaptor TRAF2 to phosphorylated IRE1, and regulated IRE1-dependent decay (RIDD) of various mRNAs in a relatively nonspecific manner...
September 27, 2017: ELife
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