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https://www.readbyqxmd.com/read/28632992/targeting-the-rhogtpase-rock-pathway-for-the-treatment-of-vhl-hif-pathway-driven-cancers
#1
Jordan M Thompson, Jaime Landman, Olga V Razorenova
The loss of the von Hippel-Lindau (VHL) tumor-suppressor is a major driver of Clear Cell Renal Cell Carcinoma (CC-RCC) resulting in the stabilization and overactivation of hypoxia inducible factors (HIFs). ROCK 1 is a well-known protein serine/threonine kinase which is recognized as having a role in cancer including alterations in cell motility, metastasis and angiogenesis. As a function of the later effect, we recently investigated and identified a synthetic lethal interaction between VHL loss and ROCK1 inhibition in CC-RCC that is dependent on HIF overactivation...
June 20, 2017: Small GTPases
https://www.readbyqxmd.com/read/28630416/hif-1-mediated-suppression-of-mitochondria-electron-transport-chain-function-confers-resistance-to-lidocaine-induced-cell-death
#2
Akihisa Okamoto, Chisato Sumi, Hiromasa Tanaka, Munenori Kusunoki, Teppei Iwai, Kenichiro Nishi, Yoshiyuki Matsuo, Hiroshi Harada, Keizo Takenaga, Hidemasa Bono, Kiichi Hirota
The local anesthetic lidocaine induces cell death by altering reactive oxygen species (ROS) generation and mitochondrial electron transport chain function. Because hypoxia-inducible factor 1 (HIF-1) is involved in determining oxygen metabolism and mitochondria function, we investigated the involvement of HIF-1 activity in lidocaine-induced cell death. We investigated the role of HIF activation on lidocaine-induced caspase activation and cell death in renal cell-derived RCC4 cells lacking functional von Hippel-Lindau (VHL) protein...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28625716/application-of-in-vitro-screening-methods-on-hypoxia-inducible-factor-prolyl-hydroxylase-inhibitors
#3
REVIEW
Yue Wu, Zhensheng Jiang, Qidong You, Xiaojin Zhang
Anemia resulting from the reduced expression of erythropoietin (EPO) is a common complication of patients with chronic kidney diseases (CKD). Hypoxia inducible transcription factor-α (HIF-α), which adapts cellular hypoxia condition, regulates the expression of many downstream genes including the EPO gene. Hypoxia inducible transcription factor prolyl hydroxylase 2 (HIF-PHD2), as the key regulator of hypoxia response, is function of hydroxylating specify proline residues of HIF-α, which may lead to the degradation of HIF-α and eventually cause disenabling the expression of erythropoietin...
May 13, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28624448/identification-of-functional-hypoxia-inducible-factor-response-elements-in-the-human-lysyl-oxidase-gene-promoter
#4
Victoria Wang, David A Davis, Robert Yarchoan
Human lysyl oxidase (LOX) is a hypoxia-responsive gene whose product catalyzes collagen crosslinking and is thought to be important in cancer metastasis and osteoarthritis. We previously demonstrated that LOX was upregulated by hypoxia inducible factor 2 (HIF-2) more strongly than hypoxia inducible 1 (HIF-1). We further investigated the response of the LOX gene and LOX promoter to HIFs. LOX mRNA, measured by real time reverse transcriptase-PCR, was strongly up-regulated (almost 40-fold), by transfection of HEK-293T cells with a plasmid encoding the HIF-2α subunit of HIF-2, but only three-fold by a plasmid encoding HIF-1α...
June 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28624236/regulation-of-the-proprotein-convertases-expression-and-activity-during-regenerative-angiogenesis-role-of-hypoxia-inducible-factor-hif
#5
Jia Ma, Serge Evrard, Iker Badiola, Geraldine Siegfried, Abdel-Majid Khatib
Proprotein convertases (PCs) are involved in various physiological and pathological processes ranging from embryogenesis to carcinogenesis. Here, using the zebrafish fin regeneration model, we report induced expression of furin and PC5 but not PACE4 and PC7 during fin regeneration that is associated with increased PC activity. Stabilization of HIF by cobalt chloride (CoCl2) further increases these processes. The use of the general PC-inhibitor decanoyl-RVKR-cholromethyl ketone (CMK) inhibited control and CoCl2-induced PC activity...
June 12, 2017: European Journal of Cell Biology
https://www.readbyqxmd.com/read/28623342/hif-1%C3%AE-knockdown-reduces-glycolytic-metabolism-and-induces-cell-death-of-human-synovial-fibroblasts-under-normoxic-conditions
#6
Manuel J Del Rey, Álvaro Valín, Alicia Usategui, Carmen M García-Herrero, María Sánchez-Aragó, José M Cuezva, María Galindo, Beatriz Bravo, Juan D Cañete, Francisco J Blanco, Gabriel Criado, José L Pablos
Increased glycolysis and HIF-1α activity are characteristics of cells under hypoxic or inflammatory conditions. Besides, in normal O2 environments, elevated rates of glycolysis support critical cellular mechanisms such as cell survival. The purpose of this study was to analyze the contribution of HIF-1α to the energy metabolism and survival of human synovial fibroblasts (SF) under normoxic conditions. HIF-1α was silenced using lentiviral vectors or small-interfering RNA (siRNA) duplexes. Expression analysis by qRT-PCR and western blot of known HIF-1α target genes in hypoxia demonstrated the presence of functional HIF-1α in normoxic SF and confirmed the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a HIF-1α target even in normoxia...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28620389/2-deoxy-d-glucose-treatment-decreases-anti-inflammatory-m2-macrophage-polarization-in-mice-with-tumor-and-allergic-airway-inflammation
#7
Qingjie Zhao, Zhulang Chu, Linnan Zhu, Tao Yang, Peng Wang, Fang Liu, Ying Huang, Fang Zhang, Xiaodong Zhang, Wenjun Ding, Yong Zhao
As important effector cells in inflammation, macrophages can be functionally polarized into either inflammatory M1 or alternatively activated anti-inflammatory M2 phenotype depending on surroundings. The key roles of glycolysis in M1 macrophage polarization have been well defined. However, the relationship between glycolysis and M2 polarized macrophages is still poorly understood. Here, we report that 2-deoxy-d-glucose (2-DG), an inhibitor of the glycolytic pathway, markedly inhibited the expressions of Arg, Ym-1, Fizz1, and CD206 molecules, the hall-markers for M2 macrophages, during macrophages were stimulated with interleukin 4...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28617871/hypoxia-inducible-factor-1%C3%AE-plays-roles-in-epstein-barr-virus-s-natural-life-cycle-and-tumorigenesis-by-inducing-lytic-infection-through-direct-binding-to-the-immediate-early-bzlf1-gene-promoter
#8
Richard J Kraus, Xianming Yu, Blue-Leaf A Cordes, Saraniya Sathiamoorthi, Tawin Iempridee, Dhananjay M Nawandar, Shidong Ma, James C Romero-Masters, Kyle G McChesney, Zhen Lin, Kathleen R Makielski, Denis L Lee, Paul F Lambert, Eric C Johannsen, Shannon C Kenney, Janet E Mertz
When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas (HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens...
June 15, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28611287/vorinostat-suppresses-hypoxia-signaling-by-modulating-nuclear-translocation-of-hypoxia-inducible-factor-1-alpha
#9
Chao Zhang, Chunzhang Yang, Michael J Feldman, Herui Wang, Ying Pang, Dominic M Maggio, Dongwang Zhu, Cody L Nesvick, Pauline Dmitriev, Petra Bullova, Prashant Chittiboina, Roscoe O Brady, Karel Pacak, Zhengping Zhuang
Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly-wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28610954/feedback-regulation-of-aldoa-activates-the-hif-1%C3%AE-mmp9-axis-to-promote-lung-cancer-progression
#10
Yu-Chan Chang, Yung-Chieh Chan, Wei-Ming Chang, Yuan-Feng Lin, Chih-Jen Yang, Chia-Yu Su, Ming-Shyan Huang, Alexander T H Wu, Michael Hsiao
Distant metastasis and recurrence are the greatest challenges in the clinical management of lung cancer. Despite advances in targeted therapies, high mortality rates persist. Therefore, alternative therapeutic interventions are urgently required. Accumulating evidence indicates that normalizing tumor metabolism may be a way to increase therapeutic efficacy and to reduce tumor malignancy. Here, we analyzed integrated transcriptomics data and an shRNA library against glycolytic enzymes and found that elevated Aldolase A expression is highly correlated with metastatic potential and a poor prognosis in patients with non-small cell lung cancer (NSCLC)...
June 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28606929/targeting-oxygen-sensing-prolyl-hydroxylase-phd-for-metformin-associated-lactic-acidosis-treatment
#11
Tomoko Oyaizu-Toramaru, Tomohiro Suhara, Noriyo Hayakawa, Takashi Nakamura, Akiko Kubo, Shizuka Minamishima, Kyoji Yamaguchi, Takako Hishiki, Hiroshi Morisaki, Makoto Suematsu, Yoji Andrew Minamishima
Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anti-cancer and anti-aging properties. However, it is known to induce metformin-associated lactic acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate transcription factor HIF (hypoxia-inducible factor) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels...
June 12, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28602978/tanshinone-iiainhibits-%C3%AE-catenin-vegf-mediated-angiogenesis-by-targeting-tgf-%C3%AE-1-in-normoxic-and-hif-1%C3%AE-inhypoxicmicroenvironments-in-human-colorectal-cancer
#12
Hua Sui, Jihui Zhao, Lihong Zhou, Haotian Wen, Wanli Deng, Chunpu Li, Qing Ji, Xuan Liu, Yuanyuan Feng, Ni Chai, Qibo Zhang, Jianfeng Cai, Qi Li
In a previous study, we demonstrated that Tanshinone IIA effectively inhibits CRC angiogenesis in vivo, but the underlying mechanisms were not elucidated. In this report, we describe experiments in which HIF-1α levels were manipulated to probe the effect of hypoxia on CRC cell angiogenesis. We studied the effects of Tan IIA on CRC pro-angiogenic factor and on human umbilical vein endothelial cell angiogenesis in normoxia and hypoxia. Our results show that Tan IIA not only lowers HIF-1α levels and inhibits secretion of VEGF and bFGF, but also efficiently suppresses the proliferation, tube formation and metastasis of HUVECs...
June 7, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28595291/the-expression-of-cxcr4-is-induced-by-the-lh-surge-and-mediated-by-progesterone-receptors-in-human-preovulatory-granulosa-cells
#13
Yohan Choi, Ji Yeon Park, Kalin Wilson, Katherine L Rosewell, Mats Brännström, James W Akin, Thomas E Curry, Misung Jo
The chemokine CXC Motif Ligand 12 (CXCL12) and its cognate receptor, CXCR4, have been implicated in the ovulatory process in various animal models. However, little is known about the expression and regulation of CXCL12 and CXCR4 and their functions during the ovulatory period in the human ovary. In the present study, we characterized the expression patterns of CXCL12 and CXCR4 in preovulatory follicles collected before the LH surge and at defined hours after hCG administration in women with the regular menstrual cycle...
June 8, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28594907/gastrointestinal-cancer-cells-treatment-with-bevacizumab-activates-a-vegf-autoregulatory-mechanism-involving-telomerase-catalytic-subunit-htert-via-pi3k-akt-hif-1%C3%AE-and-vegf-receptors
#14
Nadine Mahfouz, Roula Tahtouh, Nada Alaaeddine, Joelle El Hajj, Riad Sarkis, Ray Hachem, Issam Raad, George Hilal
BACKGROUND: Targeting angiogenesis has been considered a promising treatment of choice for a large number of malignancies, including gastrointestinal cancers. Bevacizumab is an anti-vascular endothelial growth factor (anti-VEGF) being used for this purpose. However, treatment efficacy is largely questioned. Telomerase activity, responsible for cancer cell immortality, is detected in 85-95% of human cancers and is considered a potential regulator of VEGF. The aim of our study was to investigate the interrelationship between VEGF and hTERT in gastrointestinal cancers and to explore cell response to a combined inhibition of telomerase and VEGF...
2017: PloS One
https://www.readbyqxmd.com/read/28594552/1-2-4-triazolo-1-5-a-pyridine-hif-prolylhydroxylase-domain-1-phd-1-inhibitors-with-a-novel-monodentate-binding-interaction
#15
Saleh Ahmed, Andrew Ayscough, Greg R Barker, Hannah E Canning, Richard Davenport, Robert Downham, David Harrison, Kerry Jenkins, Natasha Kinsella, David G Livermore, Susanne Wright, Anthony David Ivetac, Robert Skene, Steven J Wilkens, Natalie A Webster, Alan G Hendrick
Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe(2+) ion, whilst the benzonitrile group accepts a hydrogen bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties...
June 8, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28592747/roles-of-hypoxia-response-in-retinal-development-and-pathophysiology
#16
Toshihide Kurihara
The hypoxia response is a fundamental phenomenon mainly regulated by hypoxia-inducible factors (HIFs). For more than a decade, we have investigated and revealed the roles of the hypoxia response in the development, physiology, and pathophysiology of the retina by generating and utilizing cell-type-specific conditional knockout mice. To investigate the functions of genes related to the hypoxia response in cells composing the retina, we generated various mouse lines that lack HIFs and/or related genes specifically in retinal neurons, astrocytes, myeloid cells, or retinal pigment epithelium cells...
June 6, 2017: Keio Journal of Medicine
https://www.readbyqxmd.com/read/28592559/time-dependent-inhibition-of-phd2
#17
Isabelle Tcholakov, Charles E Grimshaw, Lihong Shi, Andre Kiryanov, Sean T Murphy, Christopher J Larson, Artur Plonowski, Jacques Ermolieff
Prolyl Hydroxylases (PHDs) down-regulate the level of hypoxia-inducible factors (HIFs) by hydroxylating key proline residues which triggers the degradation of the protein and affect the cell and its ability to respond to hypoxic stress. Several small molecule PHD inhibitors are now in various preclinical and clinical stages for the treatment of anemia. This study provides a detail kinetic analysis for some of these inhibitors. The data generated in this study suggest that these compounds are reversible and compete directly with the co-substrate, 2-oxoglutarate (2-OG) for binding at the enzyme active site...
June 7, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28592285/blockade-of-adenosine-a2a-receptor-enhances-cd8-t-cells-response-and-decreases-regulatory-t-cells-in-head-and-neck-squamous-cell-carcinoma
#18
Si-Rui Ma, Wei-Wei Deng, Jian-Feng Liu, Liang Mao, Guang-Tao Yu, Lin-Lin Bu, Ashok B Kulkarni, Wen-Feng Zhang, Zhi-Jun Sun
BACKGROUND: Cancer immunotherapy offers a promising approach in cancer treatment. The adenosine A2A receptor (A2AR) could protect cancerous tissues from immune clearance via inhibiting T cells response. To date, the role of A2AR in head and neck squamous cell carcinoma (HNSCC) has not been investigated. Here, we sought to explore the expression and immunotherapeutic value of A2AR blockade in HNSCC. METHODS: The expression of A2AR was evaluated by immunostaining in 43 normal mucosae, 48 dysplasia and 165 primary HNSCC tissues...
June 7, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28592228/anti-fibrogenic-effect-of-ppar-%C3%AE-agonists-in-human-intestinal-myofibroblasts
#19
Jun Bon Koo, Myeong-Ok Nam, Younshin Jung, Jongman Yoo, Duk Hwan Kim, Gwangil Kim, Sung Jae Shin, Kee Myung Lee, Ki Baik Hahm, Jong Woo Kim, Sung Pyo Hong, Kwang Jae Lee, Jun Hwan Yoo
BACKGROUND: Intestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohn's disease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated that peroxisome proliferator-activated receptor- γ (PPAR-γ) agonists have anti-fibrogenic properties in organs besides the gut; however, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of PPAR-γ agonists on human primary intestinal myofibroblasts (HIFs)...
June 7, 2017: BMC Gastroenterology
https://www.readbyqxmd.com/read/28589898/the-zebrafish-mir-125c-is-induced-under-hypoxic-stress-via-hypoxia-inducible-factor-1%C3%AE-and-functions-in-cellular-adaptations-and-embryogenesis
#20
Yan He, Chun-Xiao Huang, Nan Chen, Meng Wu, Yan Huang, Hong Liu, Rong Tang, Wei-Min Wang, Huan-Ling Wang
Hypoxia is a unique environmental stress. Hypoxia inducible factor-lα (HIF-lα) is a major transcriptional regulator of cellular adaptations to hypoxic stress. MicroRNAs (miRNAs) as posttranscriptional gene expression regulators occupy a crucial role in cell survival under low-oxygen environment. Previous evidences suggested that miR-125c is involved in hypoxia adaptation, but its precise biological roles and the regulatory mechanism underlying hypoxic responses remain unknown. The present study showed that zebrafish miR-125c is upregulated by hypoxia in a Hif-lα-mediated manner in vitro and in vivo...
May 18, 2017: Oncotarget
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