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Andrew J Bryant, Edward W Scott
Pulmonary hypertension complicating idiopathic pulmonary fibrosis, also known as secondary pulmonary hypertension, represents a major source of morbidity and mortality in affected patients. While the study of primary pulmonary arterial hypertension has yielded several therapies, the same is not true for the treatment of pulmonary hypertension secondary to pulmonary fibrosis. Recent studies have indicated an important role of hypoxia-inducible factor (HIF) - a regulatory protein that is vital in adaptation to hypoxic conditions - in the development of secondary pulmonary hypertension...
2016: Receptors & Clinical Investigation
Ngoc Thi Hong Hoang, Tetsuya Kadonosono, Takahiro Kuchimaru, Shinae Kizaka-Kondoh
Pancreatic cancer is one of the most lethal digestive system cancers with a 5-year survival rate of 4-7%. Despite extensive efforts, recent chemotherapeutic regimens have provided only limited benefits to pancreatic cancer patients. Gemcitabine and TS-1, the current standard-of-care chemotherapeutic drugs for treatment of this severe cancer, have a low response rate. Hypoxia is one of the factors contributing to treatment resistance. Specifically, overexpression of hypoxia-inducible factor, a master transcriptional regulator of cell adaption to hypoxia, is strongly correlated with poor prognosis in many human cancers...
August 2016: Cancer Science
Ana Laura De Lella Ezcurra, Agustina Paola Bertolin, Kevin Kim, Maximiliano Javier Katz, Lautaro Gándara, Tvisha Misra, Stefan Luschnig, Norbert Perrimon, Mariana Melani, Pablo Wappner
Cellular and systemic responses to low oxygen levels are principally mediated by Hypoxia Inducible Factors (HIFs), a family of evolutionary conserved heterodimeric transcription factors, whose alpha- and beta-subunits belong to the bHLH-PAS family. In normoxia, HIFα is hydroxylated by specific prolyl-4-hydroxylases, targeting it for proteasomal degradation, while in hypoxia the activity of these hydroxylases decreases due to low oxygen availability, leading to HIFα accumulation and expression of HIF target genes...
May 2016: PLoS Genetics
Yuki Hirota-Takahata, Hideki Kobayashi, Masaaki Kizuka, Takao Ohyama, Michiko Kitamura-Miyazaki, Yasuhiro Suzuki, Mie Fujiwara, Mutsuo Nakajima, Osamu Ando
In the course of our screening for activators of hypoxia-inducible factor (HIF), A-503451 A and virantmycin were isolated from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 60101. From the same culture, the non-active homologs A-503451 B and D were also isolated. A-503451 A and virantmycin activated HIF-dependent reporter gene expression with EC50 values of 8 and 17 ng ml(-1), respectively. They are highly potent activators of HIF and thus may be therapeutically useful for erythropoiesis and neural cell protection...
March 9, 2016: Journal of Antibiotics
Carsten C Scholz, Javier Rodriguez, Christina Pickel, Stephen Burr, Jacqueline-Alba Fabrizio, Karen A Nolan, Patrick Spielmann, Miguel A S Cavadas, Bianca Crifo, Doug N Halligan, James A Nathan, Daniel J Peet, Roland H Wenger, Alex Von Kriegsheim, Eoin P Cummins, Cormac T Taylor
The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22...
January 2016: PLoS Biology
Yogesh Saini, Steven P Proper, Peter Dornbos, Krista K Greenwood, Anna K Kopec, Scott G Lynn, Elizabeth Grier, Lyle D Burgoon, Timothy R Zacharewski, Russell S Thomas, Jack R Harkema, John J LaPres
Hypoxia is a state of decreased oxygen reaching the tissues of the body. During prenatal development, the fetus experiences localized occurrences of hypoxia that are essential for proper organogenesis and survival. The response to decreased oxygen availability is primarily regulated by hypoxia-inducible factors (HIFs), a family of transcription factors that modulate the expression of key genes involved in glycolysis, angiogenesis, and erythropoiesis. HIF-1α and HIF-2α, two key isoforms, are important in embryonic development, and likely are involved in lung morphogenesis...
2015: PloS One
L Wang, S Cui, L Ma, L Kong, X Geng
Oxygen is essential for aerobic life, and hypoxia has very severe consequences. Organisms need to overcome low oxygen levels to maintain biological functions during normal development and in disease states. The mechanism underlying the hypoxic response has been widely investigated in model animals such as Drosophila melanogaster and Caenorhabditis elegans. Hypoxia-inducible factor (HIF), a key gene product in the response to oxygen deprivation, is primarily regulated by prolyl hydroxylase domain enzymes (PHDs)...
December 2015: Insect Molecular Biology
Murtaza M Tambuwala, Mario C Manresa, Eoin P Cummins, Vincenzo Aversa, Ivan S Coulter, Cormac T Taylor
Targeting hypoxia-sensitive pathways has recently been proposed as a new therapeutic approach to the treatment of intestinal inflammation. HIF-hydroxylases are enzymes which confer hypoxic-sensitivity upon the hypoxia-inducible factor (HIF), a major regulator of the adaptive response to hypoxia. Previous studies have shown that systemic (intraperitoneal) administration of hydroxylase inhibitors such as dimethyloxalylglycine (DMOG) is profoundly protective in multiple models of colitis, however the therapeutic potential of this approach is limited due to potential side-effects associated with systemic drug exposure and the fact that orally delivered DMOG is ineffective (likely due to drug inactivation by gastric acid)...
November 10, 2015: Journal of Controlled Release: Official Journal of the Controlled Release Society
Caleb J Kelly, Leon Zheng, Eric L Campbell, Bejan Saeedi, Carsten C Scholz, Amanda J Bayless, Kelly E Wilson, Louise E Glover, Douglas J Kominsky, Aaron Magnuson, Tiffany L Weir, Stefan F Ehrentraut, Christina Pickel, Kristine A Kuhn, Jordi M Lanis, Vu Nguyen, Cormac T Taylor, Sean P Colgan
Interactions between the microbiota and distal gut are fundamental determinants of human health. Such interactions are concentrated at the colonic mucosa and provide energy for the host epithelium through the production of the short-chain fatty acid butyrate. We sought to determine the role of epithelial butyrate metabolism in establishing the austere oxygenation profile of the distal gut. Bacteria-derived butyrate affects epithelial O2 consumption and results in stabilization of hypoxia-inducible factor (HIF), a transcription factor coordinating barrier protection...
May 13, 2015: Cell Host & Microbe
Ellen Marks, Bridie J Goggins, Jocelle Cardona, Siobhan Cole, Kyra Minahan, Sean Mateer, Marjorie M Walker, Robert Shalwitz, Simon Keely
BACKGROUND: Pharmacological induction of hypoxia-inducible factor (HIF), a global transcriptional regulator of the hypoxic response, by prolyl hydroxylase inhibitors (PHDi) is protective in murine models of colitis, and epithelial cells are critical for the observed therapeutic efficacy. Because systemic HIF activation may lead to potentially negative off-target effects, we hypothesized that targeting epithelial HIF through oral delivery of PHDi would be sufficient to protect against colitis in a mouse model...
February 2015: Inflammatory Bowel Diseases
Hanna Tarhonskaya, Rasheduzzaman Chowdhury, Ivanhoe K H Leung, Nikita D Loik, James S O McCullagh, Timothy D W Claridge, Christopher J Schofield, Emily Flashman
The prolyl hydroxylase domain proteins (PHDs) catalyse the post-translational hydroxylation of the hypoxia-inducible factor (HIF), a modification that regulates the hypoxic response in humans. The PHDs are Fe(II)/2-oxoglutarate (2OG) oxygenases; their catalysis is proposed to provide a link between cellular HIF levels and changes in O2 availability. Transient kinetic studies have shown that purified PHD2 reacts slowly with O2 compared with some other studied 2OG oxygenases, a property which may be related to its hypoxia-sensing role...
November 1, 2014: Biochemical Journal
Guoshan Wang, Zhigang Yu, Yu Zhen, Tiezhu Mi, Yan Shi, Jianyan Wang, Minxiao Wang, Song Sun
The maintenance of physiological oxygen homeostasis is mediated by hypoxia-inducible factor (HIF), a key transcriptional factor of the PHD-HIF system in all metazoans. However, the molecular evolutionary origin of this central physiological regulatory system is not well characterized. As the earliest eumetazoans, Cnidarians can be served as an interesting model for exploring the HIF system from an evolutionary perspective. We identified the complete cDNA sequence of HIF-1α (ASHIF) from the Aurelia sp.1, and the predicted HIF-1α protein (pASHIF) was comprised of 674 amino acids originating from 2,025 bp nucleotides...
2014: PloS One
Shao-Chieh Lin, Wan-Lin Liao, Jenq-Chang Lee, Shaw-Jenq Tsai
Hypoxia is a common phenomenon of solid tumors and contributes to aggressive phenotype and treatment failure. Hypoxia-inducible factor (HIF), a versatile transcription factor that regulates more than 5% of total human genes, not only plays important roles in controlling physiological processes, but is also a crucial mediator in hypoxia-induced tumor progression and chemoresistance. Overexpression of HIF-1α is detected in a wide spectrum of cancers via different kinds of mechanisms, including reduced oxygen concentration, loss-of-function of tumor suppressor gene, activating mutation of oncogenes, and hyperactivation of protein kinase signaling pathways...
May 8, 2014: Experimental Biology and Medicine
Lea Rahtu-Korpela, Sara Karsikas, Sohvi Hörkkö, Roberto Blanco Sequeiros, Eveliina Lammentausta, Kari A Mäkelä, Karl-Heinz Herzig, Gail Walkinshaw, Kari I Kivirikko, Johanna Myllyharju, Raisa Serpi, Peppi Koivunen
Obesity is a major public health problem, predisposing subjects to metabolic syndrome, type 2 diabetes, and cardiovascular diseases. Specific prolyl 4-hydroxylases (P4Hs) regulate the stability of the hypoxia-inducible factor (HIF), a potent governor of metabolism, with isoenzyme 2 being the main regulator. We investigated whether HIF-P4H-2 inhibition could be used to treat obesity and its consequences. Hif-p4h-2-deficient mice, whether fed normal chow or a high-fat diet, had less adipose tissue, smaller adipocytes, and less adipose tissue inflammation than their littermates...
October 2014: Diabetes
Jian Wang, Jinkun Zhang, Chunxiao Zhou, Lei Chen, Qiang Yu
Gastric cancer (GC) is among the most common human malignancies and the second leading cause of cancer-related death worldwide. Accumulated evidence from molecular genetics indicates that an individual's genetic factors are involved in their susceptibility to GC. Hypoxia is a common feature of cancer and the hypoxia-inducible factor (HIF), a transcription factor that regulates oxygen homeostasis, plays key roles in the growth of solid tumors and regulating cellular responses to hypoxia. Prolyl hydroxylase (PHD1, also known as EGLN2) is one of the three enzymes capable of hydroxylating the alpha subunit of HIF and results in polyubiquitinylation and proteasomal degradation of HIF...
April 2014: Genetic Testing and Molecular Biomarkers
Kumi Shoji, Tetsuhiro Tanaka, Masaomi Nangaku
PURPOSE OF REVIEW: Chronic hypoxia in the tubulointerstitium has been recognized as a final common pathway that leads to the development of end-stage renal disease. Hypoxia-inducible factor (HIF), a master regulator of the adaptive response against hypoxia, is involved in the pathogenesis of chronic kidney disease (CKD). This review focuses on HIF and novel therapeutic strategies targeting HIF. RECENT FINDINGS: Although HIF upregulation is beneficial against hypoxic kidney injury, it may be harmful under certain pathological conditions...
March 2014: Current Opinion in Nephrology and Hypertension
Cristina Branco-Price, Colin E Evans, Randall S Johnson
Tumor biology is a broad and encompassing field of research, particularly given recent demonstrations of the multicellular nature of solid tumors, which have led to studies of molecular and metabolic intercellular interactions that regulate cancer progression. Hypoxia is a broad stimulus that results in activation of hypoxia inducible factors (HIFs). Downstream HIF targets include angiogenic factors (e.g. vascular endothelial growth factor, VEGF) and highly reactive molecules (e.g. nitric oxide, NO) that act as cell-specific switches with unique spatial and temporal effects on cancer progression...
December 2013: Oncotarget
Agnieszka A Rawluszko, Katarzyna E Bujnicka, Karolina Horbacka, Piotr Krokowicz, Paweł P Jagodziński
BACKGROUND: Colorectal cancer (CRC) is one of the most common and comprehensively studied malignancies. Hypoxic conditions during formation of CRC may support the development of more aggressive cancers. Hypoxia inducible factor (HIF), a major player in cancerous tissue adaptation to hypoxia, is negatively regulated by the family of prolyl hydroxylase enzymes (PHD1, PHD2, PHD3) and asparaginyl hydroxylase, called factor inhibiting HIF (FIH). METHODS: PHD1, PHD2, PHD3 and FIH gene expression was evaluated using quantitative RT-PCR and western blotting in primary colonic adenocarcinoma and adjacent histopathologically unchanged colonic mucosa from patients who underwent radical surgical resection of the colon (n=90), and the same methods were used for assessment of PHD3 gene expression in HCT116 and DLD-1 CRC cell lines...
2013: BMC Cancer
Audrey M Wall, Alan E Corcoran, Ken D O'Halloran, John J O'Connor
Chronic intermittent hypoxia (CIH) is an underlying component of obstructive sleep apnoea and has been shown to have deleterious and damaging effects on central neurons and to impair synaptic plasticity in the CA1 region of the rat hippocampus. CIH has previously been shown to impair synaptic plasticity and working memory. CIH is a potent inducer of hypoxia inducible factor (HIF), a key regulator in a cell's adaptation to hypoxia that plays an important role in the fate of neurons during ischemia. Levels of HIF-1α are regulated by the activity of a group of enzymes called HIF-prolyl 4-hydroxylases (PHDs) and these have become potential pharmacological targets for preconditioning against ischemia...
February 2014: Neurobiology of Disease
Zhenyu Huang, Kazushiro Fujiwara, Ryohei Minamide, Koichi Hasegawa, Kazuaki Yoshikawa
Neural stem cells (NSCs) reside in vivo in hypoxic environments, and NSC proliferation is enhanced in vitro under hypoxic conditions. Various adaptive responses to hypoxia are mediated by hypoxia-inducible factors (HIFs), a family of basic helix-loop-helix Per-Arnt-Sim (PAS) transcription factors. Necdin, a MAGE (melanoma antigen) family protein, is expressed abundantly in postmitotic neurons and possesses potent antimitotic and antiapoptotic activities. We here report that hypoxia induces degradation of the necdin protein in primary NSCs by HIF-mediated ubiquitin-proteasome system...
June 19, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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