scholarly journals SQAP, an acyl sulfoquinovosyl derivative, suppresses expression of histone deacetylase and induces cell death of cancer cells under hypoxic conditions

2021 ◽  
Vol 85 (1) ◽  
pp. 85-91
Author(s):  
Hirofumi Kawakubo ◽  
Shinji Kamisuki ◽  
Kei Suzuki ◽  
Jesus Izaguirre-Carbonell ◽  
Shiki Saito ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Biological Activities ◽  
Hypoxia Inducible Factor ◽  
Hdac Inhibitors ◽  
Low Oxygen ◽  
Hypoxic Conditions ◽  
Oxygen Conditions ◽  
Model Mouse ◽  
Hepatocarcinoma Cells ◽  
Hepatoma Model

Abstract Sulfoglycolipid, SQAP, is a radiosensitizing agent that makes tumor cells more sensitive to radiation therapy. A previous study revealed that SQAP induced the degradation of hypoxia-inducible factor-1α (HIF-1α) and inhibited angiogenesis in a hepatoma model mouse. Herein, we examined the biological activities of SQAP against hepatocarcinoma cells under low oxygen conditions. Cell growth inhibition of SQAP under hypoxic conditions was significantly higher than that under normoxic conditions. In addition, SQAP was found to impair the expression of histone deacetylase (HDAC) under low oxygen conditions. Our present data suggested that SQAP induced the degradation of HIF-1α and then decreased the expression of HDAC1. Unlike known HDAC inhibitors, SQAP increased the acetylation level of histone in cells without inhibition of enzymatic activity of HDACs. Our data demonstrated hypoxia-specific unique properties of SQAP.

scholarly journals Transcriptome sequencing revealed differences in the response of renal cancer cells to hypoxia and CoCl2 treatment

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1518 ◽  
Author(s):  
Nadezhda Zhigalova ◽  
Artem Artemov ◽  
Alexander M. Mazur ◽  
Egor B. Prokhortchouk
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Human Cancer Cells ◽  
Hypoxic Conditions ◽  
Pathway Activation ◽  
Oxygen Conditions ◽  
Order Of Magnitude ◽  
Transcriptional Changes

Human cancer cells are subjected to hypoxic conditions in many tumours. Hypoxia causes alterations in the glycolytic pathway activation through stabilization of hypoxia-inducible factor 1. Currently, two approaches are commonly used to model hypoxia: an alternative to generating low-oxygen conditions in an incubator, cells can be treated with CoCl2. We performed RNA-seq experiments to study transcriptomes of human Caki-1 cells under real hypoxia and after CoCl2 treatment. Despite causing transcriptional changes of a much higher order of magnitude for the genes in the hypoxia regulation pathway, CoCl2 treatment fails to induce alterations in the glycolysis / gluconeogenesis pathway. Moreover, CoCl2 caused aberrant activation of other oxidoreductases in glycine, serine and threonine metabolism pathways.

scholarly journals Induction of glucose transporter 1 expression through hypoxia-inducible factor 1α under hypoxic conditions in trophoblast-derived cells

2004 ◽  
Vol 183 (1) ◽  
pp. 145-154 ◽  
Author(s):  
Masami Hayashi ◽  
Masahiro Sakata ◽  
Takashi Takeda ◽  
Toshiya Yamamoto ◽  
Yoko Okamoto ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Oxygen Deficiency ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Level ◽  
Low Oxygen ◽  
Glucose Transporter 1 ◽  
Hypoxic Conditions ◽  
Glut1 Expression ◽  
Oxygen Conditions ◽  
Responsive Element

Glucose transporter 1 (GLUT1) plays an important role in the transport of glucose in the placenta. During early pregnancy, placentation occurs in a relatively hypoxic environment that is essential for appropriate embryonic development, and GLUT1 expression is enhanced in response to oxygen deficiency in the placenta. Hypoxia-inducible factor-1 (HIF-1)α is involved in the induction of GLUT1 expression in other cells. The present study was designed to test whether HIF-1α is involved in hypoxia-induced activation of GLUT1 expression using trophoblast-derived human BeWo and rat Rcho-1 cells as models. GLUT1 mRNA and protein expression were elevated under 5% O2 or in the presense of cobalt chloride, which has been shown to mimic hypoxia. Using rat GLUT1 (rGLUT1) promoter–luciferase constructs, we showed that this up-regulation was mediated at the transcriptional level. Deletion mutant analysis of the rGLUT1 promoter indicated that a 184 bp hypoxia-responsive element (HRE) of the promoter was essential to increase GLUT1 reporter gene expression in response to low-oxygen conditions. BeWo and Rcho-1 cells cultured under 5% O2 or with CoCl2 showed increased expression of HIF-1α protein compared with those cultured under 20% O2. To test whether this factor is directly involved in hypoxia-induced GLUT1 promoter activation, BeWo and Rcho-1 cells were transiently transfected with an HIF-1α expression vector. Exogeneous HIF-1α markedly increased the GLUT1 promoter activity from constructs containing the HRE site, while the GLUT1 promoter constructs lacking the HRE site were not activated by exogenous HIF-1α These data demonstrate that GLUT1 is up-regulated under 5% O2 or in the presence of CoCl2 in the placental cell lines through HIF-1α interaction with a consensus HRE site of the GLUT1 promoter.

scholarly journals Hypoxia-Induced Gene Expression Occurs Solely through the Action of Hypoxia-Inducible Factor 1α (HIF-1α): Role of Cytoplasmic Trapping of HIF-2α

2003 ◽  
Vol 23 (14) ◽  
pp. 4959-4971 ◽  
Author(s):  
Sang-ki Park ◽  
Agnes M. Dadak ◽  
Volker H. Haase ◽  
Lucrezia Fontana ◽  
Amato J. Giaccia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Hypoxic Conditions ◽  
Show Evidence ◽  
Dependent Protein ◽  
A Cell ◽  
Cell Type Specific ◽  
Inducible Genes

ABSTRACT The hypoxia-inducible factors 1α (HIF-1α) and 2α (HIF-2α) have extensive structural homology and have been identified as key transcription factors responsible for gene expression in response to hypoxia. They play critical roles not only in normal development, but also in tumor progression. Here we report on the differential regulation of protein expression and transcriptional activity of HIF-1α and -2α by hypoxia in immortalized mouse embryo fibroblasts (MEFs). We show that oxygen-dependent protein degradation is restricted to HIF-1α, as HIF-2α protein is detected in MEFs regardless of oxygenation and is localized primarily to the cytoplasm. Endogenous HIF-2α remained transcriptionally inactive under hypoxic conditions; however, ectopically overexpressed HIF-2α translocated into the nucleus and could stimulate expression of hypoxia-inducible genes. We show that the factor inhibiting HIF-1 can selectively inhibit the transcriptional activity of HIF-1α but has no effect on HIF-2α-mediated transcription in MEFs. We propose that HIF-2α is not a redundant transcription factor of HIF-1α for hypoxia-induced gene expression and show evidence that there is a cell type-specific modulator(s) that enables selective activation of HIF-1α but not HIF-2α in response to low-oxygen stress.

Jasus lalandii 'walkouts' or mass strandings in South Africa during the 1990s: an overview

2001 ◽  
Vol 52 (8) ◽  
pp. 1085 ◽  
Author(s):  
Andrew C. Cockcroft
Keyword(s):  
South Africa ◽  
West Coast ◽  
The Other ◽  
Fishing Industry ◽  
Low Oxygen ◽  
Rock Lobster ◽  
The West ◽  
Hypoxic Conditions ◽  
Oxygen Conditions ◽  
Mass Mortalities

Faunal mass mortalities are a sporadic, but not uncommon, feature of the West and South coasts of South Africa. Five mass mortalities of West Coast rock lobsterJasus lalandii, including three of the most severe ever recorded in South Africa, occurred in the 1990s and resulted in the stranding of about 2263 tonnes of lobster. The bulk (97%) of the loss occurred in the last three years of the decade. The five events occurred within an 80 km stretch of coastline that straddled two fishing zones and resulted from hypoxic conditions associated with highbiomass dinoflagellate blooms. In each case, the quantity of lobsters stranded was directly related to the extent or duration of low-oxygen conditions. Small females constituted the bulk of the lobster stranded in most events. The lobster fisheries in the affected fishing zones suffered severe impacts. Recovery in one zone appears to be extremely slow, whereas the other zone is more resilient. Not only would a continuation of the trend of increasing frequency and severity of lobster strandings devastate the rock-lobster fishing industry and the employment prospects of small fishing communities, but it could also seriously affect the ecology of the region.

scholarly journals The effect of alpha-v integrin inhibition on the malignant characteristics of medulloblastoma

2013 ◽  
Vol 11 (1) ◽  
pp. 60-67 ◽  
Author(s):  
Eric M. Thompson ◽  
Nathaniel L. Whitney ◽  
Y. Jeffrey Wu ◽  
Edward A. Neuwelt
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Stress Responses ◽  
Hypoxia Inducible Factor ◽  
Aggressive Phenotype ◽  
Hypoxic Conditions ◽  
Oxygen Conditions ◽  
Cellular Stress Responses ◽  
Dose Dependent Decrease ◽  
And Migration

Object Hypoxia induces an aggressive phenotype in some brain tumors in part due to hypoxia-inducible factor–1α (HIF-1α) and integrin expression. The importance of hypoxia in medulloblastoma is unclear and the interaction of HIF-1α and c-Myc in medulloblastoma has not been explored. The objective of this study was to determine if hypoxia induces an aggressive phenotype in human medulloblastoma cells that constitutively express high (D283 Med) or low (DAOY) levels of c-Myc and to determine if blocking αv integrins with the monoclonal antibody intetumumab inhibits hypoxia-induced cellular stress responses. Methods Cells were grown at 21% and 1% O2 and in the presence or absence of intetumumab. Measures of malignancy evaluated included cell proliferation, cell migration, and expression of vascular endothelial growth factor (VEGF), αv integrins, HIF-1α, and c-Myc. Results Both cell lines robustly expressed αv integrins. Hypoxic DAOY cells showed significantly increased proliferation compared with normoxic controls (p < 0.05), whereas D283 Med cells did not. Both cell lines exhibited a dose-dependent decrease in proliferation when treated with intetumumab (p < 0.05). Hypoxia did not increase DAOY migration, but intetumumab significantly inhibited migration at both oxygen conditions (p < 0.05). Intetumumab significantly decreased VEGF levels in DAOY cells at both oxygen conditions (p < 0.05) and in normoxic D283 cells (p < 0.01). Neither cell line demonstrated increased HIF-1α expression in response to hypoxia. However, hypoxic D283 Med cells grown in the presence of intetumumab demonstrated significantly decreased c-Myc expression (p < 0.05). Conclusions Hypoxia did not clearly induce a more aggressive phenotype in medulloblastoma cells. Despite this result, intetumumab decreased medulloblastoma cell proliferation and migration and variably decreased VEGF and c-Myc expression in hypoxic conditions. Targeting αv integrins represents a promising potential adjuvant modality in the treatment of medulloblastoma, particularly subtypes that metastasize and overexpress VEGF and c-Myc.

Betaine reduces the expression of inflammatory adipokines caused by hypoxia in human adipocytes

2012 ◽  
Vol 109 (1) ◽  
pp. 43-49 ◽  
Author(s):  
K. Olli ◽  
S. Lahtinen ◽  
N. Rautonen ◽  
K. Tiihonen
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Markers ◽  
Mrna Level ◽  
Low Grade ◽  
Human Adipocytes ◽  
Low Oxygen ◽  
Hypoxic Conditions ◽  
Tnf Α ◽  
Oxygen Conditions ◽  
Low Grade Inflammation

Obesity is characterised by a state of chronic low-grade inflammation and the elevated circulating and tissue levels of inflammatory markers, including inflammation-related adipokines, released from white adipose tissue. The expression and release of these adipokines generally rises as the adipose tissue expands and hypoxic conditions start to develop within the tissue. Here, the effect of betaine, a trimethylglycine having a biological role as an osmolyte and a methyl donor, on the expression of inflammation-related markers was tested in human adipocytes under hypoxia. Differentiated adipocytes were cultivated under low (1 %) oxygen tension for 8–20 h. The expression of different adipokines, including IL-6, leptin, PPARγ, TNF-α and adiponectin, was measured by quantitative PCR by determining the relative mRNA level from the adipocytes. Hypoxia, in general, led to a decrease in the expression of PPARγ mRNA in human adipocytes, whereas the expression levels of leptin and IL-6 mRNA were substantially increased by hypoxia. The cultivation of adipocytes under hypoxia also led to a reduction in the expression of TNF-α mRNA. The results showed that hypoxia increased the relative quantification of leptin gene transcription, and that betaine (250 μmol/l) reduced this effect, caused by low oxygen conditions. Under hypoxia, betaine also reduced the mRNA level of the pro-inflammatory markers IL-6 and TNF-α. These results demonstrate that the extensive changes in the expression of inflammation-related adipokines in human adipocytes caused by hypoxia can be diminished by the presence of physiologically relevant concentrations of betaine.

scholarly journals Hypoxic Environment Promotes Barrier Formation in Human Intestinal Epithelial Cells through Regulation of MicroRNA 320a Expression

2019 ◽  
Vol 39 (14) ◽  
Author(s):  
Stephanie Muenchau ◽  
Rosalie Deutsch ◽  
Ines J. de Castro ◽  
Thomas Hielscher ◽  
Nora Heber ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mirna Expression ◽  
Barrier Function ◽  
Intestinal Epithelial Cells ◽  
Hypoxia Inducible Factor ◽  
Intestinal Epithelial ◽  
Low Oxygen ◽  
Direct Role ◽  
Hypoxic Conditions ◽  
Barrier Formation

ABSTRACT Intestinal epithelial cells (IECs) are exposed to the low-oxygen environment present in the lumen of the gut. These hypoxic conditions on one hand are fundamental for the survival of the commensal microbiota and, on the other hand, favor the formation of a selective semipermeable barrier, allowing IECs to transport essential nutrients/water while keeping the sterile internal compartments separated from the lumen containing commensals. The hypoxia-inducible factor (HIF) complex, which allows cells to respond and adapt to fluctuations in oxygen levels, has been described as a key regulator in maintaining IEC barrier function by regulating their tight junction integrity. In this study, we sought to better evaluate the mechanisms by which low oxygen conditions impact the barrier function of human IECs. By profiling miRNA expression in IECs under hypoxia, we identified microRNA 320a (miRNA-320a) as a novel barrier formation regulator. Using pharmacological inhibitors and short hairpin RNA-mediated silencing, we could demonstrate that expression of this microRNA (miRNA) was HIF dependent. Importantly, using overexpression and knockdown approaches of miRNA-320a, we could confirm its direct role in the regulation of barrier function in human IECs. These results reveal an important link between miRNA expression and barrier integrity, providing a novel insight into mechanisms of hypoxia-driven epithelial homeostasis.

Chemical hypoxia in human pluripotent NT2 stem cell-derived neurons: Effect of hydroxamic acid and benzamide-based epigenetic drugs

2019 ◽  
Vol 2 (3) ◽  
pp. 12-19
Author(s):  
Rushita A Bagchi ◽  
Ashim K Bagchi ◽  
Ankita Salunke ◽  
Dipak K Hens ◽  
Pragna H Parikh
Keyword(s):  
Stem Cell ◽  
Hdac Inhibitor ◽  
Neuronal Damage ◽  
Cell Damage ◽  
Neuronal Cells ◽  
Hypoxia Inducible Factor ◽  
Hdac Inhibitors ◽  
Neuronal Cell ◽  
Low Oxygen ◽  
Chemical Hypoxia

Hypoxia-induced oxidative stress contributes to neuronal damage leading to many neurodegenerative disorders. Hypoxia promotes many downstream effectors such as hypoxia-inducible factor-1α (HIF-1α) in order to restore respiratory homeostasis due to low oxygen availability and increased ROS. Use of histone deacetylase (HDAC) inhibitors may modulate hypoxia-induced neuronal cell damage.  In this study, we used two chemically diverse HDAC inhibitors to investigate their effect on hypoxia-exposed neuronal cells. Human pluripotent NT-2 stem cell-derived neuronal differentiated cells were exposed to CoCl2 pre-treatment for 6h to induce hypoxia, prior to supplementation of HDAC inhibitor (SAHA or MGCD0103). Treatment with HDAC inhibitor improved cell viability in hypoxia-induced neuronal cells. The increased HIF1α expression in hypoxia-induced neuronal cells was blunted by these HDAC inhibitors with a concomitant decrease in ROS production. CoCl2 treatment caused an increase in IL-1β, which was significantly inhibited by these HDAC inhibitors. Furthermore, apoptosis induced in these CoCl2 treated neuronal cells was mitigated by SAHA as well MGCD0103 suggesting that these HDAC inhibitors are capable of reducing cellular toxicity, inflammation and apoptosis, and thus, could be beneficial as therapeutic molecules for many neuropathological conditions.

scholarly journals Harnessing hypoxia as an evolutionary driver of complex multicellularity

2020 ◽  
Vol 10 (4) ◽  
pp. 20190101 ◽  
Author(s):  
Emma U. Hammarlund
Keyword(s):  
Vascular Plants ◽  
Animal Tissue ◽  
Cell Phenotype ◽  
Low Oxygen ◽  
Immature Cell ◽  
Hypoxic Conditions ◽  
Animal Physiology ◽  
Animal Diversity ◽  
Oxygen Conditions ◽  
Multicellular Organisms

Animal tissue requires low-oxygen conditions for its maintenance. The need for low-oxygen conditions contrasts with the idea of an evolutionary leap in animal diversity as a result of expanding oxic conditions. To accommodate tissue renewal at oxic conditions, however, vertebrate animals and vascular plants demonstrate abilities to access hypoxia. Here, I argue that multicellular organisms sustain oxic conditions first after internalizing hypoxic conditions. The ‘harnessing’ of hypoxia has allowed multicellular evolution to leave niches that were stable in terms of oxygen concentrations for those where oxygen fluctuates. Since oxygen fluctuates in most settings on Earth's surface, the ancestral niche would have been a deep marine setting. The hypothesis that ‘large life’ depends on harnessing hypoxia is illustrated in the context of conditions that promote the immature cell phenotype (stemness) in animal physiology and tumour biology and offers one explanation for the general rarity of diverse multicellularity over most of Earth's history.

scholarly journals Cell-Free Hemoglobin Does Not Attenuate the Effects of SARS-CoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells

2021 ◽  
Vol 22 (16) ◽  
pp. 9041
Author(s):  
Sirsendu Jana ◽  
Michael R. Heaven ◽  
Abdu I. Alayash
Keyword(s):  
Endothelial Cells ◽  
Hypoxia Inducible Factor ◽  
Spike Protein ◽  
Receptor Interaction ◽  
Low Oxygen ◽  
Viral Receptor ◽  
Hypoxic Conditions ◽  
Viral Components ◽  
Induced Changes ◽  
The Impact

SARS-CoV-2 primarily infects epithelial airway cells that express the host entry receptor angiotensin-converting enzyme 2 (ACE2), which binds to the S1 spike protein on the surface of the virus. To delineate the impact of S1 spike protein interaction with the ACE2 receptor, we incubated the S1 spike protein with human pulmonary arterial endothelial cells (HPAEC). HPAEC treatment with the S1 spike protein caused disruption of endothelial barrier function, increased levels of numerous inflammatory molecules (VCAM-1, ICAM-1, IL-1β, CCL5, CXCL10), elevated mitochondrial reactive oxygen species (ROS), and a mild rise in glycolytic reserve capacity. Because low oxygen tension (hypoxia) is associated with severe cases of COVID-19, we also evaluated treatment with hemoglobin (HbA) as a potential countermeasure in hypoxic and normal oxygen environments in analyses with the S1 spike protein. We found hypoxia downregulated the expression of the ACE2 receptor and increased the critical oxygen homeostatic signaling protein, hypoxia-inducible factor (HIF-1α); however, treatment of the cells with HbA yielded no apparent change in the levels of ACE2 or HIF-1α. Use of quantitative proteomics revealed that S1 spike protein-treated cells have few differentially regulated proteins in hypoxic conditions, consistent with the finding that ACE2 serves as the host viral receptor and is reduced in hypoxia. However, in normoxic conditions, we found perturbed abundance of proteins in signaling pathways related to lysosomes, extracellular matrix receptor interaction, focal adhesion, and pyrimidine metabolism. We conclude that the spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in HPAEC, and that treatment with HbA failed to reverse the vast majority of these spike protein-induced changes.

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