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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]
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“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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HIF-prolyl hydroxylase is a potential molecular target for esculetin-mediated anti-colitic effects
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Contributions of neutrophils to resolution of mucosal inflammation
Colgan, S. P., Ehrentraut, S., Glover, L. E., Kominsky, D. J., & Campbell, E. L. (2012) · Immunologic Research · doi:10.1007/s12026-012-8350-2 · Cited by 20
Liu, Z., Shang, L., & Ge, S. (2020) · Journal of Dental Sciences · doi:10.1016/j.jds.2020.10.008 · Cited by 20
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“What is more, inhibition of PHD probably have a protective influence on epithelial barrier [69-71].”
BackgroundMethodMatellan, C., Kennedy, C., Santiago‐Vela, M. I., Hochegger, J., Chathail, M. B. N., Wu, A., Shannon, C. E., Roche, H. M., Aceves, S. S., Godson, C., et al. (2024) · The Journal of Immunology · doi:10.4049/jimmunol.2300762 · Cited by 19
The hypoxic tissue microenvironment as a driver of mucosal inflammatory resolution
Cartwright, I. M., & Colgan, S. P. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1124774 · Cited by 18
“In both situations, increased stabilization of HIF-1a results in increased barrier function in the context of colitis (26, 40, 41).”
BackgroundLombardi, F., Augello, F. R., Palumbo, P., Bonfili, L., Artone, S., Altamura, S., Sheldon, J. M., Latella, G., Cifone, M. G., Eleuteri, A. M., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098134 · Cited by 24
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“Dimethyloxalylglycine (DMOG) is a stabilizer of HIF-1a, which leads to the stabilization of HIF-1a and angiogenesis through inhibiting HIF prolylhydroxylase [33, 34].”
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The non-canonical functions of HIF prolyl hydroxylases and their dual roles in cancer
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Fagundes, R. R., Bravo‐Ruiseco, G., Hu, S., Kierans, S. J., Weersma, R. K., Taylor, C. T., Dijkstra, G. D. H., Harmsen, H. J. M., & Faber, K. N. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1298304 · Cited by 19
Self-citationRespiratory gases and the regulation of transcription
Cummins, E. P., & Keogh, C. E. (2016) · Experimental Physiology · doi:10.1113/ep085715 · Cited by 17
“Notwithstanding this, modest activation of NF-κB by hypoxia in the unstimulated state appears to be responsible, in part, for the profound anti-inflammatory effects of PHD inhibitors in cell and animal models of cytokine-induced inflammation (Cummins et al. 2008; Scholz et al. 2013).”
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Targeting hypoxia in inflammatory bowel disease
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Role of oxygen sensing and hypoxia-inducible factors in orchestrating innate immune responses
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“Although acute hypoxia promotes inflammation responses in myeloid cells, pharmacological stabilization of HIFs via hydroxylase inhibition can paradoxically elicit anti-inflammatory effects that are essential for tissue-protective adaptive responses 41–43 .”
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“ied in intestinal inflammation and tumorigenesis, albeit with conflicting results demonstrating both pro- and anti-inflammatory effects (18, 20, 23), the impact of HIF-1 on”
BackgroundHepatic PHD2/HIF‐1α axis is involved in postexercise systemic energy homeostasis
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“Under normal conditions, prolyl hydroxylases (PHDs) hydroxylate 2 specific proline residues that residewithin the oxygen-dependent domain (ODD) of HIFa in minutes.”
BackgroundMethodInfluentialHIF1α deficiency reduces colon inflammation in a mouse model of proximal colon cancer
Mladenova, D. N., Dahlstrom, J. E., Tran, P. N., Benthani, F. A., Bean, E. G., Ng, I., Pangon, L., Currey, N., & Kohonen‐Corish, M. R. J. (2015) · Disease Models & Mechanisms · doi:10.1242/dmm.019000 · Cited by 16
“Inflammation was assessed using a scoring system modified from the literature (Cummins et al., 2008; Vowinkel et al., 2004).”
Pharmacological regulation of HIF-1α, RGC death, and glaucoma
Husain, S., & Leveckis, R. (2024) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2024.102467 · Cited by 15
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Eosinophils, Hypoxia-Inducible Factors, and Barrier Dysfunction in Functional Dyspepsia
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“demonstrated to be protective during chemical models of colitis (Cummins et al., 2008; Robinson et al., 2008), and, as these are highly dependent on the presence and constitution of the gut microbiota (Gkouskou et al.”
BackgroundHypoxia inducible factor prolyl hydroxylases in inflammatory bowel disease
Lun, J., Zhang, H., Guo, J., Yu, M., & Fang, J. S. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1045997 · Cited by 15
“In 2008, two studies demonstrated the protective effects of the PHD inhibitors dimethyloxalyl glycine (DMOG) (Cummins et al., 2008) and FG4497 (Robinson et al., 2008) in experimental colitis of mice.”
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“The 200-mg/kg dose of DMOG used in this experiment is significantly lower than what has previously been shown to be effective (10, 38).”
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“Consistent with these findings, chemical or biological activators of the transcription factors have beneficial effects on experimental colitis.(8,10) Piceatannol (PCT) is a trans-3,4,3′,5′-tetrahydroxystilbene first isolated from the seeds of Euphorbia lagascae.”
BackgroundChen, G., Wang, X., Jin, Z., Hu, G., Yu, Q., & Jiang, H. (2024) · Brain and Behavior · doi:10.1002/brb3.70039 · Cited by 13
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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