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A A R Thompson, R S Dickinson, F Murphy, J P Thomson, H M Marriott, A Tavares, J Willson, L Williams, A Lewis, A Mirchandani, P Dos Santos Coelho, C Doherty, E Ryan, E Watts, N M Morton, S Forbes, R H Stimson, A G Hameed, N Arnold, J A Preston, A Lawrie, V Finisguerra, M Mazzone, P Sadiku, J Goveia, F Taverna, P Carmeliet, S J Foster, E R Chilvers, A S Cowburn, D H Dockrell, R S Johnson, R R Meehan, M K B Whyte, S R Walmsley
Hypoxia and bacterial infection frequently co-exist, in both acute and chronic clinical settings, and typically result in adverse clinical outcomes. To ameliorate this morbidity, we investigated the interaction between hypoxia and the host response. In the context of acute hypoxia, both S. aureus and S. pneumoniae infections rapidly induced progressive neutrophil mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise. Preconditioning animals through longer exposures to hypoxia, prior to infection, prevented these pathophysiological responses and profoundly dampened the transcriptome of circulating leukocytes...
February 10, 2017: Science Immunology
Agnes Juhasz, Susan Markel, Shikha Gaur, Han Liu, Jiamo Lu, Guojian Jiang, Xiwei Wu, Smitha Antony, Yongzhong Wu, Giovanni Melillo, Jennifer L Meitzler, Diana C Haines, Donna Butcher, Krishnendu Roy, James H Doroshow
Reactive oxygen species (ROS) play a critical role in cell signaling and proliferation. NADPH oxidase 1 (NOX1), a membrane-bound flavin dehydrogenase that generates O2(̇̄), is highly expressed in colon cancer. To investigate the role that NOX1 plays in colon cancer growth, we used shRNA to decrease NOX1 expression stably in HT-29 human colon cancer cells. The 80-90% decrease in NOX1 expression achieved by RNAi produced a significant decline in ROS production and a G1/S block that translated into a 2-3-fold increase in tumor cell doubling time without increased apoptosis...
May 12, 2017: Journal of Biological Chemistry
Julia A Ju, Inês Godet, I Chae Ye, Jungmin Byun, Hasini Jayatilaka, Sun Joo Lee, Lisha Xiang, Debangshu Samanta, Meng Horng Lee, Pei-Hsun Wu, Denis Wirtz, Gregg L Semenza, Daniele M Gilkes
Metastasis is the leading cause of breast cancer mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM-binding receptors in this process was explored. Using a bioinformatics approach, the expression of all integrin receptor subunits, in two independent breast cancer patient datasets, were analyzed to determine whether integrin status correlates with a validated hypoxia-inducible gene signature...
February 17, 2017: Molecular Cancer Research: MCR
Magda F Mohamed, Yasmin M Attia, Samia A Shouman, Ismail A Abdelhamid
Novel series of N-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl) cyanoacetamide derivatives are synthesized. The structure of these compounds was elucidated using different spectral tools. Compounds were evaluated for their cytotoxic activities against different types of human cancer cell lines including, breast (MCF-7, T47D, MDA MB231); liver (HEPG-2); colon (HCT116); prostate (PC3); and cervix (HELA) cells. In this study, we used compounds 11 and 12 that showed the highest cytotoxicity on PC3 and HEPG2 cells, to explore their effects on apoptosis, invasion ampamp; metastasis and angiogenesis...
January 10, 2017: Anti-cancer Agents in Medicinal Chemistry
Hui-Chun Xie, Jin-Gang Li, Jian-Ping He
With hypoxic stress, hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) are elevated and their responses are altered in skeletal muscles of plateau animals [China Qinghai-Tibetan plateau pikas (Ochotona curzoniae)] as compared with control animals [normal lowland Sprague-Dawley (SD) rats]. The results indicate that HIF-1alpha and VEGF are engaged in physiological functions under hypoxic environment. The purpose of the current study was to examine the protein levels of VEGF receptor subtypes (VEGFRs: VEGFR-1, VEGFR-2 and VEGFR-3) in the end organs, namely skeletal muscle, heart and lung in response to hypoxic stress...
May 4, 2017: Physiological Research
Guanghui Chen, Xin Gao, Jing Wang, Cheng Yang, Yang Wang, Yonggang Liu, Weiwei Zou, Tielong Liu
It has been shown that hypoxia stimulation promotes chondrocytes autophagy partly through HIF-1α, miR-146a and Bcl-2 progressively, and this mechanism represented the connection among hypoxia, miR-146a and autophagy, and provides a possible therapeutic strategy for osteoarthritis. However, the interaction between miR-146a and Bcl-2 is still unclear. Here in a hypoxic environment, we quantified the three reported miR-146a targets: two inflammation related targets Traf6, IRAK1; and the only reported target in chondrocytes Smad4...
April 1, 2017: Biological Chemistry
Leticia Serrano-Oviedo, José M Giménez-Bachs, Syongh Y Nam-Cha, Francisco J Cimas, Jesús García-Cano, Ricardo Sánchez-Prieto, Antonio S Salinas-Sánchez
OBJECTIVES: To determine the expression status of several proteins related to VHL gene function and its relationship with common clinicopathological parameters. MATERIAL AND METHODS: Observational, analytical, cross-sectional study with 50 patients diagnosed with clear cell renal cell carcinoma. The study analyzed VHL mutations and hypermethylation as well as protein expression of VHL, CA-IX, HIF-1alpha, VEGF, ERK1/2, and ERK5, relating them to clinical variables...
March 2017: Urologic Oncology
Caroline Reynaud, Laura Ferreras, Paola Di Mauro, Casina Kan, Martine Croset, Edith Bonnelye, Floriane Pez, Clémence Thomas, Géraldine Aimond, Antoine E Karnoub, Marie Brevet, Philippe Clézardin
Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase whose primary function is to drive collagen crosslinking and extracellular matrix stiffness. LOX in colorectal cancer synergizes with hypoxia-inducible factor-1 (HIF-1) to promote tumor progression. Here we investigated whether LOX/HIF1 endows colorectal cancer cells with full competence for aggressive colonization in bone. We show that a high LOX expression in primary tumors from patients with colorectal cancer was associated with poor clinical outcome, irrespective of HIF-1 In addition, LOX was expressed by tumor cells in the bone marrow from colorectal cancer patients with bone metastases...
January 15, 2017: Cancer Research
Jana Kudová, Ondřej Vašíček, Milan Číž, Lukáš Kubala
Melatonin, a molecule involved in the regulation of circadian rhythms, has protective effects against myocardial injuries. However, its capability to regulate the maturation of cardiac progenitor cells is unclear. Recently, several studies have shown that melatonin inhibits the stabilization of hypoxia-inducible factors (HIFs), important signaling molecules with cardioprotective effects. In this study, by employing differentiating mouse embryonic stem cells, we report that melatonin significantly upregulated the expression of cardiac cell-specific markers (myosin heavy chains six and seven) as well as the percentage of myosin heavy chain-positive cells...
November 2016: Journal of Pineal Research
Jana Kudová, Jiřina Procházková, Ondřej Vašiček, Tomáš Perečko, Miroslava Sedláčková, Martin Pešl, Jiří Pacherník, Lukáš Kubala
Cardiac cell formation, cardiomyogenesis, is critically dependent on oxygen availability. It is known that hypoxia, a reduced oxygen level, modulates the in vitro differentiation of pluripotent cells into cardiomyocytes via hypoxia inducible factor-1alpha (HIF-1α)-dependent mechanisms. However, the direct impact of HIF-1α deficiency on the formation and maturation of cardiac-like cells derived from mouse embryonic stem cells (mESC) in vitro remains to be elucidated. In the present study, we demonstrated that HIF-1α deficiency significantly altered the quality and quantity of mESC-derived cardiomyocytes...
2016: PloS One
Hong Li, Jishan Quan, Mengzi Zhang, Bryant C Yung, Xinwei Cheng, Yang Liu, Young B Lee, Chang-Ho Ahn, Deog Joong Kim, Robert J Lee
Lipid-albumin nanoparticles (LAN) were synthesized for delivery of RX-0047, an antisense oligonucleotide (ASO) against the hypoxia inducible factor-1 alpha (HIF-1α) to solid tumor. These lipid nanoparticles (LNs) incorporated a human serum albumin-pentaethylenehexamine (HSA-PEHA) conjugate, which is cationic and can form electrostatic complexes with negatively charged oligonucleotides. The delivery efficiency of LAN-RX-0047 was investigated in KB cells and a KB murine xenograft model. When KB cells were treated with LAN-RX-0047, significant HIF-1α downregulation and enhanced cellular uptake were observed compared to LN-RX-0047...
July 5, 2016: Molecular Pharmaceutics
Sofie Bæk Christlieb, Casper Nørgaard Strandholdt, Birgitte Brinkmann Olsen, Karen Juul Mylam, Thomas Stauffer Larsen, Anne Lerberg Nielsen, Max Rohde, Oke Gerke, Karen Ege Olsen, Michael Boe Møller, Bjarne Winther Kristensen, Niels Abildgaard, Abass Alavi, Poul Flemming Høilund-Carlsen
PURPOSE: The purpose of this study was to determine the ability of dual time-point (DTP) PET/CT with (18)F-FDG to discriminate between malignant and benign lymphadenopathies. The relationship between DTP FDG uptake and glucose metabolism/hypoxia markers in lymphadenopathies was also assessed. METHODS: Patients with suspected lymphoma or recently diagnosed treatment-naive lymphoma were prospectively enrolled for DTP FDG PET/CT (scans 60 min and 180 min after FDG administration)...
September 2016: European Journal of Nuclear Medicine and Molecular Imaging
Justin Egidius Swartz, Ajit Joe Pothen, Pauline Maria Wilhelmina van Kempen, Inge Stegeman, Fleurieke Karlijn Formsma, Ellen Maria Van Cann, Stefan Martin Willems, Wilko Grolman
BACKGROUND: Hypoxia induces stabilization of the transcription factor HIF-1alpha (HIF-1α), associated with (chemo-)radiotherapy resistance in oropharyngeal squamous cell carcinoma (SCC). We investigated the effect of HIF-1α expression on survival in relation to human papillomavirus (HPV) status in oropharyngeal SCC. METHODS: We conducted an immunohistochemical analysis of HIF-1α protein expression and downstream targets carbonic anhydrase-IX (CA-IX) and glucose transporter-1 (GLUT-1) in 274 patients with oropharyngeal SCC...
September 2016: Head & Neck
Bijaya K Nayak, Karthigayan Shanmugasundaram, William E Friedrichs, Rita C Cavaglierii, Mandakini Patel, Jeffrey Barnes, Karen Block
Hypoxia-inducible factor (HIF)-1 mediates hypoxia- and chronic kidney disease-induced fibrotic events. Here, we assessed whether HIF-1 blockade attenuates the manifestations of diabetic nephropathy in a type 1 diabetic animal model, OVE26. YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole], an HIF-1 inhibitor, reduced whole kidney glomerular hypertrophy, mesangial matrix expansion, extracellular matrix accumulation, and urinary albumin excretion as well as NOX4 protein expression and NADPH-dependent reactive oxygen species production, while blood glucose levels remained unchanged...
May 2016: Diabetes
S Perini, D Martinez, C C Montanari, C Z Fiori
INTRODUCTION: Obstructive sleep apnea has been associated with higher cancer incidence and mortality. Increased melanoma aggressivity was reported in obstructive sleep apnea patients. Mice exposed to intermittent hypoxia (IH) mimicking sleep apnea show enhanced melanoma growth. Markers of melanoma progression have not been investigated in this model. OBJECTIVE: The present study examined whether IH affects markers of melanoma tumor progression. METHODS: Mice were exposed to isocapnic IH to a nadir of 8% oxygen fraction for 14 days...
July 2016: Revista Portuguesa de Pneumologia
Wei Yu, Ryan A Denu, Kimberly A Krautkramer, Kreg M Grindle, David T Yang, Fotis Asimakopoulos, Peiman Hematti, John M Denu
B cell malignancies comprise a diverse group of cancers that proliferate in lymph nodes, bone marrow, and peripheral blood. SIRT3 (sirtuin 3) is the major deacetylase within the mitochondrial matrix that promotes aerobic metabolism and controls reactive oxygen species (ROS) by deacetylating and activating isocitrate dehydrogenase 2 (IDH2) and superoxide dismutase 2 (SOD2). There is controversy as to whether SIRT3 acts as an oncogene or a tumor suppressor, and here we investigated its role in B cell malignancies...
February 12, 2016: Journal of Biological Chemistry
Lindsay E Calderon, Shu Liu, Nova Arnold, Bethany Breakall, Joseph Rollins, Margaret Ndinguri
OBJECTIVES: Calcium independent group VIA phospholipase A2 (iPLA2β) and Matrix Metalloproteinase-9 (MMP-9) are upregulated in many disease states; their involvement with cancer cell migration has been a recent subject for study. Further, the molecular mechanisms mediating nicotine-induced breast cancer cell progression have not been fully investigated. This study aims to investigate whether iPLA2β mediates nicotine-induced breast cancer cell proliferation and migration through both in-vitro and in-vivo techniques...
2015: PloS One
Larysa V Yuzefovych, Andrea G Kahn, Michele A Schuler, Lars Eide, Ritu Arora, Glenn L Wilson, Ming Tan, Lyudmila I Rachek
Production of mitochondrial reactive oxygen species and integrity of mitochondrial DNA (mtDNA) are crucial in breast cancer progression and metastasis. Therefore, we evaluated the role of mtDNA damage in breast cancer by genetically modulating the DNA repair enzyme 8-oxoguanine DNA glycosylase (OGG1) in the PyMT transgenic mouse model of mammary tumorigenesis. We generated mice lacking OGG1 (KO), mice overexpressing human OGG1 subunit 1α in mitochondria (Tg), and mice simultaneously lacking OGG1 and overexpressing human OGG1 subunit 1α in mitochondria (KO/Tg)...
January 1, 2016: Cancer Research
Yupeng Dong, Yoshitaka Kimura, Takuya Ito, Clarissa Velayo, Takafumi Sato, Rika Sugibayashi, Kiyoe Funamoto, Kudo Hitomi, Keita Iida, Miyuki Endo, Naoaki Sato, Nobuo Yaegashi
During pregnancy, both ischemic reperfusion and bacterial agent LPS are known risk factors for fetal brain damage. However, there is a lack of evidence to explain whether vaginal LPS affects the fetus response to ischemic reperfusion. Here we reported that there was more than 2 folds higher vulnerability of fetal brain hemorrhage response to ischemic reperfusion when mother mouse was treated with vaginal LPS. As our previously reported, ischemic reperfusion induces P53-dependent fetal brain damage was based on a molecular mechanism: the transcriptional pattern was changed from HIF-1alpha-dependent to P53-dependent immediately...
December 4, 2015: Biochemical and Biophysical Research Communications
Emma J Hodson, Lynn G Nicholls, Philip J Turner, Ronan Llyr, James W Fielding, Gillian Douglas, Indrika Ratnayaka, Peter A Robbins, Christopher W Pugh, Keith J Buckler, Peter J Ratcliffe, Tammie Bishop
Ventilatory sensitivity to hypoxia increases in response to continued hypoxic exposure as part of acute acclimatisation. Although this process is incompletely understood, insights have been gained through studies of the hypoxia-inducible factor (HIF) hydroxylase system. Genetic studies implicate these pathways widely in the integrated physiology of hypoxia, through effects on developmental or adaptive processes. In keeping with this, mice that are heterozygous for the principal HIF prolyl hydroxylase, PHD2, show enhanced ventilatory sensitivity to hypoxia and carotid body hyperplasia...
March 1, 2016: Journal of Physiology
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