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https://www.readbyqxmd.com/read/29156796/downregulation-of-dna-repair-proteins-and-increased-dna-damage-in-hypoxic-colon-cancer-cells-is-a-therapeutically-exploitable-vulnerability
#1
Jennifer M J Jongen, Lizet M van der Waals, Kari Trumpi, Jamila Laoukili, Niek A Peters, Susanne J Schenning-van Schelven, Klaas M Govaert, Inne H M Borel Rinkes, Onno Kranenburg
Surgical removal of colorectal cancer (CRC) liver metastases generates areas of tissue hypoxia. Hypoxia imposes a stem-like phenotype on residual tumor cells and promotes tumor recurrence. Moreover, in primary CRC, gene expression signatures reflecting hypoxia and a stem-like phenotype are highly expressed in the aggressive Consensus Molecular Subtype 4 (CMS4). Therapeutic strategies eliminating hypoxic stem-like cells may limit recurrence following resection of primary tumors or metastases. Here we show that expression of DNA repair genes is strongly suppressed in CMS4 and inversely correlated with hypoxia-inducible factor-1 alpha (HIF1α) and HIF-2α co-expression signatures...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156788/modulation-of-hif-1%C3%AE-and-stat3-signaling-contributes-to-anti-angiogenic-effect-of-yc-1-in-mice-with-liver-fibrosis
#2
Tzung-Yan Lee, Yann-Lii Leu, Chorng-Kai Wen
Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The aim of the study was to evaluate the mechanisms of HIF-1α inhibitor, YC-1, during bile duct ligation (BDL)-induced liver fibrosis in mice. Liver fibrosis was induced in mice, and YC-1 was then given intraperitoneally (50 mg/kg) once daily following 5 days. Liver injuries mice that were treated with YC-1 showed improved inflammatory response and diminished angiogenesis and hepatic fibrosis. YC-1 treatment inhibited liver neutrophil infiltration, while a decreased in TNF-α signaling as well as macrophage aggregation...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156717/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
#3
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...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29155844/hypoxia-and-hypoxia-inducible-factor-hif-downregulate-antigen-presenting-mhc-class-i-molecules-limiting-tumor-cell-recognition-by-t-cells
#4
Shalini Sethumadhavan, Murillo Silva, Phaethon Philbrook, Thao Nguyen, Stephen M Hatfield, Akio Ohta, Michail V Sitkovsky
Human cancers are known to downregulate Major Histocompatibility Complex (MHC) class I expression thereby escaping recognition and rejection by anti-tumor T cells. Here we report that oxygen tension in the tumor microenvironment (TME) serves as an extrinsic cue that regulates antigen presentation by MHC class I molecules. In support of this view, hypoxia is shown to negatively regulate MHC expression in a HIF-dependent manner as evidenced by (i) lower MHC expression in the hypoxic TME in vivo and in hypoxic 3-dimensional (3D) but not 2-dimensional (2D) tumor cell cultures in vitro; (ii) decreased MHC in human renal cell carcinomas with constitutive expression of HIF due to genetic loss of von Hippel-Lindau (VHL) function as compared with isogenically paired cells with restored VHL function, and iii) increased MHC in tumor cells with siRNA-mediated knockdown of HIF...
2017: PloS One
https://www.readbyqxmd.com/read/29155422/secretion-mediated-stat3-activation-promotes-self-renewal-of-glioma-stem-like-cells-during-hypoxia
#5
D A Almiron Bonnin, M C Havrda, M C Lee, H Liu, Z Zhang, L N Nguyen, L X Harrington, S Hassanpour, C Cheng, M A Israel
High-grade gliomas (HGGs) include the most common and the most aggressive primary brain tumor of adults and children. Despite multimodality treatment, most high-grade gliomas eventually recur and are ultimately incurable. Several studies suggest that the initiation, progression, and recurrence of gliomas are driven, at least partly, by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew. We have identified a hypoxia-induced pathway that utilizes the Hypoxia Inducible Factor 1α (HIF-1α) transcription factor and the JAK1/2-STAT3 (Janus Kinase 1/2 - Signal Transducer and Activator of Transcription 3) axis to enhance the self-renewal of glioma stem-like cells...
November 20, 2017: Oncogene
https://www.readbyqxmd.com/read/29153032/evaluation-of-the-carcinogenic-potential-of-roxadustat-fg-4592-a-small-molecule-inhibitor-of-hypoxia-inducible-factor-prolyl-hydroxylase-in-cd-1-mice-and-sprague-dawley-rats
#6
James Beck, Carroll Henschel, James Chou, Al Lin, Ughetta Del Balzo
The carcinogenic potential of roxadustat (FG-4592), a novel orally active, heterocyclic small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzymes in clinical development for treatment of anemia, was evaluated in CD-1 mice and Sprague Dawley rats. Inhibition of HIF-PH by roxadustat leads to a rapid increase in cytoplasmic HIF-α concentrations, followed by translocation of HIF-α to the nucleus and upregulation of HIF-responsive genes, including erythropoietin. Roxadustat was dosed by oral gavage 3 times weekly (TIW) for up to 104 weeks in mice at 0, 15, 30, and 60 mg/kg and in rats at 0, 2...
January 1, 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/29152681/trichothecenes-immunomodulatory-effects-mechanisms-and-anti-cancer-potential
#7
REVIEW
Qinghua Wu, Xu Wang, Eugenie Nepovimova, Anca Miron, Qianying Liu, Yun Wang, Dongxiao Su, Hualin Yang, Li Li, Kamil Kuca
Paradoxically, trichothecenes have both immunosuppressive and immunostimulatory effects. The underlying mechanisms have not been fully explored. Early studies show that dose, exposure timing, and the time at which immune function is assessed influence whether trichothecenes act in an immunosuppressive or immunostimulatory fashion. Recent studies suggest that the immunomodulatory function of trichothecenes is also actively shaped by competing cell-survival and death-signaling pathways. Autophagy may also promote trichothecene immunosuppression, although the mechanism may be complicated...
November 20, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/29152147/microrna-370-inhibits-the-growth-and-metastasis-of-lung-cancer-by-down-regulating-epidermal-growth-factor-receptor-expression
#8
Xin Liu, You-Guang Huang, Cong-Guo Jin, Yong-Chun Zhou, Xiao-Qun Chen, Jia Li, Yan Chen, Mei Li, Qian Yao, Ke Li, Min Lan, Jia-Gui Ye, Xi-Cai Wang
Abnormal microRNA-370 (miR-370) expression has been frequently reported in several types of cancers, including lung cancer. However, the role and molecular mechanisms of miR-370 in regulating the growth and metastasis of lung cancer have not been clarified. Here, we show higher levels of epidermal growth factor receptor (EGFR), but lower levels of miR-370 expression in most human lung cancer cells and non-tumor cells. Induction of miR-370 over-expression significantly reduced the levels of EGFR expression and the EGFR 3'untranslated region (UTR)-regulated luciferase activity in XWLC-05 and H157 cells, suggesting that miR-370 may bind to the 3'UTR of EGFR mRNA...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29152120/hierarchical-clustering-analysis-identifies-metastatic-colorectal-cancers-patients-with-more-aggressive-phenotype
#9
Giuseppina Opinto, Nicola Silvestris, Matteo Centonze, Giusi Graziano, Rosamaria Pinto, Livia Fucci, Giovanni Simone, Anita Mangia
A large percentage of metastatic colorectal cancer (mCRC) patients presents metastasis at the time of diagnosis. In the last years, great efforts have been made in the treatment of these patients with the identification of different phenotypes playing a key role in the definition of new systemic therapies. Unsupervised hierarchical clustering analysis (HCA) was performed considering the clinicopathological characteristics of 51 mCRCs. Using immunohistochemistry on tissue microarrays, we assessed the expression of β-catenin, NHERF1, RASSF1A, TWIST1, HIF-1α proteins in tumors and paired liver metastases...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29149745/household-air-pollution-and-chronic-hypoxia-in-the-placenta-of-pregnant-nigerian-women-a-randomized-controlled-ethanol-cookstove-intervention
#10
Anindita Dutta, Galina Khramtsova, Katherine Brito, Donee Alexander, Ariel Mueller, Sireesha Chinthala, Damilola Adu, Tope Ibigbami, John Olamijulo, Abayomi Odetunde, Kehinde Adigun, Liese Pruitt, Ian Hurley, Olufunmilayo Olopade, Oladosu Ojengbede, Sarosh Rana, Christopher O Olopade
BACKGROUND: Household air pollution (HAP) is associated with adverse pregnancy outcomes. OBJECTIVES: Investigate impact of in-utero HAP exposure on placental development and chronic hypoxia. METHODS: Markers of chronic placental hypoxia [Hofbauer cells (HBC), syncytial knots (SK), chorionic vascular density (cVD) and hypoxia-inducible factor (HIF)] were stained by hematoxylin-eosin and/or immunohistochemically in placenta samples collected from firewood-/kerosene-users (A,n=16), and ethanol-users (B,n=20) that participated in a randomized controlled intervention trial in Ibadan, Nigeria...
November 14, 2017: Science of the Total Environment
https://www.readbyqxmd.com/read/29148169/antitumor-and-anti-metastatic-mechanisms-of-rhizoma-paridis-saponins-in-lewis-mice
#11
Shuli Man, Hongyan Chai, Jingxia Cui, Jingwen Yao, Long Ma, Wenyuan Gao
Lung cancer is one of the most common causes of death in the world. Rhizoma paridis saponins (RPS) have been found to show inhibition of pulmonary adenoma in previous research. However, the detailed mechanisms of RPS from a holistic view have not been established. In this study, Lewis pulmonary adenoma mice were successfully established to analyze the pathways involved in RPS intervening tumor formation and progression. As a result, RPS inhibited levels of cytokines or receptors such as VEGFD, VEGFR3, RAGE, IL6R, IL17BR, and CXCL16 which were regarded as the initiators induced tumor cell proliferation, adhesion, angiogenesis, and invasion...
November 17, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/29147618/programmed-cell-death-ligands-expression-in-phaeochromocytomas-and-paragangliomas-relationship-with-the-hypoxic-response-immune-evasion-and-malignant-behavior
#12
David J Pinato, James R Black, Sebastian Trousil, Roberto E Dina, Pritesh Trivedi, Francesco A Mauri, Rohini Sharma
The hypoxic response underlies the pathogenesis and malignant behavior of PCC/PGL. Regulation of PD-1 receptor-ligand signaling, a therapeutically actionable driver of the anti-tumor immune response, is a hypoxic-driven trait across malignancies. We evaluated the prognostic role of PD ligands in association with biomarkers of hypoxia and angiogenesis in patients with PCC/PGL. Tissue microarrays sections including consecutive cases diagnosed between 1983-2011 were stained for PD-L1 and 2, hypoxia inducible factor 1a (Hif-1a), Carbonic Anhydrase IX (CaIX), Vascular Endothelial Growth Factor-A (VEGF-A)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29146180/chlorogenic-acid-attenuates-diabetic-retinopathy-by-reducing-vegf-expression-and-inhibiting-vegf-mediated-retinal-neoangiogenesis
#13
Xiyu Mei, Lingyu Zhou, Tianyu Zhang, Bin Lu, Yuchen Sheng, Lili Ji
Diabetic retinopathy (DR) is one of the most common and serious complications of diabetes mellitus (DM). This study aims to investigate the amelioration of chlorogenic acid (CGA) on proliferative DR (PDR) via focusing on inhibiting retinal neoangiogenesis. CGA reduced the increased cell proliferation, migration and tube formation induced by vascular endothelial growth factor (VEGF) in human retinal endothelial cells (HREC) and choroid-retinal endothelial RF/6A cells. CGA abrogated VEGF-induced the phosphorylation of VEGFR2 and its downstream mitogen-activated extracellular regulated kinase (MEK1/2), extracellular regulated protein kinase (ERK1/2) and p38 kinase...
November 13, 2017: Vascular Pharmacology
https://www.readbyqxmd.com/read/29144820/pheochromocytoma-a-genetic-and-diagnostic-update
#14
Leilani B Mercado-Asis, Katherine I Wolf, Ivana Jochmanova, David Taïeb
OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathological studies are performed to prove, localize, treat, and monitor disease progression. Recently, improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (less than 1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment...
November 16, 2017: Endocrine Practice
https://www.readbyqxmd.com/read/29140729/gene-expression-and-gene-associations-during-the-development-of-heart-failure-with-preserved-ejection-fraction-in-the-dahl-salt-sensitive-model-of-hypertension
#15
Jeffrey Yim, Hyokeun Cho, Simon W Rabkin
Gene expression and associations were examined in a model of heart failure with preserved ejection fraction (HFpEF), a condition with minimal effective treatment. Genes with at least two studies showing significant changes in Dahl rat with heart failure were examined by meta-analysis. Significantly increased in expression were iNOS, p47phox, ADM, ANP, OPN, ACE, MCP-1, GP91PHOX, ICAM-1, TGF-β1, CTGF, ET-1, p22phox, ETB, BNP, ETA, MMP13, Col1a1, MMP2, TIMP1, Col3a1, Il-1β, β-MHC, ECE1, MMP14, AGT, and MMP9...
November 15, 2017: Clinical and Experimental Hypertension: CHE
https://www.readbyqxmd.com/read/29133037/the-novel-4-phenyl-2-phenoxyacetamide-thiazoles-modulates-the-tumor-hypoxia-leading-to-the-crackdown-of-neoangiogenesis-and-evoking-the-cell-death
#16
Yasser Hussein Eissa Mohammed, Vikas H Malojirao, Prabhu Thirusangu, Mohammed Al-Ghorbani, B T Prabhakar, Shaukath Ara Khanum
Tumor microenvironment is a complex multistep event which involves several hallmarks that transform the normal cell into cancerous cell. Designing the novel antagonistic molecule to reverse the tumor microenvironment with specific target is essential in modern biological studies. The novel 4-phenyl-2-phenoxyacetamide thiazole analogues 8a-ab were synthesized in multistep process, then screened and assessed for cytotoxic and anti-proliferative effects in vitro against multiple cancer cells of different origin such as MCF-7, A549, EAC and DLA cells which revealed that compound 8f with fluoro and methyl substitute has potential cytotoxic efficacy with an average IC50 value of ˜ 13 μM...
November 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29132131/il-6-promotes-fsh-induced-vegf-expression-through-jak-stat3-signaling-pathway-in-bovine-granulosa-cells
#17
Meng Yang, Lei Wang, Xurong Wang, Xuezhi Wang, Zhiqiang Yang, Jianxi Li
BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) has been demonstrated to play a pivotal role in the regulation of angiogenesis in ovarian follicular development, particularly during the preovulatory period. Although numerous studies have shown that interleukin-6 (IL-6) is one of the major inducing factors that regulate the expression of VEGF in non-ovarian cells, whether it involved in regulating the expression of VEGF in normal ovarian granulosa cells is still unknown. The aim of this study was to elucidate the mechanisms underlying the effect of IL-6 on FSH-induced VEGF expression in bovine granulosa cells derived from large follicles...
November 13, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29131087/deferoxamine-induced-migration-and-odontoblast-differentiation-via-ros-dependent-autophagy-in-dental-pulp-stem-cells
#18
Xuan Wang, Tian Tian Wu, Long Jiang, Du Rong, Ya Qin Zhu
BACKGROUND/AIMS: As a vital degradation and recycling system, autophagy plays an essential role in regulating the differentiation of stem cells. We previously showed that iron chelator deferoxamine (DFO) could promote the repair ability of dental pulp stem cells (DPSCs). Here, we investigated the effect of DFO in autophagy and the role of autophagy in regulating the migration and odontoblast differentiation of DPSCs. METHODS: Transmission electron microscopy, immunofluorescence staining and western blotting were performed to evaluate the autophagic activity of DPSCs...
November 1, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29130678/-expression-of-lox-in-colorectal-cancer-tissues-and-its-relationship-with-progress-and-prognosis
#19
Xiao-Ming Shi, Wei Zhao, Yong-Bin Yang, Bo-Nan Lü
OBJECTIVE: To analyze the expression of lysyl oxidase (LOX) in colorectal cancer and its relationship with clinicopathological characteristics, prognosis, and its progress. METHODS: 82 cases of colorectal tumor paraffin-embedded specimens and paired tumor-adjacent tissues were collected, and data of clinicopathological characteristics and prognosis of these patients were also recorded from 2009.1 to 2010.5. Expressions of LOX, hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase (MMP)-2, MMP-7 were determined by immunohistochemistry...
July 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/29129792/the-hypoxia-mimetic-protocatechuic-acid-ethyl-ester-inhibits-synaptic-signaling-and-plasticity-in-the-rat-hippocampus
#20
Sinead M Lanigan, John J O'Connor
During hypoxia a number of physiological changes occur within neurons including the stabilization of hypoxia-inducible factors (HIFs). The activity of these proteins is regulated by O2, Fe(2+), 2-OG and ascorbate-dependant hydroxylases which contain prolyl-4-hydroxylase domains (PHDs). PHD inhibitors have been widely used and have been shown to have a preconditioning and protective effect against a later and more severe hypoxic insult. In this study we have investigated the neuroprotective effects of the PHD inhibitor, protocatechuic acid ethyl ester (ethyl 3,4, dihydroxybenzoate: EDHB) as well as its effects on synaptic transmission and plasticity in the rat hippocampus using electrophysiological techniques...
November 10, 2017: Neuroscience
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