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Hif inhibitor

Fang Gao, Yanping Wang, Shulin Li, Zhuojun Wang, Caixia Liu, Dong Sun
AIMS: Cellular hypoxia has been proposed as a major factor contributing to the pathogenesis of chronic renal injury. Much of our understanding of how mitogen-activated protein kinases (MAPK) signaling promotes renal fibrosis has been based on cell culture studies. Therefore, we used the unilateral ureteral occlusion (UUO) model to further elucidate the role of the p38 MAPK pathway in renal interstitial fibrosis induced by hypoxia. MATERIALS AND METHODS: In the present study, 24 male mice were randomized into the following three groups (n=8 each): Sham group (DMSO solution), UUO group (UUO+DMSO solution) and UP group (UUO+p38 inhibitor)...
October 20, 2016: Life Sciences
Patrick R Arsenault, Daisheng Song, Marian Bergkamp, Andrew M Ravaschiere, Bradleigh E Navalsky, Paul M Lieberman, Frank S Lee
The Prolyl Hydroxylase Domain protein (PHD):Hypoxia Inducible Factor (HIF) pathway is the main pathway by which changes in oxygen concentration are transduced to changes in gene expression. In mammals, there are three PHD paralogues, and PHD2 has emerged as a particularly critical one for regulating HIF target genes such as ERYTHROPOIETIN (EPO), which controls red cell mass and hematocrit. PHD2 is distinctive among the three PHDs in that it contains an N-terminal MYND type zinc finger. We have proposed that this zinc finger binds a Pro-Xaa-Leu-Glu (PXLE) motif found in proteins of the HSP90 pathway to facilitate HIF-α hydroxylation...
October 22, 2016: Chembiochem: a European Journal of Chemical Biology
Chengxing Zhu, Jiong Yu, Qiaoling Pan, Jinfeng Yang, Guangshu Hao, Yingjie Wang, Lanjuan Li, Hongcui Cao
Human placenta-derived mesenchymal stem cells (hPMSCs) reside in a physiologically low-oxygen microenvironment. Hypoxia influences a variety of stem cell cellular activities, frequently involving hypoxia-inducible factor-2 alpha (HIF-2α). This research showed that hPMSCs cultured in hypoxic conditions (5% O2) exhibited a more naïve morphology and had a higher proliferative capability and higher HIF-2α expression than hPMSCs cultured in normoxic conditions (21% O2). Similar to the hypoxic cultures, hPMSCs over-expressing HIF-2α showed higher proliferative potential and higher expression of CCND1 (CyclinD1), MYC (c-Myc), POU5F1 (Oct4) and the components of the MAPK/ERK pathway...
October 21, 2016: Scientific Reports
Yan Long, Wen-Bin Tsai, Jeffrey T Chang, Marcos Estecio, Medhi Wangpaichitr, Naramol Savaraj, Lynn G Feun, Helen H W Chen, Macus Tien Kuo
Many human tumors require extracellular arginine (Arg) for growth because the key enzyme for de novo biosynthesis of Arg, argininosuccinate synthetase 1 (ASS1), is silenced. These tumors are sensitive to Arg-starvation therapy using pegylated arginine deiminase (ADI-PEG20) which digests extracellular Arg. Many previous studies reported that ASS1 silencing is due to epigenetic inactivation of ASS1 expression by DNA methylation, and that the demethylation agent 5-aza-deoxycytidine (Aza-dC) can induce ASS1 expression...
September 28, 2016: Oncotarget
Darren M Hutt, Daniela Martino Roth, Christelle Marchal, Marion Bouchecareilh
Gene expression is regulated in part through the reversible acetylation of histones, by the action of histone acetyltransferases (HAT) and histone deacetylases (HDAC). HAT activity results in the addition of acetyl groups on the lysine residues of histone tails leading to decondensation of the chromatin, and increased gene transcription in general, whereas HDACs remove these acetyl groups, thus leading to an overall suppression of gene transcription. Recent evidence has elucidated that histones are not the only components of the proteome that are targeted by HATs and HDACs...
2017: Methods in Molecular Biology
Natalya A Goloviznina, Santhosh Chakkaramakkil Verghese, Young Me Yoon, Oleh Taratula, Daniel L Marks, Peter Kurre
Mesenchymal stromal cells (MSC) present in the bone marrow (BM) microenvironment secrete cytokines and angiogenic factors that support the maintenance and regenerative expansion of hematopoietic stem and progenitor cells (HSPC). Here, we tested the hypothesis that extracellular vesicles (EVs) released by MSC contribute to the paracrine crosstalk that shapes hematopoietic function. We systematically characterized EV release by murine stromal cells and demonstrate that MSC-derived EVs prompt a loss of HSPC quiescence with concomitant expansion of murine myeloid progenitors...
October 7, 2016: Journal of Biological Chemistry
Hyoung Sook Park, Ji Hye Kim, Bo Kyung Sun, Sun U Song, Wonhee Suh, Jong-Hyuk Sung
It has previously been demonstrated that hypoxia has diverse stimulatory effects on adipose‑derived stem cells (ASCs), however, metabolic responses under hypoxia remain to be elucidated. Thus, the present study aimed to investigate the glucose uptake and metabolism of ASCs under hypoxic conditions, and to identify the underlying molecular mechanisms. ASCs were cultured in 1% oxygen, and experiments were conducted in vitro. As determined by proteomic analysis and western blotting, GAPDH and enolase 1 (ENO1) expression were upregulated under hypoxia...
October 5, 2016: Molecular Medicine Reports
Ho Shin Kim, Mannkyu Hong, Jihyae Ann, Suyoung Yoon, Cong-Truong Nguyen, Su-Chan Lee, Ho-Young Lee, Young-Ger Suh, Ji Hae Seo, Hoon Choi, Jun Yong Kim, Kyu-Won Kim, Joohwan Kim, Young-Myeong Kim, So-Jung Park, Hyun-Ju Park, Jeewoo Lee
Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure-activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80...
September 30, 2016: Bioorganic & Medicinal Chemistry
Chen Tu, Shuang Wang, Xiao Hu, Wenju Wang, Yingying Dong, Shengxiang Xiao, Xiaopeng Wang
Bacterial infection is an important factor that can trigger and exacerbate psoriasis. The protein triggering receptor expressed on myeloid cells type-1 (TREM-1) is overexpressed in psoriasis and decreased after a successful treatment. Hypoxia inducible factor-1α (HIF-1α), subunit of the transcription factor HIF-1, has participated in angiogenesis and inflammation in psoriasis. Increased expressions of TREM-1 and HIF-1α are associated with the infection of microbial pathogens. However, the association between TREM-1 and HIF-1α still need to be elucidated...
October 15, 2016: Cell Biology International
Christina M Wyatt, Tilman B Drüeke
The treatment of anemia with erythropoiesis-stimulating agents and iron supplementation has become the standard of care in patients with chronic kidney disease. Because of the risks associated with this approach, hypoxia inducible factor stabilizing prolyl hydroxylase inhibitors were developed as a potential treatment alternative. In recent phase 2 trials, these agents raised hemoglobin in a predictable and controlled manner and improved markers of iron metabolism. More experience is needed to establish long-term efficacy, tolerability, and safety, and to determine whether their use is associated with lower iron requirements...
November 2016: Kidney International
Shasha Liu, Qidi Ai, Kai Feng, Yubing Li, Xiang Liu
Reperfusion therapy is widely used to treat acute myocardial infarction (AMI). However, further injury to the heart induced by rapidly initiating reperfusion is often encountered in clinical practice. A lack of pharmacological strategies in clinics limits the prognosis of patients with myocardial ischemia-reperfusion injury (MIRI). Dihydromyricetin (DMY) is one of the most abundant components in vine tea, commonly known as the tender stems and leaves of Ampelopsis grossedentata. The aim of this study was to evaluate the cardioprotection of DMY against myocardial ischemia-reperfusion (I/R) injury and to further investigate the underlying mechanism...
October 13, 2016: Apoptosis: An International Journal on Programmed Cell Death
Jianming Wu, Xiao Ke, Na Ma, Wei Wang, Wei Fu, Hongcheng Zhang, Manxi Zhao, Xiaoping Gao, Xiaofeng Hao, Zhirong Zhang
BACKGROUND: It has been reported that formononetin (FMN), one of the main ingredients from famous traditional Chinese medicine "Huang-qi" (Astragalus membranaceus [Fisch] Bunge) for Qi-tonifying, exhibits the effects of immunomodulation and tumor growth inhibition via antiangiogenesis. Furthermore, A. membranaceus may alleviate the retinal neovascularization (NV) of diabetic retinopathy. However, the information of FMN on retinal NV is limited so far. In the present study, we investigated the effects of FMN on the hypoxia-induced retinal NV and the possible related mechanisms...
2016: Drug Design, Development and Therapy
Chengdu Sun, Liming Wang, Dan Gao, Yuanming Pan, Yuliang Zhao, Chunying Chen, Mingzhou Guo
C60(OH)22 has been reported to suppress human cancer by inhibiting angiogenesis. However, its mechanism of action remains unclear. To explore the role and mechanism of C60(OH)22 in human pancreatic cancer, siRNA knockdown, immunofluorescence and a matrigel plug mouse model were employed. The results demonstrated that C60(OH)22 suppresses endothelial cell invasion and tube formation in vitro. C60(OH)22 suppresses angiogenesis in human umbilical vein endothelial cell (HUVEC) xenograft mice. The enzymatic activities of MMP2 and MMP9, as well as the expression levels of HDAC1, HDAC2, HIF-1α and VEGF, were inhibited by C60(OH)22...
September 15, 2016: Nanoscale
Xiaofang Huo, Agoston T Agoston, Kerry B Dunbar, Daisha J Cipher, Xi Zhang, Chunhua Yu, Edaire Cheng, Qiuyang Zhang, Thai H Pham, Uttam K Tambar, Richard K Bruick, David H Wang, Robert D Odze, Stuart J Spechler, Rhonda F Souza
OBJECTIVE: In an earlier study wherein we induced acute reflux by interrupting proton pump inhibitor (PPI) therapy in patients with reflux oesophagitis (RO) healed by PPIs, we refuted the traditional concept that RO develops as an acid burn. The present study explored our alternative hypothesis that RO results from reflux-stimulated production of pro-inflammatory molecules mediated by hypoxia-inducible factors (HIFs). DESIGN: Using oesophageal biopsies taken from patients in our earlier study at baseline and at 1 and 2 weeks off PPIs, we immunostained for HIF-1α, HIF-2α and phospho-p65, and measured pro-inflammatory molecule mRNAs...
September 30, 2016: Gut
Jingtao Luo, Yun Hong, Yang Lu, Songbo Qiu, Bharat K R Chaganty, Lun Zhang, Xudong Wang, Qiang Li, Zhen Fan
Cetuximab inhibits HIF-1-regulated glycolysis in cancer cells, thereby reversing the Warburg effect and leading to inhibition of cancer cell metabolism. AMP-activated protein kinase (AMPK) is activated after cetuximab treatment, and a sustained AMPK activity is a mechanism contributing to cetuximab resistance. Here, we investigated how acetyl-CoA carboxylase (ACC), a downstream target of AMPK, rewires cancer metabolism in response to cetuximab treatment. We found that introduction of experimental ACC mutants lacking the AMPK phosphorylation sites (ACC1_S79A and ACC2_S212A) into head and neck squamous cell carcinoma (HNSCC) cells protected HNSCC cells from cetuximab-induced growth inhibition...
September 28, 2016: Cancer Letters
Gustavo Silveira Breguez, Leandro Xavier Neves, Karina Taciana Santos Silva, Lorran Miranda Andrade de Freitas, Gabriela de Oliveira Faria, Mauro César Isoldi, William Castro-Borges, Milton Hércules Guerra de Andrade
The PR-11 peptide corresponds to the N-terminal and active region of the endogenously synthesized PR-39 molecule, of porcine origin. It is known to possess various biological effects including antimicrobial properties, angiogenic and anti-inflammatory activities. Apart from its reported activity as a proteasome inhibitor, a more comprehensive understanding of its function, at the molecular level, is still lacking. In this study, we used a label-free shotgun strategy to evaluate the proteomic alterations caused by exposure of cultured fibroblasts to the peptide PR-11...
September 28, 2016: Biochimica et Biophysica Acta
Jose J G Marin, Elisa Lozano, Maria J Perez
Alterations in mitochondrial DNA (mtDNA) and autophagy activation are common events in tumors. Here we have investigated the effect of mitochondrial genome depletion on chemical hypoxia-induced autophagy in liver tumor cells. Human SK-Hep-1 wild-type and mtDNA-depleted (Rho) cells were exposed to the hypoxia mimetic agents CoCl2 and deferoxamine (DFO). Up-regulation of HIF-1α, but not HIF-2α was observed. The expression of several HIF-1α target genes was also found. In human SK-Hep-1 and mouse Hepa 1-6 liver tumor cells, but not in the counterpart Rho derived lines, chemical hypoxia increased the abundance of autophagosomes and autolysosomes...
September 26, 2016: Free Radical Biology & Medicine
Evanthia Pangou, Christina Befani, Ilias Mylonis, Martina Samiotaki, George Panayotou, George Simos, Panagiotis Liakos
Hypoxia Inducible Factor 2 (HIF-2) is a transcriptional activator implicated in the cellular response to hypoxia. Regulation of its inducible subunit, HIF-2α, involves post-translational modifications. Here, we demonstrate that casein kinase 1δ (CK1δ) phosphorylates HIF-2α at Ser383 and Thr528 in vitro Disruption of these phosphorylation sites and silencing or chemical inhibition of CK1δ reduced the expression of HIF-2 target genes and the secretion of erythropoietin (EPO) in two hepatic cancer cell lines, Huh7 and HepG2, without affecting levels of HIF-2α protein expression...
September 29, 2016: Journal of Cell Science
Zengyang Yu, Tianyu Zhang, Chenyuan Gong, Yuchen Sheng, Bin Lu, Lingyu Zhou, Lili Ji, Zhengtao Wang
Erianin is a natural compound found in Dendrobium chrysotoxum Lindl. Diabetic retinopathy (DR) is a serious and common microvascular complication of diabetes. This study aims to investigate the inhibitory mechanism of erianin on retinal neoangiogenesis and its contribution to the amelioration of DR. Erianin blocked high glucose (HG)-induced tube formation and migration in choroid-retinal endothelial RF/6A cells. Erianin inhibited HG-induced vascular endothelial growth factor (VEGF) expression, hypoxia-inducible factor 1-alpha (HIF-1α) translocation into nucleus and ERK1/2 activation in RF/6A and microglia BV-2 cells...
September 28, 2016: Scientific Reports
Yuh-Feng Lin, I-Jen Chiu, Fong-Yu Cheng, Yu-Hsuan Lee, Ying-Jan Wang, Yung-Ho Hsu, Hui-Wen Chiu
BACKGROUND: Zinc oxide nanoparticles (ZnO NPs) are used in an increasing number of products, including rubber manufacture, cosmetics, pigments, food additives, medicine, chemical fibers and electronics. However, the molecular mechanisms underlying ZnO NP nephrotoxicity remain unclear. In this study, we evaluated the potential toxicity of ZnO NPs in kidney cells in vitro and in vivo. RESULTS: We found that ZnO NPs were apparently engulfed by the HEK-293 human embryonic kidney cells and then induced reactive oxygen species (ROS) generation...
September 27, 2016: Particle and Fibre Toxicology
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