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The Hydroxylase Inhibitor Dimethyloxalylglycine Is Protective in a Murine Model of Colitis
Open accessAbstract
Background & aims Prolyl and asparaginyl hydroxylases are key oxygen-sensing enzymes that confer hypoxic sensitivity to transcriptional regulatory pathways including the hypoxia inducible factor 1 (HIF-1) and nuclear factor-kappaB (NF-kappaB). Knockout of either HIF-1 or (IKKbeta-dependent) NF-kappaB pathways in intestinal epithelial cells promotes inflammatory disease in murine models of colitis. Both HIF-1 and NF-kappaB pathways are repressed by the action of hydroxylases through the hydroxylation of key regulatory molecules.Methods In this study we have investigated the effects of the hydroxylase inhibitor dimethyloxalylglycine (DMOG) on Caco-2 intestinal epithelial cells in vitro and in a dextran sodium sulfate-induced model of murine colitis.Results DMOG induces both HIF-1 and NF-kappaB activity in cultured intestinal epithelial cells, and is profoundly protective in dextran-sodium sulfate colitis in a manner that is at least in part reflected by the development of an anti-apoptotic phenotype in intestinal epithelial cells, which we propose reduces epithelial barrier dysfunction.Conclusions These data show that hydroxylase inhibitors such as DMOG represent a new strategy for the treatment of inflammatory bowel disease.
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“and to limit inflammation in models of inflammatory bowel disease and LPS-induced shock [117–120].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [117]
In the citing paper
“Likewise, NF-κB is thought to be largely protective in the intestinal epithelium via the inhibition of enterocyte apoptosis leading to enhanced intestinal barrier function23.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [23]
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“Indeed, these studies have shown that both DMOG and FG-4497 provide an overall beneficial influence on multiple parameters studied in chemically induced (trinitrobenzene sulfonic acid [TNBS] or dextran sodium sulfate [DSS] mouse models of colitis.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [23]
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“Within the gastrointestinal tract, the PHD inhibitors DMOG and FG-4497 have been used effectively to reduce symptoms in at least two mouse models of colitis23,26.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [23]
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“In these mouse models, the drugs were well tolerated with no significant adverse side effects.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [23]
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“(8 mg) every other day prior to CS exposure (3× weekly) as previously described (74).”
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“Inhibition of such hydroxylases can be achieved by exposure of cells to DMOG, a pan hydroxylase inhibitor (6).”
BackgroundSelf-citationHIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury
Feinman, R., Deitch, E. A., Watkins, A. C., Abungu, B., Colorado, I., Kannan, K. B., Sheth, S. U., Caputo, F. J., Lu, Q., Ramanathan, M., et al. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00065.2010 · Cited by 138
“These models included 2,4,6-trinitrobenzene sulfonic acid -induced colitis (12, 37, 56), chronic hypoxia (24), and Yersinia enterocolitica orogastric infection (28).”
MethodActivation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney
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Hypoxia and Mucosal Inflammation
Colgan, S. P., Campbell, E. L., & Kominsky, D. J. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044231 · Cited by 136
“All three PHDs are found in the mucosa (27, 30, 135).”
BackgroundPHD Inhibition Mitigates and Protects Against Radiation-Induced Gastrointestinal Toxicity via HIF2
Taniguchi, C. M., Miao, Y. R., Diep, A. N., Wu, C., Rankin, E. B., Atwood, T. F., Xing, L., & Giaccia, A. J. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008523 · Cited by 131
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“The role of HIF-1α and its activated pathways was revealed to be a protective one, with suggested mechanisms that include improved barrier protection and prevention of epithelial cell apoptosis [21, 67].”
BackgroundFundamental role for HIF-1α in constitutive expression of human β defensin-1
Kelly, C. J., Glover, L. E., Campbell, E. L., Kominsky, D., Ehrentraut, S., Bowers, B., Bayless, A. J., Saeedi, B. J., & Colgan, S. P. (2013) · Mucosal Immunology · doi:10.1038/mi.2013.6 · Cited by 133
Mechanisms and Consequences of Oxygen and Carbon Dioxide Sensing in Mammals
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“This is at least in part due to PHD1 inhibition in intestinal epithelial cells leading to decreased rates of apoptosis and subsequent enhancement of intestinal barrier function (44, 176, 196).”
BackgroundSelf-citationAherne, C. M., Collins, C. B., Masterson, J. C., Tizzano, M., Boyle, T. A., Westrich, J. A., Parnes, J. A., Furuta, G. T., Rivera–Nieves, J., & Eltzschig, H. K. (2011) · Gut · doi:10.1136/gutjnl-2011-300012 · Cited by 129
Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD
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Hypoxia and sterile inflammation in cystic fibrosis airways: mechanisms and potential therapies
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“Interestingly, genetic studies on the role of HIF uncovered that stabilization of HIF provides a protective and anti-inflammatory pathway during intestinal inflammation [10, 11, 25, 95–97].”
BackgroundProlyl 4‐hydroxylases, master regulators of the hypoxia response
Myllyharju, J. (2013) · Acta Physiologica · doi:10.1111/apha.12096 · Cited by 122
“…sulphonic acid-induced colonic inflammation in mice, resulting in anti-apoptosis of intestinal epithelial cells and concomitant improvements in the protective barrier function of the intestinal epithelium and wound healing at the site of inflammation (Cummins et al. 2008, Robinson et al. 2008).”
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“Besides HIF activation, DMOG has been reported to activate NF-jB presumably by regulating IKKb in experimental colitis models and ameliorating the colonic inflammation [27].”
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“Verapamil and felodipine are both calcium channel blockers, whereas dimethyloxalylglycine is a hydroxylase inhibitor thought to increase resistance to oxidative stress (24, 25).”
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“In addition, the use of prolyl hydroxylase inhibitors, which stabilize the HIF complex, provided beneficial effects in two different murine colitis models.(10,33) Various studies have shown that not only the epithelium but also the whole intestinal tissue is exposed to hypoxia during inflammation,(5,8) and it becomes…”
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“Several studies demonstrate that pharmacological compounds that stabilize HIFs provided potent protection during intestinal inflammation (23, 44, 52, 116).”
BackgroundAttenuating myocardial ischemia by targeting A2B adenosine receptors
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“Many studies based on cells or animals have revealed that oxoglutarate analogues can produce beneficial biological results by stabilising HIFs [28–31].”
BackgroundHypoxia Inducible Factor (HIF) Hydroxylases as Regulators of Intestinal Epithelial Barrier Function
Manresa, M. C., & Taylor, C. T. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.02.004 · Cited by 107
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Self-citationHypoxia Inducible Factor-1α: The Curator of Gut Homeostasis
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“Additionally, Dimethyloxalylglycine (DMOG), an inhibitor of PHDs and Factor Inhibiting HIF (FIH) have been shown to ameliorate dextran-sodium sulfate (DSS)-induced colitis by stabilizing HIF-1α (Cummins et al., 2008).”
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“Pharmacologic targeting of adenosine pathways such as Adora2b may also synergize with modalities that activate the hypoxic response and have been shown to be tissue-protective in models of colitis [56,57].”
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“These results suggested that in vivo DMOG administration can increase O2 availability in inflamed colon tissue, and improved tissue oxygenation may contribute to the therapeutic effects of DMOG shown previously in mice with DSS-induced colitis [20,63].”
BackgroundInfluentialHypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease
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Activation of hypoxia-inducible factor 1 attenuates periapical inflammation and bone loss
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Selective induction of integrin βi by hypoxia‐inducible factor: implications for wound healing
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“Nonetheless, considering that it is (1) activated early in response to hypoxia at concentrations of oxygen consistent with those seen in ALI, (2) controls a network of inflammatory cytokines, and (3) maintains significant crosstalk with the HIF pathway, NF-kB may play an important role in the initiation and propagatio…”
BackgroundHypoxia/HIF Modulates Immune Responses
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Metadata
- Authors
- Cummins, E. P., Seeballuck, F., Keely, S. J., Mangan, N. E., Callanan, J. J., Fallon, P. G., & Taylor, C. T.
- Affiliations
- University College Dublin (IE)
- Royal College of Surgeons in Ireland (IE)
- Trinity College Dublin (IE)
- Corresponding author
- Taylor, Cormac T.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 134
- Issue
- 1
- Pages
- 156-165.e1
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2005539293
- Cited by
- 407
- References
- 39
- Citations by year
- 2026: 13 · 2025: 10 · 2024: 18 · 2023: 18 · 2022: 21 · 2021: 24 · 2020: 24 · 2019: 18 · 2018: 28 · 2017: 25 · 2016: 31 · 2015: 23 · 2014: 22 · 2013: 28 · 2012: 27
- FWCI
- 9.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Health Research Board
- Science Foundation Ireland
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Health Sciences › Medicine › Gastroenterology › Microscopic Colitis
- Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
- Keywords
- dimethyloxalylglycine, colitis, inflammatory bowel disease, HIF-1, NF-κB, prolyl hydroxylase, asparaginyl hydroxylase, intestinal epithelial cells, Caco-2 cells, DSS-induced colitis, apoptosis, epithelial barrier dysfunction, hypoxia
- MeSH terms
- Amino Acids, Dicarboxylic, Animals, Colitis, Disease Models, Animal, Enzyme Inhibitors, Female, Humans, Mixed Function Oxygenases, Mice, Inbred C57BL, NF-kappa B, Cell Culture Techniques, Caco-2 Cells, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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