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https://www.readbyqxmd.com/read/27919930/mir-17-20-controls-prolyl-hydroxylase-2-phd2-hypoxia-inducible-factor-1-hif1-to-regulate-pulmonary-artery-smooth-muscle-cell-proliferation
#1
Tianji Chen, Qiyuan Zhou, Haiyang Tang, Melike Bozkanat, Jason X-J Yuan, J Usha Raj, Guofei Zhou
BACKGROUND: Previously we found that smooth muscle cell (SMC)-specific knockout of miR-17~92 attenuates hypoxia-induced pulmonary hypertension. However, the mechanism underlying miR-17~92-mediated pulmonary artery SMC (PASMC) proliferation remains unclear. We sought to investigate whether miR-17~92 regulates hypoxia-inducible factor (HIF) activity and PASMC proliferation via prolyl hydroxylases (PHDs). METHODS AND RESULTS: We show that hypoxic sm-17~92(-/-) mice have decreased hematocrit, red blood cell counts, and hemoglobin contents...
December 5, 2016: Journal of the American Heart Association
https://www.readbyqxmd.com/read/27904680/enhancement-of-early-cardiac-differentiation-of-dedifferentiated-fat-cells-by-dimethyloxalylglycine-via-notch-signaling-pathway
#2
Fuhai Li, Zongzhuang Li, Zhi Jiang, Ye Tian, Zhi Wang, Wei Yi, Chenyun Zhang
Background: Hypoxia has been reported to possess the ability to induce mature lipid-filled adipocytes to differentiate into fibroblast-like multipotent dedifferentiated fat (DFAT) cells and stem cells such as iPSCs (interstitial pluripotent stem cells) and ESCs (embryonic stem cells) and then to differentiate into cardiomyocytes. However, the effect of hypoxia on cardiac differentiation of DFAT cells and its underlying molecular mechanism remains to be investigated. Objective: To investigate the role of hypoxia in early cardiac differentiation of DFAT cells and the underlying molecular mechanism...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27903985/the-tissue-inhibitor-of-metalloproteinases-1-timp-1-promotes-survival-and-migration-of-acute-myeloid-leukemia-cells-through-cd63-pi3k-akt-p21-signaling
#3
Dorian Forte, Valentina Salvestrini, Giulia Corradi, Lara Rossi, Lucia Catani, Roberto M Lemoli, Michele Cavo, Antonio Curti
We and others have shown that the Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), a member of the inflammatory network exerting pleiotropic effects in the bone marrow (BM) microenvironment, regulates the survival and proliferation of different cell types, including normal hematopoietic progenitor cells. Moreover, TIMP-1 has been shown to be involved in cancer progression. However, its role in leukemic microenvironment has not been addressed. Here, we investigated the activity of TIMP-1 on Acute Myelogenous Leukemia (AML) cell functions...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27901482/hyperglycemia-triggers-hipk2-protein-degradation
#4
Silvia Baldari, Alessia Garufi, Marisa Granato, Laura Cuomo, Giuseppa Pistritto, Mara Cirone, Gabriella D'Orazi
Homeodomain interacting protein kinase-2 (HIPK2) is an evolutionary conserved kinase that modulates several key molecular pathways to restrain tumor growth and induce p53-depending apoptotic cell-death in response to anticancer therapies. HIPK2 silencing in cancer cells leads to chemoresistance and cancer progression, in part due to p53 inhibition. Recently, hyperglycemia has been shown to reduce p53 phosphorylation at serine 46 (Ser46), the target residue of HIPK2, thus impairing p53 apoptotic function. Here we asked whether hyperglycemia could, upstream of p53, target HIPK2...
November 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27896629/remote-limb-ischemic-preconditioning-protects-rats-against-cerebral-ischemia-via-hif-1%C3%AE-ampk-hsp70-pathway
#5
Ming Xia, Qian Ding, Zhidan Zhang, Qinggen Feng
Remote limb ischemic preconditioning (RIPC) is a clinically feasible strategy to protect against ischemia/reperfusion injury, but the knowledge concerning the mechanism underlying RIPC is scarce. This study was performed to examine the effect of RIPC on brain tissue suffering from ischemia challenge and explore its underlying mechanism in a rat model. The animals were divided into four groups: Sham, middle cerebral artery occlusion (MCAO), RIPC, and MCAO+RIPC. We found that previous exposure to RIPC significantly attenuated neurological dysfunction and lessened brain edema in MCAO+RIPC group...
November 28, 2016: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/27880046/docosahexaenoic-acid-mediated-inhibition-of-heat-shock-protein-90-p23-chaperone-complex-and-downstream-client-proteins-in-lung-and-breast-cancer
#6
Michael Mouradian, Irvin V Ma, Erika D Vicente, Keith D Kikawa, Ronald S Pardini
The molecular chaperone, heat shock protein 90 (Hsp90), is a critical regulator for the proper folding and stabilization of several client proteins, and is a major contributor to carcinogenesis. Specific Hsp90 inhibitors have been designed to target the ATP-binding site in order to prevent Hsp90 chaperone maturation. The current study investigated the effects of docosahexaenoic acid (DHA; C22:6 n-3) on Hsp90 function and downstream client protein expression. In vitro analyses of BT-474 human breast carcinoma and A549 human lung adenocarcinoma cell lines revealed dose-dependent decreases in intracellular ATP levels by DHA treatment, resulting in a significant reduction of Hsp90 and p23 association in both cell lines...
November 23, 2016: Nutrition and Cancer
https://www.readbyqxmd.com/read/27877088/aloe-emodin-suppresses-hypoxia-induced-retinal-angiogenesis-via-inhibition-of-hif-1%C3%AE-vegf-pathway
#7
Jianming Wu, Xiao Ke, Wei Wang, Hongcheng Zhang, Na Ma, Wei Fu, Manxi Zhao, Xiaoping Gao, Xiaofeng Hao, Zhirong Zhang
Background: Aloe-emodin (AE) has been reported to possess the antiangiogenic effect on laser induced choroidal neovascularization. AE inhibits the vessel formation in the zebrafish embryos. However, it is still unclear whether AE can alleviate neovascularization. Here, we investigated the inhibitory effect of AE on the hypoxia-induced retinal neovascularization and the possible mechanisms. Methods: We established a vascular endothelial growth factor (VEGF) secretion model under chemical induced hypoxia by exposure of 150 µM CoCl2 to the ARPE-19 cells, then treated the cells with different concentrations of AE (0...
2016: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/27869227/hypoxia-induced-vasculogenic-mimicry-formation-in-human-colorectal-cancer-cells-involvement-of-hif-1a-claudin-4-and-e-cadherin-and-vimentin
#8
Wen Li, ShaoQi Zong, Qi Shi, HongJia Li, Jian Xu, Fenggang Hou
Vasculogenic mimicry (VM) plays an important role in colorectal cancer (CRC) metastasis, and both hypoxia and the epithelial-mesenchymal transition (EMT) are necessary for VM. In this study, HIF-1α expression was upregulated in the VM-positive CRC cell line HCT-116 and thereby affected the expression of the EMT-related markers Claudin-4, E-cadherin (E-cd) and Vimentin(VIM). SB431542 and U0126EtOH, which can inhibit of EMT were used to treat HCT-116 and HCT-8 in these experiments. Both of the inhibitors had significant effect on EMT markers and the formations of VM in CRC cells...
November 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27863375/h2o2-treatment-or-serum-deprivation-induces-autophagy-and-apoptosis-in-naked-mole-rat-skin-fibroblasts-by-inhibiting-the-pi3k-akt-signaling-pathway
#9
Shanmin Zhao, Li Li, Shiyong Wang, Chenlin Yu, Bang Xiao, Lifang Lin, Wei Cong, Jishuai Cheng, Wenjing Yang, Wei Sun, Shufang Cui
Naked mole-rats (NMR; Heterocephalus glaber) display extreme longevity and resistance to cancer. Here, we examined whether autophagy contributes to the longevity of NMRs by assessing the effects of the PI3K/Akt pathway inhibitor LY294002 and the autophagy inhibitor chloroquine (CQ) on autophagy and apoptosis in NMR skin fibroblasts. Serum starvation, H2O2 treatment, and LY294002 treatment all increased the LC3-II/LC3-I ratio and numbers of double-membraned autophagosomes and autophagic vacuoles, and decreased levels of p70S6K, p-AktSer473, and p-AktThr308...
November 12, 2016: Oncotarget
https://www.readbyqxmd.com/read/27862498/all-trans-retinoic-acid-preconditioning-enhances-proliferation-angiogenesis-and-migration-of-mesenchymal-stem-cell-in-vitro-and-enhances-wound-repair-in-vivo
#10
M Pourjafar, M Saidijam, K Mansouri, H Ghasemibasir, F Karimi Dermani, R Najafi
OBJECTIVES: Stem cell therapy is considered to be a suitable alternative in treatment of a number of diseases. However, there are challenges in their clinical application in cell therapy, such as to reduce survival and loss of transplanted stem cells. It seems that chemical and pharmacological preconditioning enhances their therapeutic efficacy. In this study, we investigated effects of all-trans retinoic acid (ATRA) on survival, angiogenesis and migration of mesenchymal stem cells (MSCs) in vitro and in a wound-healing model...
November 10, 2016: Cell Proliferation
https://www.readbyqxmd.com/read/27848972/androgen-receptor-ar-signaling-promotes-rcc-progression-via-increased-endothelial-cell-proliferation-and-recruitment-by-modulating-akt%C3%A2-%C3%A2-%C3%A2-nf-%C3%AE%C2%BAb%C3%A2-%C3%A2-%C3%A2-cxcl5-signaling
#11
Zhenfeng Guan, Chong Li, Jinhai Fan, Dalin He, Lei Li
Androgen receptor (AR) signaling may promote renal cell carcinoma (RCC) progression via altered HIF-2α/VEGF signaling. However, it remains unclear whether AR signaling also promotes RCC progression by recruiting vascular endothelial cells (ECs), key players in the development of blood vessels. In our study, AR increased EC proliferation and recruitment to the tumor microenvironment and promoted RCC progression. Mechanistically, AR modulated cytokine CXCL5 expression by altering AKT → NF-κB signaling, and interruption of AKT → NF-κB → CXCL5 signaling using either specific inhibitors or siRNA suppressed AR-enhanced EC recruitment and AR-EC-promoted RCC progression...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27847273/development-of-1-aryl-3-furanyl-thienyl-imidazopyridine-templates-for-inhibitors-against-hypoxia-inducible-factor-hif-1-transcriptional-activity
#12
Shinichiro Fuse, Toshiaki Ohuchi, Yasunobu Asawa, Shinichi Sato, Hiroyuki Nakamura
1,3-Disubstituted-imidazopyridines were designed for developing inhibitors against HIF-1 transcriptional activity. Designed compounds were rapidly synthesized from a key aromatic scaffold via microwave-assisted Suzuki-Miyaura coupling/CH direct arylation sequence. Evaluation of ability to inhibit the hypoxia induced transcriptional activity of HIF-1 revealed that the compound 2i and 3a retained the same level of the inhibitory activity comparing with that of known inhibitor, YC-1 (1). Identified, readily accessible 1-aryl-3-furanyl/thienyl-imidazopyridine templates should be useful for future drug development...
December 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27844272/resistance-to-targeted-therapies-in-renal-cancer-the-importance-of-changing-the-mechanism-of-action
#13
I Duran, J Lambea, P Maroto, J L González-Larriba, Luis Flores, S Granados-Principal, M Graupera, B Sáez, A Vivancos, O Casanovas
Renal cell carcinoma (RCC) is a complex disease characterized by mutations in several genes. Loss of function of the von Hippel-Lindau (VHL) tumour suppressor gene is a very common finding in RCC and leads to up-regulation of hypoxia-inducible factor (HIF)-responsive genes accountable for angiogenesis and cell growth, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Binding of these proteins to their cognate tyrosine kinase receptors on endothelial cells promotes angiogenesis...
November 15, 2016: Targeted Oncology
https://www.readbyqxmd.com/read/27836733/activation-of-gper-suppresses-migration-and-angiogenesis-of-triple-negative-breast-cancer-via-inhibition-of-nf-%C3%AE%C2%BAb-il-6-signals
#14
Shuwei Liang, Zhuojia Chen, Guanmin Jiang, Yan Zhou, Qiao Liu, Qiao Su, Weidong Wei, Jun Du, Hongsheng Wang
Triple-negative breast cancer (TNBC) is characterized by high vascularity and frequent metastasis. Here, we found that activation of G protein-coupled estrogen receptor (GPER) by its specific agonist G-1 can significantly inhibit interleukin 6 (IL-6) and vascular endothelial growth factor A (VEGF-A). TNBC tissue microarrays from 100 TNBC patients revealed GPER is negatively associated with IL-6 levels and higher grade and stage. Activation of GPER or anti-IL-6 antibody can inhibit both in vitro tube formation of human umbilical vein endothelial cells (HUVECs) and migration of TNBC cells...
November 9, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27832958/hypoxia-inducible-factor-prolyl-4-hydroxylase-inhibition-in-cardiometabolic-diseases
#15
REVIEW
Peppi Koivunen, Raisa Serpi, Elitsa Y Dimova
Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs, also called PHDs and EglNs) are enzymes that act as cellular oxygen sensors. They are the main downregulators of the hypoxia-inducible factor (HIF). HIF-P4Hs can be targeted with small molecule inhibitors, which stabilize HIF under normoxia and initiate the hypoxia response. Such inhibitors are in phase 2 and 3 clinical trials for the treatment of anemia due to their ability to induce erythropoietin and iron metabolism genes. Recent data suggest that HIF-P4H inhibition has a therapeutic role beyond anemia in cardiac ischemia, obesity and metabolic dysfunction, and atherosclerosis...
November 8, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27830025/sevoflurane-postconditioning-improves-myocardial-mitochondrial-respiratory-function-and-reduces-myocardial-ischemia-reperfusion-injury-by-up-regulating-hif-1
#16
Long Yang, Peng Xie, Jianjiang Wu, Jin Yu, Tian Yu, Haiying Wang, Jiang Wang, Zhengyuan Xia, Hong Zheng
BACKGROUND: Sevoflurane postconditioning (SPostC) can exert myocardial protective effects similar to ischemic preconditioning. However, the exact myocardial protection mechanism by SPostC is unclear. Studies indicate that hypoxia-inducible factor-1 (HIF-1) maintains cellular respiration homeostasis by regulating mitochondrial respiratory chain enzyme activity under hypoxic conditions. This study investigated whether SPostC could regulate the expression of myocardial HIF-1α and to improve mitochondrial respiratory function, thereby relieving myocardial ischemia-reperfusion injury in rats...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27826618/valproic-acid-inhibits-irradiation-induced-epithelial-mesenchymal-transition-and-stem-cell-like-characteristics-in-esophageal-squamous-cell-carcinoma
#17
Ayako Kanamoto, Itasu Ninomiya, Shinichi Harada, Tomoya Tsukada, Koichi Okamoto, Shinichi Nakanuma, Seisho Sakai, Isamu Makino, Jun Kinoshita, Hironori Hayashi, Katsunobu Oyama, Tomoharu Miyashita, Hidehiro Tajima, Hiroyuki Takamura, Sachio Fushida, Tetsuo Ohta
Esophageal carcinoma is one of the most aggressive malignancies, and is characterized by poor response to current therapy and a dismal survival rate. In this study we investigated whether irradiation induces epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC) TE9 cells and whether the classic histone deacetylase (HDAC) inhibitor valproic acid (VPA) suppresses these changes. First, we showed that 2 Gy irradiation induced spindle cell-like morphologic changes, decreased expression of membranous E-cadherin, upregulated vimentin expression, and altered the localization of β-catenin from its usual membrane-bound location to cytoplasm in TE9 cells...
November 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27822416/hydroxyl-hif2-alpha-is-potential-therapeutic-target-for-renal-cell-carcinomas
#18
Takahiro Isono, Tokuhiro Chano, Tetsuya Yoshida, Susumu Kageyama, Akihiro Kawauchi, Masafumi Suzaki, Takeshi Yuasa
Dormant cancer cells are deprivation-resistant, and cause a number of problems for therapeutic approaches for cancers. Renal cell carcinomas (RCCs) include deprivation-resistant cells that are resistant to various treatments. In this study, the specific characteristics of deprivation-resistant cells were transcriptionally identified by next generation sequencing. The hypoxia-inducible factors (HIF) transcription factor network was significantly enhanced in deprivation-resistant RCCs compared to the sensitive RCCs...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27821815/everolimus-rad001-sensitizes-prostate-cancer-cells-to-docetaxel-by-down-regulation-of-hif-1%C3%AE-and-sphingosine-kinase-1
#19
Heba Alshaker, Qi Wang, Yoshiaki Kawano, Tawfiq Arafat, Torsten Böhler, Mathias Winkler, Colin Cooper, Dmitri Pchejetski
Resistance to docetaxel is a key problem in current prostate cancer management. Sphingosine kinase 1 (SK1) and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways have been implicated in prostate cancer chemoresistance. Here we investigated whether their combined targeting may re-sensitize prostate cancer cells to docetaxel.In hormone-insensitive PC-3 and DU145 prostate cancer cells the mTOR inhibitor everolimus (RAD001) alone did not lead to significant cell death, however, it strongly sensitized cells to low levels (5 nM) of docetaxel...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27811928/potent-and-selective-chemical-probe-of-hypoxic-signalling-downstream-of-hif-%C3%AE-hydroxylation-via-vhl-inhibition
#20
Julianty Frost, Carles Galdeano, Pedro Soares, Morgan S Gadd, Katarzyna M Grzes, Lucy Ellis, Ola Epemolu, Satoko Shimamura, Marcus Bantscheff, Paola Grandi, Kevin D Read, Doreen A Cantrell, Sonia Rocha, Alessio Ciulli
Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes...
November 4, 2016: Nature Communications
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