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https://www.readbyqxmd.com/read/29333574/unique-metabolic-activation-of-adipose-tissue-macrophages-in-obesity-promotes-inflammatory-responses
#1
Lily Boutens, Guido J Hooiveld, Sourabh Dhingra, Robert A Cramer, Mihai G Netea, Rinke Stienstra
AIMS/HYPOTHESIS: Recent studies have identified intracellular metabolism as a fundamental determinant of macrophage function. In obesity, proinflammatory macrophages accumulate in adipose tissue and trigger chronic low-grade inflammation, that promotes the development of systemic insulin resistance, yet changes in their intracellular energy metabolism are currently unknown. We therefore set out to study metabolic signatures of adipose tissue macrophages (ATMs) in lean and obese conditions...
January 14, 2018: Diabetologia
https://www.readbyqxmd.com/read/29330785/genetic-knockdown-and-pharmacologic-inhibition-of-hypoxia-inducible-factor-hif-hydroxylases
#2
Christina Pickel, Cormac T Taylor, Carsten C Scholz
Reduced oxygen supply that does not satisfy tissue and cellular demand (hypoxia) regularly occurs both in health and disease. Hence, the capacity for cellular oxygen sensing is of vital importance for each cell to be able to alter its energy metabolism and promote adaptation to hypoxia. The hypoxia-inducible factor (HIF) prolyl hydroxylases 1-3 (PHD1-3) and the asparagine hydroxylase factor-inhibiting HIF (FIH) are the primary cellular oxygen sensors, which confer cellular oxygen-dependent sensitivity upon HIF as well as other hypoxia-sensitive pathways, such as nuclear factor κB (NF-κB)...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29330051/anti-tumor-effects-of-triptolide-on-angiogenesis-and-cell-apoptosis-in-osteosarcoma-cells-by-inducing-autophagy-via-repressing-wnt-%C3%AE-catenin-signaling
#3
Xugui Li, Qilin Lu, Wei Xie, Yang Wang, Guanqing Wang
Osteosarcoma is a common malignant bone tumor occurring in adolescents and children. The poor prognosis and low 5-year survival rate of osteosarcoma partly due to high metastasis of osteosarcoma. Triptolide (TPL), an extract from Tripterygium wilfordii, is widely used in cancer treatment. In our present study, we aimed to study the effect of TPL in osteosarcoma treatment and explore the associated regulation mechanism. Our study revealed that TPL inhibited angiogenesis by suppressing the expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in dose dependent manner...
January 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29328465/effects-of-diphyllin-as-a-novel-v-atpase-inhibitor-on-te-1-and-eca-109-cells
#4
Haijiao Chen, Pengfei Liu, Ting Zhang, Yi Gao, Yingdi Zhang, Xiuyun Shen, Xiao Li, Weidong Shen
Diphyllin is a natural component of traditional Chinese medicine, which effectively inhibits V-ATPase activity and affects the progression of cancer. However, few studies have been conducted on esophageal cancer, and the mechanisms remain to be elucidated. The present study revealedthat diphyllin inhibited proliferation and induced S arrest in esophageal cancer cell lines TE-1 and ECA-109. Further experiments revealed that diphyllin inhibited V-ATPase activity and decreased the mRNA expression of mammalian target of rapamycin complex 1 (mTORC1), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF)...
January 4, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29325224/hereditary-kidney-cancer-syndromes-genetic-disorders-driven-by-alterations-in-metabolism-and-epigenome-regulation
#5
Hisashi Hasumi, Masahiro Yao
Although hereditary kidney cancer syndrome accounts for around five percent of all kidney cancers, the mechanistic insight into tumor development in these rare conditions has provided the foundation for the development of molecular targeting agents currently used for sporadic kidney cancer. In the late 1980s, the comprehensive study for hereditary kidney cancer syndrome was launched in the National Cancer Institute, U.S.A. and the first kidney cancer associated gene, VHL was identified through kindred analysis of von Hippel-Lindau syndrome in 1993...
January 11, 2018: Cancer Science
https://www.readbyqxmd.com/read/29317342/imaging-guided-photo-therapeutic-nanoporphyrin-synergized-hsp90-inhibitor-in-patient-derived-xenograft-bladder-cancer-model
#6
Qilai Long, Tzu-Yin Lin, Yee Huang, Xiaocen Li, Ai-Hong Ma, Hongyong Zhang, Randy Carney, Susan Airhart, Kit S Lam, Chong-Xian Pan, Yuanpei Li
Photodynamic therapy is a promising and effective non-invasive therapeutic approach for the treatment of bladder cancers. Therapies targeting HSP90 have the advantage of tumor cell selectivity and have shown great preclinical efficacy. In this study, we evaluated a novel multifunctional nanoporphyrin platform loaded with an HSP90 inhibitor 17AAG (NP-AAG) for use as a multi-modality therapy against bladder cancer. NP-AAG was efficiently accumulated and retained at bladder cancer patient-derived xenograft (PDX) over 7 days...
January 6, 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/29304733/cobalt-chloride-compromises-transepithelial-barrier-properties-of-caco-2-bbe-human-gastrointestinal-epithelial-cell-layers
#7
K M DiGuilio, M C Valenzano, E Rybakovsky, J M Mullin
BACKGROUND: Elevation of the transcription factor HIF-1 is a prominent mediator of not only processes that accompany hypoxia, but also the tumor microenvironment and tissue regeneration. This study uses mediators of "chemical hypoxia" to ask the question whether HIF-1α elevation in a healthy epithelial cell layer leads to leakiness in its tight junctional seals. METHODS: Transepithelial electrical resistance and transepithelial diffusion of 14C-D-mannitol and other radiolabeled probes are used as indicators of transepithelial barrier function of CaCo-2 BBe human gastrointestinal epithelial cell layers cultured on permeable supports...
January 5, 2018: BMC Gastroenterology
https://www.readbyqxmd.com/read/29299781/slit2-robo1-signaling-is-involved-in-angiogenesis-of-glomerular-endothelial-cells-exposed-to-a-diabetic-like-environment
#8
Junhui Liu, Weiping Hou, Tao Guan, Luyao Tang, Xufei Zhu, Yi Li, Shihui Hou, Jun Zhang, Hua Chen, Yunjian Huang
Abnormal angiogenesis plays a pathological role in diabetic nephropathy (DN), contributing to glomerular hypertrophy and microalbuminuria. Slit2/Robo1 signaling participates in angiogenesis in some pathological contexts, but whether it is involved in glomerular abnormal angiogenesis of early DN is unclear. The present study evaluated the effects of Slit2/Robo1 signaling pathway on angiogenesis of human renal glomerular endothelial cells (HRGECs) exposed to a diabetic-like environment or recombinant Slit2-N...
January 3, 2018: Angiogenesis
https://www.readbyqxmd.com/read/29298915/hypoxia-induced-transcription-factor-signaling-is-essential-for-larval-growth-of-the-mosquito-aedes-aegypti
#9
Luca Valzania, Kerri L Coon, Kevin J Vogel, Mark R Brown, Michael R Strand
Gut microbes positively affect the physiology of many animals, but the molecular mechanisms underlying these benefits remain poorly understood. We recently reported that bacteria-induced gut hypoxia functions as a signal for growth and molting of the mosquito Aedes aegypti In this study, we tested the hypothesis that transduction of a gut hypoxia signal requires hypoxia-induced transcription factors (HIFs). Expression studies showed that HIF-α was stabilized in larvae containing bacteria that induce gut hypoxia but was destabilized in larvae that exhibit normoxia...
January 3, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29295858/hif-1%C3%AE-stabilization-reduces-retinal-degeneration-in-a-mouse-model-of-retinitis-pigmentosa
#10
Lorena Olivares-González, Cristina Martínez-Fernández de la Cámara, David Hervás, José María Millán, Regina Rodrigo
Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive and irreversible loss of vision due to rod and cone degeneration. Evidence suggests that an inappropriate oxygen level could contribute to its pathogenesis. Rod cell death could increase oxygen concentration, reduce hypoxia-inducible factor 1 (HIF-1α) and contribute to cone cell death. The purposes of this study were: 1) to analyze the temporal profile of HIF-1α, its downstream effectors VEGF, endothelin-1 (ET-1), iNOS, and glucose transporter 1 (GLUT1), and neuroinflammation in retinas of the murine model of rd10 (retinal degeneration 10) mice with RP; 2) to study oxygen bioavailability in these retinas; and 3) to investigate how stabilizing HIF-1α proteins with dimethyloxaloglycine (DMOG), a prolyl hydroxylase inhibitor, affects retinal degeneration, neuroinflammation, and antioxidant response in rd10 mice...
January 2, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29289682/l-ascorbic-acid-a-true-substrate-for-hif-proly-hydroxylase
#11
A I Osipyants, A A Poloznikov, N A Smirnova, D M Hushpulian, A Yu Khristichenko, T A Chubar, A A Zakhariants, M Ahuja, I N Gaisina, B Thomas, A M Brown, I G Gazaryan, V I Tishkov
L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-luc reporter activation induced by various inhibitors of HIF prolyl hydroxylase (PHD). The efficiency of suppression by L-Asc was sensitive to the nature of HIF PHD inhibitor chosen for reporter activation. In particular, the inhibitors developed to compete with alpha-ketoglutarate (αKG), were less sensitive to suppression by the physiological range of L-Asc (40-100 μM) than those having a strong iron chelation motif...
December 28, 2017: Biochimie
https://www.readbyqxmd.com/read/29278273/hypoxia-inducible-factor-1-hif-1-inhibitors-from-the-last-decade-2007-to-2016-a-structure-activity-relationship-perspective
#12
REVIEW
Deepak Bhattarai, Xuezhen Xu, Kyeong Lee
Tumor hypoxia is a common feature in most solid tumors and is associated with overexpression of the hypoxia response pathway. Overexpression of the hypoxia-inducible factor (HIF-1) protein leads to angiogenesis, metastasis, apoptosis resistance, and many other pro-tumorigenic responses in cancer development. HIF-1 is a promising target in cancer drug development to increase the patient's response to chemotherapy and radiotherapy as well as the survival rate of cancer patients. Since up to 1% of genes are hypoxia-sensitive, a target-specific HIF-1 inhibitor may be a better clinical candidate in cancer drug discovery...
December 26, 2017: Medicinal Research Reviews
https://www.readbyqxmd.com/read/29277653/microrna-191-regulated-by-hif-2%C3%AE-is-involved-in-emt-and-acquisition-of-a-stem-cell-like-phenotype-in-arsenite-transformed-human-liver-epithelial-cells
#13
Chao Chen, Qianlei Yang, Dapeng Wang, Fei Luo, Xinlu Liu, Junchao Xue, Ping Yang, Hui Xu, Jiachun Lu, Aihua Zhang, Qizhan Liu
Inorganic arsenic is widely distributed in the environment, and epidemiologic data show a strong association between arsenic exposure and risk of liver cancer. An understanding of the mechanisms underlying development of liver cancer and metastasis would be useful in reducing the incidence and mortality of liver cancer. MicroRNAs (miRs) act as regulators in liver cancer. Here, we show that acute or chronic exposure of human liver epithelial L-02 cells to arsenite increased expression of miR-191. There were decreased levels of BASP-1 and E-cadherin and increased levels of WT-1 and N-cadherin, indicating that arsenite induced epithelial-mesenchymal transition (EMT)...
December 22, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/29260521/-research-on-relationship-of-hif-1-signaling-pathway-and-postmenstrual-osteoporosis
#14
Hang Zhong, Can Cao, Jing Yang, Qiang Huang
OBJECTIVE: Exploring the role of hypoxia-induceibal factor-1 (HIF-1) signaling pathway in postmenstrual osteoporosis (PMOP) and how to play a role in PMOP. METHODS: Sixty C57BL/6J female mouse were randomly divided into 4 groups: sham-operation group (A group),ovariectomized PMOP group (B group),HIF-1 alpha inhibitor 2-methoxy estradiol (2ME2) treatment group(D group) and solvent control group(C group),15 mice in each group. There months after modeling,the metabolism product of mouse bone tissue including serum propeptide of typeⅠ procollagen (PINP),C-terminal telopeptide-Ⅰ (CTX-1) and serum estrogen were quantified by enzyme-linked immunosorbent assay (ELISA)...
November 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/29259755/discovery-of-jtz-951-a-hif-prolyl-hydroxylase-inhibitor-for-the-treatment-of-renal-anemia
#15
Yosuke Ogoshi, Takuya Matsui, Ikuo Mitani, Masahiro Yokota, Masakazu Terashita, Dai Motoda, Kazuhito Ueyama, Takahiro Hotta, Takashi Ito, Yasunori Hase, Kenji Fukui, Katsuya Deai, Hiromi Yoshiuchi, Soichiro Ito, Hiroyuki Abe
Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π-π stacking interactions with Tyr310...
December 14, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29250198/novel-concepts-of-antiangiogenic-therapies-in-metastatic-renal-cell-cancer
#16
REVIEW
Renate Pichler, Isabel Heidegger
The era of antiangiogenic drugs targeting the vascular endothelial growth factor (VEGF) signaling pathway has become a mainstay in the treatment of metastatic renal cell carcinoma (mRCC), showing primary responses in 65-70% of patients. Nevertheless, most of those patients progress to angiogenesis inhibitors over time due to different modes of resistance (adaptive and intrinsic). Both in vitro and in vivo analyses provided evidence that PD-L1 upregulation in hypoxia conditions is dependent on hypoxia-inducible factor (HIF)-2alpha and is associated with an overexpression of VEGF...
2017: Memo
https://www.readbyqxmd.com/read/29245898/a-novel-small-molecule-arylsulfonamide-causes-energetic-stress-and-suppresses-breast-and-lung-tumor-growth-and-metastasis
#17
Xin Dai, Stefan Kaluz, Ying Jiang, Lei Shi, DeAngelo Mckinley, Yingzhe Wang, Binghe Wang, Erwin G Van Meir, Chalet Tan
Neoplastic cells display reprogrammed metabolism due to the heightened energetic demands and the need for biomass synthesis of a growing tumor. Targeting metabolic vulnerabilities is thus an important goal for cancer therapy. Here, we describe a novel small-molecule arylsulfonamide (N-cyclobutyl-N-((2,2-dimethyl-2H-pyrano[3,2-b]pyridin-6-yl)methyl)-3,4-dimethoxybenzenesulfonamide) that exerts potent cytotoxicity and energetic stress on tumor cells while largely sparing non-cancerous human cells. In tumor cells, it stimulates glycolysis and accelerates glucose consumption...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29242064/hypoxia-inducible-factor-1-in-clinical-and-experimental-aortic-aneurysm-disease
#18
Wei Wang, Baohui Xu, Haojun Xuan, Yingbin Ge, Yan Wang, Lixin Wang, Jianhua Huang, Weiguo Fu, Sara A Michie, Ronald L Dalman
OBJECTIVE: Mural angiogenesis and macrophage accumulation are two pathologic hallmarks of abdominal aortic aneurysm (AAA) disease. The heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) is an essential regulator of angiogenesis and macrophage function. In this study, we investigated HIF-1 expression and activity in clinical and experimental AAA disease. METHODS: Human aortic samples were obtained from 24 AAA patients and six organ donors during open abdominal surgery...
December 11, 2017: Journal of Vascular Surgery
https://www.readbyqxmd.com/read/29237157/hypoxia-accelerates-aggressiveness-of-hepatocellular-carcinoma-cells-involving-oxidative-stress-epithelial-mesenchymal-transition-and-non-canonical-hedgehog-signaling
#19
Zhikui Liu, Kangsheng Tu, Yufeng Wang, Bowen Yao, Qing Li, Liang Wang, Changwei Dou, Qingguang Liu, Xin Zheng
BACKGROUND/AIMS: Hypoxic microenvironment, a common feature of hepatocellular carcinoma (HCC), can induce HIF-1α expression and promote the epithelial-mesenchymal transition (EMT) and invasion of cancer cells. However, the underlying molecular mechanisms have not fully elucidated. METHODS: HCC cells were cultured under controlled hypoxia conditions or normoxic conditions. Transwell assays were used to examine the migration and invasion capacity. HIF-1α siRNA, cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1α transcription or Hh signaling activation...
December 11, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29227282/hypoxia-induced-upregulation-of-bmx-kinase-mediates-therapeutic-resistance-in-acute-myeloid-leukemia
#20
Jolieke G van Oosterwijk, Daelynn R Buelow, Christina D Drenberg, Aksana Vasilyeva, Lie Li, Lei Shi, Yong-Dong Wang, David Finkelstein, Sheila A Shurtleff, Laura J Janke, Stanley Pounds, Jeffrey E Rubnitz, Hiroto Inaba, Navjotsingh Pabla, Sharyn D Baker
Oncogenic addiction to the Fms-like tyrosine kinase 3 (FLT3) is a hallmark of acute myeloid leukemia (AML) that harbors the FLT3-internal tandem duplication (FLT3-ITD) mutation. While FLT3 inhibitors like sorafenib show initial therapeutic efficacy, resistance rapidly develops through mechanisms that are incompletely understood. Here, we used RNA-Seq-based analysis of patient leukemic cells and found that upregulation of the Tec family kinase BMX occurs during sorafenib resistance. This upregulation was recapitulated in an in vivo murine FLT3-ITD-positive (FLT3-ITD+) model of sorafenib resistance...
December 11, 2017: Journal of Clinical Investigation
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