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https://www.readbyqxmd.com/read/28810656/hypoxia-inducible-factor-1%C3%AE-participates-in-hypoxia-induced-epithelial-mesenchymal-transition-via-response-gene-to-complement-32
#1
Liang Zhu, Qiu Zhao
The aim of the present study was to explore the function of response gene to complement 32 (RGC-32) in hypoxia-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer. Three kinds of hypoxia-inducible factor 1α (HIF-1α) small interfering (si)RNA were synthesized and the different effects on the expression of HIF-1α were detected by western blotting. In human pancreatic cancer BxPC-3 cells, HIF-1α levels were diminished using siRNA transfection or HIF-1α inhibitor pretreatment, and the expression levels of RGC-32 and EMT-associated proteins were analyzed using reverse transcription-quantitative polymerase chain reaction and western blotting...
August 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28810543/atorvastatin-has-a-protective-effect-in-a-mouse-model-of-bronchial-asthma-through-regulating-tissue-transglutaminase-and-triggering-receptor-expressed-on-myeloid-cells-1-expression
#2
Ming-Wei Liu, Rong Liu, Hai-Ying Wu, Mei Chen, Min-Na Dong, Yun-Qiao Huang, Chun-Hai Zhang, Yin-Zhong Wang, Jing Xia, Yang Shi, Feng-Mei Xie, Hua Luo, Xin-Yuan Zhao, Wei Wei, Mei-Xian Su
Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. Statin drugs have improved respiratory health and their therapeutic potential in asthma has been tested in clinical trials. However, the mechanism of action of statins in this context has remained elusive. The present study hypothesized that atorvastatin treatment of ovalbumin-exposed mice attenuates early features of airway remodeling via a mevalonate-dependent mechanism...
August 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28805660/prolyl-hydroxylase-2-inactivation-enhances-glycogen-storage-and-promotes-excessive-neutrophilic-responses
#3
Pranvera Sadiku, Joseph A Willson, Rebecca S Dickinson, Fiona Murphy, Alison J Harris, Amy Lewis, David Sammut, Ananda S Mirchandani, Eilise Ryan, Emily R Watts, A A Roger Thompson, Helen M Marriott, David H Dockrell, Cormac T Taylor, Martin Schneider, Patrick H Maxwell, Edwin R Chilvers, Massimilliano Mazzone, Veronica Moral, Chris W Pugh, Peter J Ratcliffe, Christopher J Schofield, Bart Ghesquiere, Peter Carmeliet, Moira Kb Whyte, Sarah R Walmsley
Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival...
August 14, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28790514/the-vhl-tumor-suppressor-gene-insights-into-oxygen-sensing-and-cancer
#4
William G Kaelin
Mammalian cells sense changes in oxygen and transduce that information into adaptive changes in gene expression using a conserved pathway that converges on the heterodimeric transcription factor called hypoxia-inducible factor (HIF), which contains a labile alpha subunit and a stable beta subunit. In the presence of oxygen, the alpha subunit is hydroxylated on one (or both) of two highly conserved prolyl residues by an Egg-Laying Defective Nine (EglN) [also called Prolyl Hydroxylase Domain (PHD)] dioxygenase, which recruits an ubiquitin ligase complex containing the VHL tumor suppressor gene product...
2017: Transactions of the American Clinical and Climatological Association
https://www.readbyqxmd.com/read/28789925/hif-1%C3%AE-represses-the-expression-of-the-angiogenesis-inhibitor-thrombospondin-2
#5
Susan C MacLauchlan, Nicole E Calabro, Yan Huang, Meenakshi Krishna, Tara Bancroft, Tanuj Sharma, Jun Yu, William C Sessa, Frank Giordano, Themis R Kyriakides
Thrombospondin-2 (TSP2) is a potent inhibitor of angiogenesis whose expression is dynamically regulated following injury. In the present study, it is shown that HIF-1α represses TSP2 transcription. Specifically, in vitro studies demonstrate that the prolyl hydroxylase inhibitor DMOG or hypoxia decrease TSP2 expression in fibroblasts. This effect is shown to be via a transcriptional mechanism as hypoxia does not alter TSP2 mRNA stability and this effect requires the TSP2 promoter. In addition, the documented repressive effect of nitric oxide (NO) on TSP2 is shown to be non-canonical and involves stabilization of HIF-1α...
August 5, 2017: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/28782191/tadalafil-a-phosphodiesterase-type-5-inhibitor-improves-bladder-blood-supply-and-restores-the-initial-phase-of-lower-urinary-tract-dysfunction-in-diabetic-rats
#6
Daisuke Gotoh, Kazumasa Torimoto, Yoshihiro Tatsumi, Shunta Hori, Atsushi Yamada, Makito Miyake, Yosuke Morizawa, Katsuya Aoki, Nobumichi Tanaka, Akihide Hirayama, Kiyohide Fujimoto
AIMS: To investigate the effect of tadalafil on bladder blood flow and lower urinary tract function in a rat model of diabetes. MATERIALS AND METHODS: We studied female Sprague-Dawley rats and induced diabetes in some using a single intraperitoneal injection of streptozotocin. We divided the rats into nondiabetes (ND), diabetes (D), and diabetes with tadalafil (DT) groups. The rats were raised for an additional 7 weeks after diabetes induction. The DT group received oral tadalafil (2 mg/kg/day) for 7 days before the experiments...
August 7, 2017: Neurourology and Urodynamics
https://www.readbyqxmd.com/read/28775317/interaction-between-von-hippel-lindau-protein-and-fatty-acid-synthase-modulates-hypoxia-target-gene-expression
#7
Wendi Sun, Hiroyuki Kato, Shojiro Kitajima, Kian Leong Lee, Katarina Gradin, Takashi Okamoto, Lorenz Poelllinger
Hypoxia-inducible factors (HIFs) play a central role in the transcriptional response to changes in oxygen availability. Stability of HIFs is regulated by multi-step reactions including recognition by the von Hippel-Lindau tumour suppressor protein (pVHL) in association with an E3 ligase complex. Here we show that pVHL physically interacts with fatty acid synthase (FASN), displacing the E3 ubiquitin ligase complex. This results in HIF-α protein stabilization and activation of HIF target genes even in normoxia such as during adipocyte differentiation...
August 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28775234/oligomer-procyanidins-f2-repress-hif-1%C3%AE-expression-in-human-u87-glioma-cells-by-inhibiting-the-egfr-akt-mtor-and-mapk-erk1-2-signaling-pathways-in-vitro-and-in-vivo
#8
Hong-Li Zheng, Li-Hui Wang, Bao-Shan Sun, Yi Li, Jing-Yu Yang, Chun-Fu Wu
Hypoxia-inducible factor-1 (HIF-1) is over-expressed in gliomas and has become one of the most compelling tumor targets. In this study, we found that oligomer procyanidins (F2) can suppress the expressions of HIF-1α and its target genes in U87 cells, and also down-regulate the EGFR/PI3K/AKT/mTOR and MAPK/ERK1/2 pathways in vitro and in vivo. Furthermore, hypoxia-induced formation of tubular structures by human umbilical vascular endothelial cells and the migration and invasion of U87 cells could be inhibited by F2 in a HIF-1 dependent manner...
July 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28771276/downregulation-of-hypoxia-inducible-factor-1%C3%AE-contributes-to-impaired-megakaryopoiesis-in-immune-thrombocytopenia
#9
Jiaqian Qi, Tao You, Tingting Pan, Qi Wang, Li Zhu, Yue Han
Impaired megakaryocyte maturation and exaggerated platelet destruction play a pivotal role in the pathogenesis of immune thrombocytopenia (ITP). Previous studies have shown that HIF-1α promotes the homing and engraftment of haematopoietic stem cells (HSCs), thereby stimulating HSC differentiation. However, whether HIF-1α plays a role in megakaryocytic maturation and platelet destruction in ITP remains elusive. Using enzyme-linked immunosorbent assays (ELISAs), we demonstrated that there were lower HIF-1α levels in the bone marrow (BM) of ITP patients than in that of healthy donors and patients with chemotherapy-related thrombocytopenia...
August 3, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28768664/preventative-effects-of-a-hif-inhibitor-17-dmag-on-partial-bladder-outlet-obstruction-induced-bladder-dysfunction
#10
Nao Iguchi, M İrfan Dönmez, Anna P Malykhina, Alonso Carrasco, Duncan T Wilcox
Posterior urethral valves are the most common cause of partial bladder outlet obstruction (PBOO) in the pediatric population. Pathological changes in the bladder developed during PBOO are responsible for long-lasting voiding dysfunction in this population despite early surgical interventions. Increasing evidence showed PBOO induces an upregulation of Hypoxia inducible factors (HIFs) and their transcriptional target genes, and they play a role in pathophysiological changes in the obstructed bladders. We hypothesized that blocking HIF pathways can prevent PBOO-induced bladder dysfunction...
August 2, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28766956/design-and-synthesis-of-benzopyran-based-inhibitors-of-the-hypoxia-inducible-factor-1-pathway-with-improved-water-solubility
#11
Jalisa H Ferguson, Zeus De Los Santos, Saroja N Devi, Stefan Kaluz, Erwin G Van Meir, Sarah K Zingales, Binghe Wang
While progress has been made in treating cancer, cytotoxic chemotherapeutic agents are still the most widely used drugs and are associated with severe side-effects. Drugs that target unique molecular signalling pathways are needed for treating cancer with low or no intrinsic toxicity to normal cells. Our goal is to target hypoxic tumours and specifically the hypoxia inducible factor (HIF) pathway for the development of new cancer therapies. To this end, we have previously developed benzopyran-based HIF-1 inhibitors such as arylsulfonamide KCN1...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28756150/a-marine-sponge-alkaloid-derivative-4-chloro-fascaplysin-inhibits-tumor-growth-and-vegf-mediated-angiogenesis-by-disrupting-pi3k-akt-mtor-signaling-cascade
#12
Sonia Sharma, Santosh Kumar Guru, Sudhakar Manda, Ashok Kumar, Mubashir J Mintoo, Venna Deva Prasad, Parduman R Sharma, Dilip M Mondhe, Sandip B Bharate, Shashi Bhushan
Tumor angiogenesis and PI3K/Akt/mTOR pathway are two major molecular objectives for the treatment and management of breast cancer. Here we first time report the molecular mechanism of a marine sponge alkaloid derivative 4-chloro fascapysin (4-CF) for its anticancer and antiangiogenesis potential. It simultaneously targets multiple cancer and angiogenesis dynamics, such as proliferation, chemotaxis cell migration, and invasion, growth factors signaling cascade, autophagy and apoptosis in HUVEC and MDAMB-231 breast cancer cells...
July 26, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28753585/overriding-tki-resistance-of-renal-cell-carcinoma-by-combination-therapy-with-il-6-receptor-blockade
#13
Kei Ishibashi, Tobias Haber, Ines Breuksch, Susanne Gebhard, Takashi Sugino, Hitoshi Kubo, Junya Hata, Tomoyuki Koguchi, Michihiro Yabe, Masao Kataoka, Soichiro Ogawa, Hiroyuki Hiraki, Tomohiko Yanagida, Nobuhiro Haga, Joachim W Thüroff, Dirk Prawitt, Walburgis Brenner, Yoshiyuki Kojima
Metastatic renal cell carcinoma (RCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKI) represent the standard of care for RCCs, however a significant proportion of RCC patients develop resistance to this therapy. Interleukin-6 (IL-6) is considered to be associated with poor prognosis in RCCs. We therefore hypothesized that TKI resistance and IL-6 secretion are causally connected. We first analyzed IL-6 expression after TKI treatment in RCC cells and RCC tumor specimens...
July 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28753560/enhancement-of-the-anti-tumor-activity-of-fgfr1-inhibition-in-squamous-cell-lung-cancer-by-targeting-downstream-signaling-involved-in-glucose-metabolism
#14
Claudia Fumarola, Daniele Cretella, Silvia La Monica, Mara A Bonelli, Roberta Alfieri, Cristina Caffarra, Federico Quaini, Denise Madeddu, Angela Falco, Andrea Cavazzoni, Graziana Digiacomo, Giulia Mazzaschi, Valentina Vivo, Elisabetta Barocelli, Marcello Tiseo, Pier Giorgio Petronini, Andrea Ardizzoni
Fibroblast Growth Factor Receptor (FGFR) signaling is a complex pathway which controls several processes, including cell proliferation, survival, migration, and metabolism. FGFR1 signaling is frequently deregulated via amplification/over-expression in NSCLC of squamous histotype (SQCLC), however its inhibition has not been successfully translated in clinical setting. We determined whether targeting downstream signaling implicated in FGFR1 effects on glucose metabolism potentiates the anti-tumor activity of FGFR1 inhibition in SQCLC...
July 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28747725/echinomycin-inhibits-adipogenesis-in-3t3-l1-cells-in-a-hif-independent-manner
#15
Junna Yamaguchi, Tetsuhiro Tanaka, Hisako Saito, Seitaro Nomura, Hiroyuki Aburatani, Hironori Waki, Takashi Kadowaki, Masaomi Nangaku
Obesity is a risk factor for many diseases including diabetes, cancer, cardiovascular disease, and chronic kidney disease. Obesity is characterized by the expansion of white adipose tissue (WAT). Hypertrophy and hyperplasia of adipocytes cause tissue hypoxia followed by inflammation and fibrosis. Its trigger, preadipocyte differentiation into mature adipocytes, is finely regulated by transcription factors, signal molecules, and cofactors. We found that echinomycin, a potent HIF-1 inhibitor, completely inhibited adipogenesis in 3T3-L1 WAT preadipocytes by affecting the early phase of mitotic clonal expansion...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28747716/burn-induced-muscle-metabolic-derangements-and-mitochondrial-dysfunction-are-associated-with-activation-of-hif-1%C3%AE-and-mtorc1-role-of-protein-farnesylation
#16
Harumasa Nakazawa, Kazuhiro Ikeda, Shohei Shinozaki, Masayuki Kobayashi, Yuichi Ikegami, Ming Fu, Tomoyuki Nakamura, Shingo Yasuhara, Yong-Ming Yu, J A Jeevendra Martyn, Ronald G Tompkins, Kentaro Shimokado, Tomoko Yorozu, Hideki Ito, Satoshi Inoue, Masao Kaneki
Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28738389/pdgf-promotes-the-warburg-effect-in-pulmonary-arterial-smooth-muscle-cells-via-activation-of-the-pi3k-akt-mtor-hif-1%C3%AE-signaling-pathway
#17
Yunbin Xiao, Hongyan Peng, Chenliang Hong, Zhi Chen, Xicheng Deng, Aiping Wang, Fang Yang, Li Yang, Chen Chen, Xuping Qin
BACKGROUND/AIMS: The enhanced proliferation of pulmonary arterial smooth muscle cells (PASMCs) is a central pathological component in pulmonary arterial hypertension (PAH). Both the Warburg effect and platelet-derived growth factor (PDGF) are involved in the proliferation of PASMCs. However, the mechanism underlying the crosstalk between the Warburg effect and PDGF during PASMC proliferation is still unknown. We hypothesized that PDGF promotes the Warburg effect via activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway and hypoxia-inducible factor 1-α (HIF-1α) in proliferative PASMCs...
July 24, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28736181/succinate-accumulation-impairs-cardiac-pyruvate-dehydrogenase-activity-through-grp91-dependent-and-independent-signaling-pathways-therapeutic-effects-of-ginsenoside-rb1
#18
Jia Li, Yi-Lin Yang, Lan-Zhu Li, Lei Zhang, Qun Liu, Kang Liu, Ping Li, Baolin Liu, Lian-Wen Qi
Altered mitochondrial oxidation increases vulnerability to cardiac ischemia/reperfusion (I/R) injury in metabolic disorders. However, the metabolic signaling responsible for the dysfunction remains partly unknown. We sought to test whether or not hypoxic succinate accumulation could inhibit pyruvate dehydrogenase (PDH) activity and subsequently aggravate I/R injury. Results showed that saturated fatty acid palmitate stimulation increased fatty acid oxidation and induced hypoxia in cardiomyocytes, leading to succinate accumulation...
July 20, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28734156/a-novel-hypoxia-response-element-regulates-oxygen-related-repression-of-tissue-factor-pathway-inhibitor-in-the-breast-cancer-cell-line-mcf-7
#19
Xue Yan Cui, Grethe Skretting, Mari Tinholt, Benedicte Stavik, Anders Erik Astrup Dahm, Kristine Kleivi Sahlberg, Sandip Kanse, Nina Iversen, Per Morten Sandset
BACKGROUND: Hypoxia is one of the most pervasive physiological stresses in solid tumors. We have previously demonstrated that tissue factor (TF) pathway inhibitor (TFPI) expression was transcriptionally repressed by the activation of hypoxia inducible factor (HIF)-1α under hypoxic conditions. However, the role of HIF-2α, also known as endothelial PAS domain-containing protein 1 (EPAS1), on TFPI expression remains unclear. AIM: To explore the role of HIF-2α/EPAS1 in the regulation of TFPI expression under hypoxia in breast cancer cells...
July 14, 2017: Thrombosis Research
https://www.readbyqxmd.com/read/28731464/trophoblast-survival-signaling-during-human-placentation-requires-hsp70-activation-of-mmp2-mediated-hbegf-shedding
#20
Chandni V Jain, Philip Jessmon, Charbel T Barrak, Alan D Bolnick, Brian A Kilburn, Michael Hertz, D Randall Armant
Survival of trophoblast cells in the low oxygen environment of human placentation requires metalloproteinase-mediated shedding of HBEGF and downstream signaling. A matrix metalloproteinase (MMP) antibody array and quantitative RT-PCR revealed upregulation of MMP2 post-transcriptionally in human first trimester HTR-8/SVneo trophoblast cells and placental villous explants exposed to 2% O2. Specific MMP inhibitors established the requirement for MMP2 in HBEGF shedding and upregulation. Because α-amanitin inhibited the upregulation of HBEGF, differentially expressed genes were identified by next-generation sequencing of RNA from trophoblast cells cultured at 2% O2 for 0, 1, 2 and 4 h...
July 21, 2017: Cell Death and Differentiation
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