The Hydroxylase Inhibitor Dimethyloxalylglycine Is Protective in a Murine Model of Colitis

Cummins, Eoin P.; Seeballuck, Fergal; Keely, Stephen J.; Mangan, Niamh E.; Callanan, John J.; Fallon, Padraic G.; Taylor, Cormac T.

doi:10.1053/j.gastro.2007.10.012

Cited by 373 publications

(447 citation statements)

References 36 publications

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“…This is consistent with the findings of a previous genetic study showing lower levels of ROS production and mitochondrial oxidative damage in muscle cells from PHD-deficient mice (47). In inflammatory bowel disease and chronic kidney failure, DMOG reduced secretion of proinflammatory cytokines, macrophage infiltration, and oxidative stress (48,49). Furthermore, in PHD2-haplodeficient mice, HIF-1 activity normalized blood vessel maturation and oxygen supply (50).…”

Section: Discussionsupporting

confidence: 91%

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Biniecka¹,

Fox²,

Gao³

et al. 2011

Arthritis & Rheumatism

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Objective. To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels.Methods. Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO 2 ) were measured at arthroscopy using a Results. The median tPO 2 level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P ‫؍‬ 0.05) and with higher synovial 4-HNE cytoplasmic expression (P ‫؍‬ 0.04). Synovial expression of CytcO II correlated with in vivo tPO 2 levels (P ‫؍‬ 0.03), and levels were lower in patients with tPO 2 <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC.Conclusion. These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.

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Section: Discussionsupporting

confidence: 91%

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Biniecka¹,

Fox²,

Gao³

et al. 2011

Arthritis & Rheumatism

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“…It is interesting to note that NF-κB activates transcriptional upregulation of HIF-1a mRNA indicating one level at which these two pathways interact to regulate hypoxia-dependent gene transcription Our results show that the PHD inhibition provides an overall beneficial influence on clinical symptoms (weight loss, colon length, tissue tumor necrosis factor-α/interferon-γ) in multiple murine models of colitis. These effects are most likely due to their barrier-protective function and enhancement of wound healing at the site of inflammation [22][23]. Taken together, these findings emphasize the role of epithelial HIF-1α during inflammatory diseases in the colon and may provide the basis for a therapeutic use of PHD inhibitors in inflammatory mucosal disease.…”

Section: Hif Is Protective For Mucosal Inflammationmentioning

confidence: 68%

“…PHD3 mRNA is also expressed in many tissues but is most abundant in the heart and placenta [24,28]. In mouse intestinal mucosal tissue, we have found expression all three isoforms of PHDs with a distribution of PHD1< PHD2=PHD3 [22][23].…”

Section: Hif Is Protective For Mucosal Inflammationmentioning

confidence: 69%

“…Further evidence in support of a protective role for HIF in mucosal disease are provided by studies directed at HIF prolyl hydroxylase (PHD) inhibitors [22,23]. These enzymes were identified on the principle that other mammalian PHDs such as those which target extracellular collagen were 2-oxoglutarate dependent [24], and it was predicted that the HIF PHDs would also belong to this family of enzymes.…”

Section: Hif Is Protective For Mucosal Inflammationmentioning

confidence: 99%

“…This effect is likely mediated through increased expression of antiapoptotic genes in the intestinal epithelium resulting in enhanced epithelial barrier function. Thus, a significant part of the protective effect of hydroxylase inhibition in models of colitis may be through the promotion of intestinal epithelial NF-κB activity [22] (Fig. 3).…”

Section: Hif Is Protective For Mucosal Inflammationmentioning

confidence: 99%

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Hypoxia and gastrointestinal disease

2007

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The gastrointestinal mucosa is a richly perfused vascular bed directly juxtaposed with the anaerobic and nonsterile lumen of the gut. As such, intestinal epithelial cells, which line the mucosa, experience a uniquely steep physiologic oxygen gradient in comparison with other cells of the body. Inflammation associated with a loss of epithelial barrier function and unregulated exposure of the mucosal immune system to luminal antigens leads to inflammatory bowel disease (IBD), a relatively common disorder with severe morbidity and a limited therapeutic repertoire. During IBD, increased tissue metabolism and vasculitis renders the chronically inflamed mucosa and particularly the epithelium hypoxic, giving rise to the activation of the hypoxia-responsive transcription factor hypoxia-inducible factor (HIF). Recent studies utilizing conditional intestinal epithelial hif1a-null mice have revealed a protective role for epithelial HIF-1α in murine models of IBD. Such protection occurs, at least in part, through HIF-dependent induction of barrier-protective genes in the epithelium. More recently, studies employing pharmacologic activation of HIF via inhibition of HIF prolyl hydroxylases revealed a profoundly protective effect of these agents in murine models of colitis. In this paper, we review this pathway in detail and examine the therapeutic potential for targeting HIF hydroxylases in intestinal mucosal inflammatory disease.

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Optimizing fluorescent protein expression for quantitative fluorescence microscopy and spectroscopy using herpes simplex thymidine kinase promoter sequences

et al. 2018

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The modulation of expression levels of fluorescent fusion proteins ( FFP s) is central for recombinant DNA technologies in modern biology as overexpression of proteins contributes to artifacts in biological experiments. In addition, some microscopy techniques such as fluorescence correlation spectroscopy ( FCS ) and single‐molecule‐based techniques are very sensitive to high expression levels of FFP s. To reduce the levels of recombinant protein expression in comparison with the commonly used, very strong CMV promoter, the herpes simplex virus thymidine kinase ( TK ) gene promoter, and mutants thereof were analyzed. Deletion mutants of the TK promoter were constructed and introduced into the Gateway ® system for ectopic expression of enhanced green fluorescent protein ( eGFP ), monomeric cherry ( mC herry), and FFP s containing these FP s. Two promoter constructs, TK 2 ST and TKTSC , were established, which have optimal low expression levels suitable for FCS studies in U2 OS , HeLa CCL 2, NIH 3T3, and BALB /c cells. Interestingly, when tested in these four cell lines, promoter constructs having a deletion within TK gene 5′‐ UTR showed significantly higher protein expression levels than the equivalent constructs lacking this deletion. This suggests that a negative regulatory element is localized within the TK gene 5′‐UTR.

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The Hydroxylase Inhibitor Dimethyloxalylglycine Is Protective in a Murine Model of Colitis

Cited by 373 publications

References 36 publications

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Hypoxia and gastrointestinal disease

Optimizing fluorescent protein expression for quantitative fluorescence microscopy and spectroscopy using herpes simplex thymidine kinase promoter sequences

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