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Hypoxia induced factor

N S Bayin, J D Frenster, J R Kane, J Rubenstein, A S Modrek, R Baitalmal, I Dolgalev, K Rudzenski, L Scarabottolo, D Crespi, L Redaelli, M Snuderl, J G Golfinos, W Doyle, D Pacione, E C Parker, A S Chi, A Heguy, D J MacNeil, N Shohdy, D Zagzag, D G Placantonakis
Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM...
October 24, 2016: Oncogenesis
Shaohong Cheng, Patrick Aghajanian, Sheila Pourteymoor, Catrina Alarcon, Subburaman Mohan
Endochondral ossification plays an important role in the formation of the primary ossification centers (POCs) and secondary ossification centers (SOCs) of mammalian long bones. However, the molecular mechanisms that regulate POC and SOC formation are different. We recently demonstrated that Prolyl Hydroxylase Domain-containing Protein 2 (Phd2) is a key mediator of vitamin C effects on bone. We investigated the role of Phd2 on endochondral ossification of the epiphyses by conditionally deleting the Phd2 gene in osteoblasts and chondrocytes...
October 24, 2016: Scientific Reports
Steffen Grampp, James L Platt, Victoria Lauer, Rafik Salama, Franziska Kranz, Viviana K Neumann, Sven Wach, Christine Stöhr, Arndt Hartmann, Kai-Uwe Eckardt, Peter J Ratcliffe, David R Mole, Johannes Schödel
Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins...
October 24, 2016: Nature Communications
Shizhong Ke, Shuzhen Chen, Zihui Dong, Christopher S Hong, Qi Zhang, Liang Tang, Pinghua Yang, Jian Zhai, Hexin Yan, Feng Shen, Zhengping Zhuang, Wen Wen, Hongyang Wang
: Erythrocytosis is a common paraneoplastic syndrome associated with hepatocellular carcinoma (HCC). Although increased erythropoietin (EPO) is found in these patients, the clinical significance and molecular mechanisms underlying this observation are unclear. Here we demonstrated an inverse relationship between EPO production and overall prognosis in our cohort of 664 patients as well as in data from The Cancer Genome Atlas (TCGA). In the subset of HCC patients with erythrocytosis, we identified somatic mutations of mitochondrial DNA, resulting impairment of respiratory metabolism, which sequentially led to depletion of α-ketoglutarate, stabilization of hypoxia inducible factor-α and expression of target genes such as EPO...
October 24, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Stephanie Seneff, Nancy L Swanson, Gerald Koenig, Chen Li
Osteonecrosis of the jaw (ONJ), a rare side effect of bisphosphonate therapy, is a debilitating disorder with a poorly understood etiology. FDA's Adverse Event Reporting System (FAERS) provides the opportunity to investigate this disease. Our goals were to analyze FAERS data to discover possible relationships between ONJ and specific conditions and drugs and then to consult the scientific literature to deduce biological explanations. Our methodology revealed a very strong association between gastroesophageal reflux and bisphosphonate-induced ONJ, suggesting acidosis as a key factor...
2016: Disease Markers
Fang Gao, Yanping Wang, Shulin Li, Zhuojun Wang, Caixia Liu, Dong Sun
AIMS: Cellular hypoxia has been proposed as a major factor contributing to the pathogenesis of chronic renal injury. Much of our understanding of how mitogen-activated protein kinases (MAPK) signaling promotes renal fibrosis has been based on cell culture studies. Therefore, we used the unilateral ureteral occlusion (UUO) model to further elucidate the role of the p38 MAPK pathway in renal interstitial fibrosis induced by hypoxia. MATERIALS AND METHODS: In the present study, 24 male mice were randomized into the following three groups (n=8 each): Sham group (DMSO solution), UUO group (UUO+DMSO solution) and UP group (UUO+p38 inhibitor)...
October 20, 2016: Life Sciences
Yaling Wu, Dingbin Tang, Na Liu, Wei Xiong, Huanwei Huang, Yang Li, Zhixiong Ma, Haijiao Zhao, Peihao Chen, Xiangbing Qi, Eric Erquan Zhang
Circadian regulation is critically important in maintaining metabolic and physiological homeostasis. However, little is known about the possible influence of the clock on physiological abnormalities occurring under pathological conditions. Here, we report the discovery that hypoxia, a condition that causes catastrophic bodily damage, is gated by the circadian clock in vivo. Hypoxia signals conversely regulate the clock by slowing the circadian cycle and dampening the amplitude of oscillations in a dose-dependent manner...
October 14, 2016: Cell Metabolism
Clara Bien Peek, Daniel C Levine, Jonathan Cedernaes, Akihiko Taguchi, Yumiko Kobayashi, Stacy J Tsai, Nicolle A Bonar, Maureen R McNulty, Kathryn Moynihan Ramsey, Joseph Bass
Circadian clocks are encoded by a transcription-translation feedback loop that aligns energetic processes with the solar cycle. We show that genetic disruption of the clock activator BMAL1 in skeletal myotubes and fibroblasts increased levels of the hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions. Bmal1(-/-) myotubes displayed reduced anaerobic glycolysis, mitochondrial respiration with glycolytic fuel, and transcription of HIF1α targets Phd3, Vegfa, Mct4, Pk-m, and Ldha, whereas abrogation of the clock repressors CRY1/2 stabilized HIF1α in response to hypoxia...
October 19, 2016: Cell Metabolism
Yonghong Shi, Jing Zhao, Ling Hai
No abstract text is available yet for this article.
February 2016: Pathology
Patrick R Arsenault, Daisheng Song, Marian Bergkamp, Andrew M Ravaschiere, Bradleigh E Navalsky, Paul M Lieberman, Frank S Lee
The Prolyl Hydroxylase Domain protein (PHD):Hypoxia Inducible Factor (HIF) pathway is the main pathway by which changes in oxygen concentration are transduced to changes in gene expression. In mammals, there are three PHD paralogues, and PHD2 has emerged as a particularly critical one for regulating HIF target genes such as ERYTHROPOIETIN (EPO), which controls red cell mass and hematocrit. PHD2 is distinctive among the three PHDs in that it contains an N-terminal MYND type zinc finger. We have proposed that this zinc finger binds a Pro-Xaa-Leu-Glu (PXLE) motif found in proteins of the HSP90 pathway to facilitate HIF-α hydroxylation...
October 22, 2016: Chembiochem: a European Journal of Chemical Biology
Danielle E Jenkins, Dharshini Sreenivasan, Fiona Carman, Samal Babru, Lee E Eiden, Stephen J Bunn
The pro-inflammatory cytokines, tumor necrosis factor-α and interleukin-1β/α modulate catecholamine secretion, and long-term gene regulation, in chromaffin cells of the adrenal medulla. Since interleukin-6 (IL6) also plays a key integrative role during inflammation, we have examined its ability to affect both tyrosine hydroxylase activity and adrenomedullary gene transcription in cultured bovine chromaffin cells. IL6 caused acute tyrosine/threonine phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), and serine/tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3)...
October 22, 2016: Journal of Neurochemistry
Hung-Yi Liu, Tanja Greene, Tsai-Yu Lin, Camron S Dawes, Murray Korc, Chien-Chi Lin
: The complex network of biochemical and biophysical cues in the pancreatic desmoplasia not only presents challenges to the fundamental understanding of tumor progression, but also hinders the development of therapeutic strategies against pancreatic cancer. Residing in the desmoplasia, pancreatic stellate cells (PSCs) are the major stromal cells affecting the growth and metastasis of pancreatic cancer cells by means of paracrine effects and extracellular matrix protein deposition. PSCs remain in a quiescent/dormant state until they are 'activated' by various environmental cues...
October 18, 2016: Acta Biomaterialia
Dongdong Chai, Hong Jiang, Qifang Li
OBJECTIVE: Previously, we found that the inhaled anesthetic isoflurane up-regulated the transcriptional factor hypoxia inducible factor (HIF)-1α protein levels during induction of neurodegeneration in the brain of neonatal rats. Here, we investigated the role of HIF-1α and the underlying signaling pathway in the neurodegenration induced by isoflurane in rodent developing brain. METHODS: Primary hippocampal neurons were exposed to isoflurane (0.4mM) for 12h. Neuron injury was analyzed by 3-(4,5-dimethyithiazol-2-yl)-2,5-diphenyl-tetra-zolium bromide (MTT) test and quantification of lactate dehydrogenaserelease...
October 18, 2016: Brain Research
Vanessa D Ortiz, Alexandre L de Castro, Cristina Campos, Rafael O Fernandes, Jéssica H P Bonetto, Rafaela Siqueira, Adriana Conzatti, Tânia R G Fernandes, Adriane Belló-Klein, Alex S R Araujo
Studies have shown a cardioprotective role of thyroid hormones (THs) in cardiac remodeling after acute myocardial infarction (MI). However, there is no data in the literature examining the influence of TH administration on the aortic tissue in an animal model of MI. This study aimed to evaluate the effects of thyroid hormones on the aorta after MI. Male Wistar rats were divided into a sham group (SHAM), infarcted group (AMI), sham+TH (SHAMT) and AMI+TH (AMIT). After MI, the animals received T3 and T4 (2 and 8μg/100g/day, respectively) by oral gavage for 12 days...
October 18, 2016: European Journal of Pharmacology
Qian-Qian Luo, Zhong-Ming Qian, Yu-Fu Zhou, Meng-Wan Zhang, Dang Wang, Li Zhu, Ya Ke
The inconsistent of responses of IRP1 and HIF-1 alpha to hypoxia and the similar tendencies in the changes of IRP1 and pCREB contents led us to hypothesize that pCREB might be involved in the regulation of IRP1 under hypoxia. Here, we investigated the role of pCREB in IRP1 expression in HepG2 cells under hypoxia using quantitative PCR, western blot, immunofluorescence, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). We demonstrated that 1) Hypoxia increased pCREB levels inside of the nucleus; 2) Putative CREs were found in the IRP1 gene; 3) Nuclear extracts of HepG2 cells treated with hypoxia could bind to CRE1 and CRE3, and 100-fold competitor of putative CREs could abolish the binding activity to varying degrees; 4) pCREB was found in the CRE1 and CRE3 DNA-protein complexes of EMSA; 5) CRE1 and CRE3 binding activity of IRP1 depended on CREB activation but not on HIF-1; 6) Increased IRP1 expression under hypoxia could be prevented by LY294002; 7) ChIP assays demonstrated that pCREB binds to IRP1 promoter; and 8) HIF-1 and/or HIF-2 siRNA had no effect on the expression of pCREB and IRP1 proteins in cells treated with hypoxia for 8 hours...
2016: International Journal of Biological Sciences
Chengxing Zhu, Jiong Yu, Qiaoling Pan, Jinfeng Yang, Guangshu Hao, Yingjie Wang, Lanjuan Li, Hongcui Cao
Human placenta-derived mesenchymal stem cells (hPMSCs) reside in a physiologically low-oxygen microenvironment. Hypoxia influences a variety of stem cell cellular activities, frequently involving hypoxia-inducible factor-2 alpha (HIF-2α). This research showed that hPMSCs cultured in hypoxic conditions (5% O2) exhibited a more naïve morphology and had a higher proliferative capability and higher HIF-2α expression than hPMSCs cultured in normoxic conditions (21% O2). Similar to the hypoxic cultures, hPMSCs over-expressing HIF-2α showed higher proliferative potential and higher expression of CCND1 (CyclinD1), MYC (c-Myc), POU5F1 (Oct4) and the components of the MAPK/ERK pathway...
October 21, 2016: Scientific Reports
Mark A Applebaum, Aashish R Jha, Clara Kao, Kyle M Hernandez, Gillian DeWane, Helen R Salwen, Alexandre Chlenski, Marija Dobratic, Christopher J Mariani, Lucy A Godley, Nanduri Prabhakar, Kevin White, Barbara E Stranger, Susan L Cohn
Neuroblastoma is notable for its broad spectrum of clinical behavior ranging from spontaneous regression to rapidly progressive disease. Hypoxia is well known to confer a more aggressive phenotype in neuroblastoma. We analyzed transcriptome data from diagnostic neuroblastoma tumors and hypoxic neuroblastoma cell lines to identify genes whose expression levels correlate with poor patient outcome and are involved in the hypoxia response. By integrating a diverse set of transcriptome datasets, including those from neuroblastoma patients and neuroblastoma derived cell lines, we identified nine genes (SLCO4A1, ENO1, HK2, PGK1, MTFP1, HILPDA, VKORC1, TPI1, and HIST1H1C) that are up-regulated in hypoxia and whose expression levels are correlated with poor patient outcome in three independent neuroblastoma cohorts...
October 17, 2016: Oncotarget
Dongkyu Kim, Sook Hee Ku, Hyosuk Kim, Ji Hoon Jeong, Minhyung Lee, Ick Chan Kwon, Donghoon Choi, Sun Hwa Kim
Gene therapy is aimed at selectively knocking up or knocking down the target genes involved in the development of diseases. In many human diseases, dysregulation of disease-associated genes is occurred concurrently: some genes are abnormally turned up and some are turned down. In the field of non-viral gene therapy, plasmid DNA (pDNA) and small interfering RNA (siRNA) are suggested as representative regulation tools for activating and silencing the expression of genes of interest, representatively. Herein, we simultaneously loaded both siRNA (Src homology region 2 domain-containing tyrosine phosphatase-1 siRNA, siSHP-1) for anti-apoptosis and pDNA (hypoxia-inducible vascular endothelial growth factor expression vector, pHI-VEGF) for angiogenesis in a single polymeric nanocarrier and used to synergistically attenuate ischemia-reperfusion (IR)-induced myocardial infarction, which is mainly caused by dysregulating of cardiac apoptosis and angiogenesis...
October 17, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
Minghui Ou, Xuezhi Sun, Jiancheng Liang, Fei Liu, Liqin Wang, Xiaomin Wu, Jie Tu
A water-soluble polysaccharide (STPC2) was isolated from the boiling-water extract of Sargassum thunbergii, purified by CaCl2 precipitation and chromatography on DEAE-cellulose and Sephacryl S-300 column. It was found that STPC2, with a molecular weight of 57kD, was composed of fucose, xylose, galactose and glucuronic acid, in a ratio of 8.1: 3.8: 2.1: 1.0. Additionally, we found that STPC2 significantly inhibited endothelial cell migration and tube formation without toxicity. Moreover, STPC2 significantly inhibited lung cancer cell A549 migration and proliferation...
October 17, 2016: International Journal of Biological Macromolecules
J Y Dong, F Song, Y K Liu, X Q Wang
Objective: To simulate the environmental factors during the process of formation and evolution of hypertrophic scar, so as to explore the effects of moderate and severe hypoxia and low concentration of serum protein on the function of human hypertrophic scar fibroblasts (HSFs). Methods: Human HSFs were routinely cultured. Cells of the 3rd to the 6th passage were divided into 10.0% oxygen+ 10.0% fetal calf serum (FCS), 5.0% oxygen+ 5.0% FCS, and 0.5% oxygen+ 0.5% FCS groups according to the random number table...
October 20, 2016: Zhonghua Shao Shang za Zhi, Zhonghua Shaoshang Zazhi, Chinese Journal of Burns
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