• Title, Summary, Keyword: hypoxia

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Hypoxia suffocates histone demethylases to change gene expression: a metabolic control of histone methylation

  • Park, Hyunsung
    • BMB Reports
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    • v.50 no.11
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    • pp.537-538
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    • 2017
  • Hypoxia affects various physiological and pathophyological processes. Hypoxia changes the expression of hypoxia-responsive genes through two main pathways. First, hypoxia activates transcription factors (TF) such as Hypoxia-inducible Factor (HIF). Second, hypoxia decreases the activity of Jumonji C domain-containing histone demethylases (JMJDs) that require $O_2$ and ${\alpha}$-Ketoglutarate (${\alpha}$-KG) as substrates. The JMJDs affect gene expression through their regulation of active or repressive histone methylations. Profiling of H3K4me3, H3K9me3, and H3K27me3 under both normoxia and hypoxia identified 75 TFs whose binding motifs were significantly enriched in the methylated regions of the genes. TFs showing similar binding strengths to their target genes might be under the 'metabolic control' which changes histone methylation and gene expression by instant changing catalytic activities of resident histone demethylases.

Changes in Stanniocalcin-2 and Hypoxia-Inducible Factor-1α mRNA Expression in Medaka Oryzias dancena Exposed to Acute Hypoxia (저산소환경에 의한 송사리(Oryzias dancena)의 Stanniocalcin-2와 Hypoxia-Inducible Factor-1α mRNA 발현의 변화)

  • Shin, Ji Hye;Sohn, Young Chang
    • Korean Journal of Fisheries and Aquatic Sciences
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    • v.46 no.1
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    • pp.70-76
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    • 2013
  • Some fish live in aquatic environments with low or temporally changing $O_2$ availability. Variation in dissolved oxygen (DO) levels requires behavioral, physiological, and biochemical adaptations to ensure the uptake of sufficient $O_2$. Several species are relatively well adapted to tolerate low $O_2$ partial pressures (hypoxia). The medaka (Oryzias dancena ) is an important model organism for biomedical research that shows remarkable tolerance to hypoxia. We investigated the regulation and role of hypoxia-inducible factor-1 (HIF-$1{\alpha}$) as a general hypoxia-response gene and stanniocalcin-2 (STC2), which is one of the genes regulated by HIF-$1{\alpha}$ in mammals under hypoxia. We subjected adult male medaka to the following three acute hypoxia regimes: 1, 24, and 72 h at DO = $1.8{\pm}0.5$ ppm. The changes in STC2 and HIF-$1{\alpha}$ mRNA were monitored using quantitative real-time reverse-transcription PCR. We found strong upregulation of HIF-$1{\alpha}$ mRNA in the livers of fish exposed to hypoxia. Hypoxia rapidly upregulated STC-2 mRNA expression in muscle, but not in the brain, gills, liver, or intestine. Therefore, unlike in mammals, hypoxia might regulate O. dancena STC-2 expression in an HIF-$1{\alpha}$-independent manner.

Hypoxia Inducible Factor-$1{\alpha}$ Directly Induces the Expression of Receptor Activator of Nuclear Factor-${\kappa}B$ Ligand in MLO-Y4 Osteocytes

  • Baek, Kyunghwa;Park, Hyun-Jung;Baek, Jeong-Hwa
    • International Journal of Oral Biology
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    • v.40 no.1
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    • pp.19-25
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    • 2015
  • Osteocytes may function as mechanotransducers by regulating local osteoclastogenesis. Reduced availability of oxygen, i.e. hypoxia, could occur during disuse, bone development, and fracture. Receptor activator of nuclear factor-${\kappa}B$ ligand (RANKL) is an osteoblast/stromal cell derived essential factor for osteoclastogenesis. The hypoxia induced osteoclastogenesis via increased RANKL expression in osteoblasts was demonstrated. Hypoxic regulation of gene expression generally involves activation of the hypoxia-inducible factor (HIF) transcription pathway. In the present study, we investigated whether hypoxia regulates RANKL expression in murine osteocytes and HIF-$1{\alpha}$ mediates hypoxia-induced RANKL expression by transactivating RANKL promoter, to elucidate the role of osteocyte in osteoclastogenesis in the context of hypoxic condition. The expression levels of RANKL mRNA and protein, as well as hypoxia inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) protein, were significantly increased in hypoxic condition in MLO-Y4s. Constitutively active HIF-$1{\alpha}$ alone significantly increased the levels of RANKL expression in MLO-Y4s under normoxic conditions, whereas dominant negative HIF-$1{\alpha}$ blocked hypoxia-induced RANKL expression. To further explore to find if HIF-$1{\alpha}$ directly regulates RANKL transcription, a luciferase reporter assay was conducted. Hypoxia significantly increased RANKL promoter activity, whereas mutations of putative HIF-$1{\alpha}$ binding elements in RANKL promoter prevented this hypoxia-induced RANKL promoter activity in MLO-Y4s. These results suggest that HIF-$1{\alpha}$ mediates hypoxia-induced up-regulation of RANKL expression, and that in osteocytes of mechanically unloaded bone, hypoxia enhances osteoclastogenesis, at least in part, via an increased RANKL expression in osteocytes.

Acid Secretion and Nitric Oxide Synthase Activity in Gastric Glands Following Hypoxia/Reoxygenation and Acidosis (Hypoxia/Reoxygenation과 Acidosis가 위선세포에서 위산분비와 NO Synthase 활성에 미치는 영향)

  • Kim Hye-Young;Kim Kyung-Hwan
    • The Korean Journal of Pharmacology
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    • v.31 no.1
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    • pp.75-84
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    • 1995
  • Acid secretion and NO synthase activity were determined in isolated gastric glands following hypoxia/reoxygenation and acidosis to investigate the involvement of NO in acid secretion. Isolated gastric glands were exposed to hypoxia (30 min)/reoxygenation (1 h) and/or to acidosis (pH 6.0 and 4.0). Acid secretion was measured by the ratio of $[^{14}C]-aminopyrine$ accumulation between intra- and extraglands. NO synthase activity was determined by percent conversion to $[^{14}C]-citrulline\;from\;[^{14}C]L-arginine$, a precursor of NO. The results indicate that dibutyryl cAMP stimulated acid secretion dose-dependently but had no effect on NO synthase activity in basal gastric glands. Hypoxia/reoxygenation significantly suppressed acid secretion both in unstimulated and stimulated gastric glands, which was exaggerated by acidosis. Constitutive NO synthase, activity, not responded to dibutyryl cAMP, was also inhibited by hypoxia/reoxygenation and acidosis. In conclusion, pathologic state of gastric mucosa such as hypoxia/reoxygenation and acidosis suppresses both acid secretion and NO release but the role of NO in acid secretion stimulated by dibutyryl cAMP in basal gastric glands is not significant.

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Changes in drug metabolism during hypoxia/reoxygenation in isolated perfused rat

  • Seo, Min-Young;Cho, Tai-Soon;Lee, Sun-Mee
    • Proceedings of the Korean Society of Applied Pharmacology
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    • pp.98-98
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    • 1997
  • This study was done to investigate the effect of vitamin E on hypoxia/reoxygenation-induced hepatic injury in isolated perfused rat liver. Rats were pretreated with vitamin E or vehicle(soybean oil). Isolated livers from fasted 18 hours were subjected to 45min of low flow hypoxia or N$_2$ hypoxia followed by reoxygenation for 30min. The perfusion medium used was KHBB(pH 7.4) and 50${\mu}$㏖/$\ell$ of ethoxycoumarin was added to the perfusate to determine the ability of hepatic drug-metabolizing systems, In low flow hypoxia model, total glutathione and oxidised glutathione levels were significantly increased by hepoxia/reoxygenation with slight increase in LDH levels. These increases were prevented by vitamin E pretreatment. In N$_2$ hypoxia model, LDH, total glutathione and oxidized glutathione levels were increased significantly by hypoxia but restored to normal level by reoxygenation. Vitamin E had little effect on this hypoxic damage. There were no significant changes in the rate of hepatic oxidation of 7-EC to 7-HC in both hepoxic models. But, the subsequent conjugation of 7-HC by sulfate or glucuronic acid were significantly decreased by hypoxia, but restored by reoxygenation in both hypoxia models. As opposed to our expectation, treatment with vitamin E aggrevated the decrease of the rate of conjugation and even inhibited the restoration by reoxygenation. Our findings suggest that hypoxia/reoxygenation diminishes phase II drug metabolizing function and this is, in part, related to decreased energy level.

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Vasorelaxing Effect of Hypoxia via Rho-kinase Inhibition on the Agonist-specific Vasoconstriction

  • Je, Hyun-Dong;Shin, Chang-Yell
    • Biomolecules & Therapeutics
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    • v.16 no.3
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    • pp.249-254
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    • 2008
  • The present study was undertaken to determine whether hypoxia influences on the agonist-induced vascular smooth muscle contraction and, if so, to investigate the related mechanism. The measurement of isometric contractions using a computerized data acquisition system was combined with molecular experiments. Hypoxia significantly inhibited fluoride-induced contraction regardless of endothelial function, but there was no relaxation on thromboxane $A_2$ mimetic U-46619-induced contraction suggesting that other pathway such as $Ca^{2+}$ entry or thin filament regulation was not affected. In addition, hypoxia significantly decreased fluoride-induced increase of phospho-myosin-targeting subunit of myosin light chain phosphatase (pMYPT1). Interestingly, hypoxia didn't inhibit significantly phenylephrine-induced contraction suggesting that myosin light chain kinase (MLCK) activity or thin filament regulation is less important on the hypoxia-induced vasorelaxation in the denuded muscle than Rho-kinase activity. In conclusion, this study provides the evidence and possible related mechanism concerning the vasodilation effect of hypoxia on the agonist-specific contraction in rat aortic rings regardless of endothelial function.

The effects of Hwangryunhaedoktang and herbs on Mouse neuroblastoma 2a cells damaged by hypoxia-reoxygenation (황연해독탕(黃連解毒湯)이 Hypoxia-reoxygenation에 의해 손상 받은 Mouse Neuroblastoma 2a Cells에 미치는 영향(影響))

  • Ahn, Sang-Hoon;Kim, Jong-Woo;Kang, Chul-Hun;Whang, Wei-Wan
    • Journal of Oriental Neuropsychiatry
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    • v.17 no.2
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    • pp.37-59
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    • 2006
  • Objective : This study was designed to asses the effect of Hwangryunhaedoktang and herbs on Mouse neuroblastoma 2a cells damaged by hypoxia-reoxygenation. Method : Mouse neuroblastoma 2a (N2a) cells were measured by MTT assay and LDH assay after 48h hypoxia and 6h reoxygenation. Mouse neuroblastoma 2a (N2a) cells were treated by Hwangryunhaedoktang and herbs. Result : 1. Hwangryunhaedoktang was effective on LDH assay of hypoxia and reoxygenation. 2. All of herbs were generally effective on LDH assay of hypoxia and reoxygenation. In LDH assay of hypoxia, the effects of herbs depended on concentration. In MTT assay of hypoxia, Coptidis Rhizoma and Gardeniae Fructus were effective. In MTT assay of reoxygenation most of herbs were not effective. But Phellodendri Cortex was effective in high concentration. Conclusion : The results imply that Hwangryunhaedoktang and all herbs of it nay have protective effect on dementia and aging.

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Effect of Trolox C on Hypoxia/Reoxygenation-Induced Injury in Isolated Perfused Rat Liver

  • Lee, Sun-Mee;Cho, Tai-Soon
    • Archives of Pharmacal Research
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    • v.20 no.5
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    • pp.471-475
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    • 1997
  • Livers isolated from 18 hours fasted rats were subjected to N$_{2}$ hypoxia (for 45 min) followed by reoxygenation (for 45 min). The perfusion medium used was Krebs-Henseleit bicarbonate buffer (KHBB, pH 7.4). Lactate and alanine were added as gluconeogenic and ureagenic substrates and Trolox C was also added to perfusate. Oxygen consumption, lactate dehydrogenase (LDH), alanine transaminase (ALT), total glutathione, oxidized glutathione, bile flow, glucose and urea were measured. After hypoxia oxygen consumption significantly dropped but Trolox C had no influence on this decrease. ALT and LDH were significantly increased by hypoxia/reoxygenation. This increase was markedly attenuated in the presence of Trolox C. The total glutathione and oxidized glutathione efflux increased following hypoxia, which were prevented by the treatment of Trolox C. Bile flow rate decreased following hypoxia/reoxygenation but did not continue to decrease in the reoxygenation phase by Trolox C. Following hypoxia/reoxygenation glucose and urea releases decreased. Trolox C had no influence on inhibition of glucose and urea production. These results suggest that Trolox C protected the liver cells against hypoxia/reoxygenation injury, yielding further evidence for a causative role of oxidative stress in this model.

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Beneficial Effect of Pentoxifylline on Hypoxia-Induced Cell Injury in Renal Proximal Tubular Cells

  • Jung Soon-Hee
    • Biomedical Science Letters
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    • v.10 no.4
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    • pp.341-346
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    • 2004
  • Tumor necrosis factor-α (TNF-α) or its mRNA expression are increased in acute nephrosis of various types including ischemia/reperfusion injury. This study was undertaken to determine whether pentoxifylline (PTX), an inhibitor of TNF-α production, provides a protective effect against hypoxia-induced cell injury in rabbit renal cortical slices. To induce hypoxia-induced cell injury, renal cortical slices were exposed to 100% N₂ atmosphere. Control slices were exposed to 100% O₂ atmosphere. The cell injury was estimated by measuring lactate dehydrogenase (LDH) release and p-aminohippurate (PAH) uptake. Exposure of slices to hypoxia increased the LDH release in a time-dependent manner. However, when slices were exposed to hypoxia in the presence of PTX, the LDH release was decreased. The protective effect of PTX was dose-dependent over the concentrations of 0.05∼1 mM. Hypoxia did not increase lipid peroxidation, whereas an organic hydroperoxide t-butylhydroperoxide (tBHP) resulted in a significant increase in lipid peroxidation. PTX did not affect tBHP-induced lipid peroxidation. Hypoxia decreased PAH uptake, which was significantly attenuated by PTX and glycine. tBHP-induced inhibition of PAH uptake was not altered by PTX, although it was prevented by antioxidant deferoxarnine. The PAH uptake by slices in rabbits with ischemic acute renal failure was prevented by PTX pretreatment. These results suggest that PTX may exert a protective effect against hypoxia-induced cell injury and its effect may due to inhibition of the TNF-α production, but not by its antioxidant action.

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Protective effect of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride on hypoxia-induced toxicity by suppressing microglial activation in BV-2 cells

  • Kim, Jiae;Kim, Su-Min;Na, Jung-Min;Hahn, Hoh-Gyu;Cho, Sung-Woo;Yang, Seung-Ju
    • BMB Reports
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    • v.49 no.12
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    • pp.687-692
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    • 2016
  • We recently reported the anti-inflammatory effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) on the ATP-induced activation of the NFAT and MAPK pathways through the P2X7 receptor in microglia. To further investigate the underlying mechanism of KHG26792, we studied its protective effects on hypoxia-induced toxicity in microglia. The administration of KHG26792 significantly reduced the hypoxia-induced expression and activity of caspase-3 in BV-2 microglial cells. KHG26792 also reduced hypoxia-induced inducible nitric oxide synthase protein expression, which correlated with reduced nitric oxide accumulation. In addition, KHG26792 attenuated hypoxia-induced protein nitration, reactive oxygen species production, and NADPH oxidase activity. These effects were accompanied by the suppression of hypoxia-induced protein expression of hypoxia-inducible factor 1-alpha and NADPH oxidase-2. Although the clinical relevance of our findings remains to be determined, these data results suggest that KHG26792 prevents hypoxia-induced toxicity by suppressing microglial activation.