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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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“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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In the citing paper
“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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“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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“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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“DMOG itself, in models of ischemic heart and muscle disease and inflammatory bowel disease, is reported to attenuate proinflammatory mediators and create a pro-angiogenic microenvironment (Cummins et al, 2008; Milkiewicz et al, 2004; Ockaili et al, 2005).”
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Role of Intestinal HIF-2α in Health and Disease
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“Currently, HIF-1α is a bona fide therapeutic target for IBD, and several PHD inhibitors are protective in mouse models of colitis (114, 115).”
InfluentialQuaegebeur, A., Segura, I., Schmieder, R., Verdegem, D., Decimo, I., Bifari, F., Dresselaers, T., Eelen, G., Ghosh, D., Davidson, S. M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.007 · Cited by 96
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“In a recent study we demonstrated that DMOG is profoundly protective in a murine model of dextran sulphate sodium colitis [66].”
InfluentialSelf-citationTargeting Hypoxia Signaling for Perioperative Organ Injury
Yuan, X., Lee, J. W., Bowser, J. L., Neudecker, V., Sridhar, S., & Eltzschig, H. K. (2017) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000002288 · Cited by 95
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“Indeed, stabilization of HIF-1a with dimethyloxallyl glycine (DMOG) (Cummins et al., 2008) decreased sensitivity of the RCC4-VHL cells to the drug combination (Figures S7B and S7C).”
BackgroundInfluentialZheng, W. S., Kuhlicke, J., Jäckel, K., Eltzschig, H. K., Singh, A. K., Sjöblom, M., Riederer, B., Weinhold, C., Seidler, U. E., Colgan, S. P., et al. (2008) · The FASEB Journal · doi:10.1096/fj.08-110221 · Cited by 91
“Such treatment had induced activation of HIF-1 in a previous study (22).”
MethodOxygen-Independent Stabilization of Hypoxia Inducible Factor (HIF)-1 during RSV Infection
Haeberle, H. A., Dürrstein, C., Rosenberger, P., Hosakote, Y. M., Kuhlicke, J., Kempf, V. A. J., Garofalo, R. P., & Eltzschig, H. K. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003352 · Cited by 89
“Other studies confirmed several parallels between the transcriptional regulation of hypoxia and inflammation/infection [21-27].”
ResultChassin, C., Hempel, C., Stockinger, S., Dupont, A., Kübler, J. F., Wedemeyer, J., Vandewalle, A., & Hornef, M. W. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201201298 · Cited by 87
“…on an ecto-5 0 nucleotidase (CD73)- and A2B adenosine receptor (A2BAR)-mediated protective effect of systemic DMOG administration on Hif-1 a -mediated I/R injury (Hart et al, 2011) and other models of intestinal mucosal inflammation (Cummins et al, 2008; Hindryckx et al, 2010; Robinson et al, 2008).”
The role of hypoxia in intestinal inflammation
Shah, Y. M. (2016) · Molecular and Cellular Pediatrics · doi:10.1186/s40348-016-0030-1 · Cited by 85
“and HIF-2α, are protective in acute colitis models through a HIF-1α-dependent mechanism [12, 14, 15].”
BackgroundTan, S. C., Carr, C. A., Yeoh, K. K., Schofield, C. J., Davies, K. E., & Clarke, K. J. (2011) · Molecular Biology Reports · doi:10.1007/s11033-011-1281-5 · Cited by 85
“The PHDIs used in this study included dimethyloxaloylglycine (DMOG) – a cell permeable, competitive inhibitor of 2-oxoglutarate [11], ethyl 2-(2,3-dihydroxybenzamido) acetate (EDBA) – an aspirin metabolite that activates the HIF system via generic 2-oxoglutarate oxygenase inhibition [14], and 2-(1-chloro4-hydroxyisoqu…”
MethodLoss of the Oxygen Sensor PHD3 Enhances the Innate Immune Response to Abdominal Sepsis
Kiss, J., Mollenhauer, M., Walmsley, S. R., Kirchberg, J., Radhakrishnan, P., Niemietz, T., Dudda, J., Steinert, G., Whyte, M. K. B., Carmeliet, P., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103471 · Cited by 81
“On the one hand, it should be considered that interference with PHD3 function might lead to unfavorable effects in critically ill patients, a notion that might become of clinical relevance in the prospect of applying pharmaceutical PHD inhibitors to treat anemia (54) or hypoxic organ damage (55, 56).”
BackgroundKim, Y.-E., Lee, M., Gu, H., Kim, J., Jeong, S., Yeo, S., Lee, Y. J., Im, S., Sung, Y., Kim, H. J., et al. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.033241 · Cited by 82
“…of dimethyloxalylglycine (DMOG), a proline hydroxylase inhibitor, to stabilize HIF exerts a significant protective effect against DSS-induced colitis by preventing tumor necrosis factor-α (TNF-α; also known as TNF)-induced epithelial apoptosis (Cummins et al., 2008; Hindryckx et al., 2010).”
BackgroundHypoxia and inflammatory bowel disease
Cummins, E. P., & Crean, D. (2016) · Microbes and Infection · doi:10.1016/j.micinf.2016.09.004 · Cited by 88
Self-citationCane, G., Ginouvès, A., Marchetti, S., Buscà, R., Pouysségur, J., Berra, E., Hofman, P. M., & Vouret‐Craviari, V. (2009) · Cellular Microbiology · doi:10.1111/j.1462-5822.2009.01422.x · Cited by 84
“…conditional intestinal epithelial hif1a-null mice, vhl-null mice or inhibitors of prolyl hydroxylases have been performed in order to clarify the function of HIF in a mice model of experimental-induced colitis (Karhausen et al., 2004; Cummins et al., 2008; Robinson et al., 2008; Shah et al., 2008).”
BackgroundLonghi, M. S., Robson, S. C., Bernstein, S. H., Serra, S., & Deaglio, S. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-012-0991-z · Cited by 79
“examined the effect of dimethyl oxalyl glycine (DMOG), a hydroxylase inhibitor, on Caco-2 intestinal cells and reported that DMOG was able to induce HIF-1 and protect mice from dextran sodium solfate (DSS)-induced colitis [17].”
BackgroundBarrett, T. D., Palomino, H. L., Brondstetter, T. I., Kanelakis, K. C., Wu, X., Haug, P. V., Yan, W., Young, A., Hua, H., Hart, J. C., et al. (2011) · Molecular Pharmacology · doi:10.1124/mol.110.070508 · Cited by 78
“In addition, stimulating the hypoxic response has been shown recently to promote an antiapoptotic phenotype in intestinal epithelial cells and improve disease indices in mouse models of ulcerative colitis (Cummins et al., 2008; Robinson et al., 2008).”
BackgroundZhang, H., Zhou, Y., Qu, M., Yu, Y., Chen, Z., Zhu, S., Guo, K., Chen, W., & Miao, C. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.677902 · Cited by 80
Macrophage polarization: an effective approach to targeted therapy of inflammatory bowel disease
Du, Y., Rong, L., Cong, Y., Shen, L., Zhang, N., & Wang, B. (2021) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2021.1901079 · Cited by 81
Therapeutic Manipulation of the HIF Hydroxylases
Nagel, S., Talbot, N. P., Mecinović, J., Smith, T. G., Buchan, A. M., & Schofield, C. J. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2711 · Cited by 77
“Both DMOG and the specific PHD inhibitor FG-4497 are reportedly protective in mouse models of inflammatory bowel disease (42, 160).”
Zhang, Q., Oh, J.-H., Park, C. H., Baek, J., Ryoo, H., & Woo, K. M. (2017) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.6b15815 · Cited by 77
The role of mucosal barriers in human gut health
Seo, K., Seo, J.-M., Yeun, J., Choi, H., Kim, Y., & Chang, S.-Y. (2021) · Archives of Pharmacal Research · doi:10.1007/s12272-021-01327-5 · Cited by 76
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“protective effects in the gut (6), the terminal ileal epithelial barrier function of TNF mice was compared with that of healthy controls after 4 d of treatment with either DMOG or vehicle alone.”
BackgroundInfluentialInterplay of Hypoxia and A2B Adenosine Receptors in Tissue Protection
Koeppen, M., Eckle, T. D. L. G., & Eltzschig, H. K. (2011) · Advances in pharmacology · doi:10.1016/b978-0-12-385526-8.00006-0 · Cited by 73
Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury
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“Additionally, the pharmacological activation of HIF-1 by prolyl hydroxylase inhibitors conferred mucosal protection in several murine models of colitis (8, 43).”
BackgroundTambuwala, M. M., Manresa, M. C., Cummins, E. P., Aversa, V., Coulter, I. S., & Taylor, C. T. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.09.022 · Cited by 69
Self-citationZhang, H.-S., Chen, Y., Fan, L., Xi, Q., Wu, G., Li, X.-X., Yuan, T.-L., He, S.-Q., Yu, Y., Shao, M., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.633560 · Cited by 74
“Body weight was recorded daily, and rectal bleeding was assessed (0 –1, normal; 2–3, blood visible; 4, gross bleeding) as described (28).”
MethodHypoxia-inducible factor 1 in autoimmune diseases
Deng, W., Feng, X., Li, X., Wang, D., & Sun, L. (2016) · Cellular Immunology · doi:10.1016/j.cellimm.2016.04.001 · Cited by 70
Xie, L., Xue, X., Taylor, M. J., Ramakrishnan, S. K., Nagaoka, K., Hao, C., Gonzalez, F. J., & Shah, Y. M. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00324-14 · Cited by 71
HIF-1 in T cells ameliorated dextran sodium sulfate-induced murine colitis
Higashiyama, M., Hokari, R., Hozumi, H., Kurihara, C., Ueda, T., Watanabe, C., Tomita, K., Nakamura, M., Komoto, S., Okada, Y., et al. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.1011518 · Cited by 68
“Previous studies have already shown that some PHD inhibitors work to support mucosal barrier dysfunction by activation of HIF-1 in the epithelium on the inflamed intestine [13, 14].”
BackgroundResultRider, P., Kaplanov, I., Romžová, M., Bernardis, L., Braiman, A., Voronov, E., & Apte, R. N. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00290 · Cited by 68
“Several other models of inflammation showed attenuating effects of HIFα (Kojima et al., 2007; Cummins et al., 2008; Kobayashi et al., 2012).”
BackgroundTakeda, K., Ichiki, T., Narabayashi, E., Inanaga, K., Miyazaki, R., Hashimoto, T., Matsuura, H., Ikeda, J., Miyata, T., & Sunagawa, K. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.196071 · Cited by 70
Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage
Ternet, C., & Kiel, C. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-021-00712-3 · Cited by 73
“Cummins and colleagues also reported the protective role of HIF-1 in in vivo mice model of colonic inflammation by showing that the protection from colitis is associated with reduced apoptosis of colon epithelial cells when HIF-1 is activated [55].”
BackgroundHypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia
Selfridge, A. C., Cavadas, M. A. S., Scholz, C. C., Campbell, E. L., Welch, L. C., Lecuona, E., Colgan, S. P., Barrett, K. E., Sporn, P. H. S., Sznajder, J. I., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.713941 · Cited by 68
“In each case, mice were administered an 8-mg intraperitoneal injection of the pharmacologic hypoxia mimetic dimethyloxalylglycine (DMOG) or the equivalent saline vehicle control (25).”
MethodSelf-citationNeuroprotective effect of peroxiredoxin 6 against hypoxia-induced retinal ganglion cell damage
Tulsawani, R., Kelly, L. S., Fatma, N., Chhunchha, B., Kubo, E., Kumar, A., & Singh, D. P. (2010) · BMC Neuroscience · doi:10.1186/1471-2202-11-125 · Cited by 66
“Hypoxia induced activation of NF- B occurs through IkB activation and its phosphorylation [83,84].”
BackgroundKim, S. Y., & Yang, E. (2015) · Molecules · doi:10.3390/molecules201119717 · Cited by 67
“In addition to these findings, PHD inhibitors such as DMOG and FG-4497 were shown to significantly improve intestinal inflammation [94,95].”
BackgroundChen, Y., Zhang, H.-S., Fong, G., Xi, Q., Wu, G., Bai, C., Ling, Z., Li, F., Xu, Y., Qin, Y.-Q., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.653584 · Cited by 64
“PHDs inhibitors have been shown to ameliorate experimental colitis in murine models (20, 21).”
BackgroundKhan, M. N., Lane, M. E., McCarron, P. A., & Tambuwala, M. M. (2017) · Inflammopharmacology · doi:10.1007/s10787-017-0364-x · Cited by 68
“Although we hypothesise that the protective effects of CAPE are mediated through the inhibition of the over activation of the NF-jb pathway, we cannot exclude the possibility of NF-jb independent mechanisms of action, such as inhibition of hydroxylases and activation of hypoxia inducible pathways (Cummins et al. 2008).”
InfluentialWoo, K. M., Jung, H., Oh, J.-H., Rahman, S. U., Kim, S. M., Baek, J., & Ryoo, H. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.10.054 · Cited by 62
Schley, G., Klanke, B., Kalucka, J. M., Schatz, V., Daniel, C., Mayer, M., Goppelt‐Struebe, M., i, M. H., Þorsteinsdóttir, M., Pálsson, R., et al. (2019) · Kidney International · doi:10.1016/j.kint.2019.02.016 · Cited by 65
Hypoxia-sensitive pathways in inflammation-driven fibrosis
Manresa, M. C., Godson, C., & Taylor, C. T. (2014) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00349.2014 · Cited by 64
Self-citationHypoxia signaling during intestinal ischemia and inflammation
Grenz, A., Clambey, E. T., & Eltzschig, H. K. (2012) · Current Opinion in Critical Care · doi:10.1097/mcc.0b013e3283514bd0 · Cited by 60
New Insights into Protein Hydroxylation and Its Important Role in Human Diseases
Zurlo, G., Guo, J., Takada, M., Wei, W., & Zhang, Q. H. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.09.004 · Cited by 62
“PHD1 and FIH have been shown to enhance inflammation [63, 64], and PHD inhibitors such as dimethyloxalylglycine (DMOG) and FG-4497 significantly improve murine models of colitis [65, 66], suggesting that a hydroxylase inhibitor can be beneficial for blunting excessive inflammation.”
BackgroundMuenchau, S., Deutsch, R., de Castro, I. J., Hielscher, T., Heber, N., Niesler, B., Lušić, M., Stanifer, M. L., & Boulant, S. (2019) · Molecular and Cellular Biology · doi:10.1128/mcb.00553-18 · Cited by 66
“Several studies (22, 28, 35) have shown that low oxygen concentrations can influence the barrier function of epithelial cells in vitro by changing gene expression profiles and inducing secretion of barrier-regulating proteins, i.”
BackgroundHypoxia-Inducible Factor Activation Protects the Kidney from Gentamicin-Induced Acute Injury
Ahn, J.-M., You, S. J., Lee, Y. M., Oh, S. W., Ahn, S. Y., Kim, S., Chin, H. J., Chae, D., & Na, K. Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048952 · Cited by 62
“In contrast, genetic or pharmacologic activation of HIF was protective in murine experimental colitis [37,38,39].”
BackgroundBäcker, V., Cheung, F.-Y., Siveke, J. T., Fandrey, J., & Winning, S. (2017) · PLoS ONE · doi:10.1371/journal.pone.0190074 · Cited by 58
The Hypoxia–Adenosine Link during Intestinal Inflammation
Bowser, J. L., Phan, L. H., & Eltzschig, H. K. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701414 · Cited by 62
Hypoxia signaling during acute lung injury
Vohwinkel, C. U., Hoegl, S., & Eltzschig, H. K. (2015) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00226.2015 · Cited by 58
“Other studies indicate an anti-inflammatory role of the PHD-HIF pathway during intestinal inflammation and provide evidence that HIF activators can be used in the treatment of inflammatory bowel disease or ischemia and reperfusion injury of different organs (12, 16, 28, 29, 66).”
BackgroundMimouna, S., Gonçalvès, D., Barnich, N., Darfeuille–Michaud, A., Hofman, P. M., & Vouret‐Craviari, V. (2011) · Gut Microbes · doi:10.4161/gmic.18771 · Cited by 58
“In epithelial cells, modulation of HIF by either chemical agents or gene silencing suggested a protective role for HIF proteins in murine experimental colitis.(19) However, results obtained from mice in which hif-1a or vhl (the von Hippel-Lindau protein Figure 5.”
BackgroundO’Shea, C. J., O’Doherty, J. V., Callanan, J. J., Doyle, D., Thornton, K. H., & Sweeney, T. (2016) · Journal of Nutritional Science · doi:10.1017/jns.2016.4 · Cited by 58
Self-citationThe hypoxia-inducible factor (HIF) couples immunity with metabolism
Halligan, D. N., Murphy, S. J. E., & Taylor, C. T. (2016) · Seminars in Immunology · doi:10.1016/j.smim.2016.09.004 · Cited by 59
Self-citationA possible role for hypoxia-induced apelin expression in enteric cell proliferation
Han, S., Wang, G., Xiang, Q., Lee, H. M., Englander, E. W., & Greeley, G. H. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00083.2008 · Cited by 57
Flannigan, K. L., Agbor, T. A., Motta, J., Ferraz, J. G., Wang, R., Buret, A. G., & Wallace, J. L. (2014) · The FASEB Journal · doi:10.1096/fj.14-266015 · Cited by 57
“At 4 hours after the final DMOG injection, the rats were killed, blindly examined for colonic damage, and samples of colon were then collected for measurement ofMPO activity and H2S synthesis.”
BackgroundMethodInfluentialOral Delivery of Prolyl Hydroxylase Inhibitor
Marks, E., Goggins, B. J., Cardona, J., Cole, S., Minahan, K., Mateer, S. W., Walker, M. M., Shalwitz, R. A., & Keely, S. (2015) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000000277 · Cited by 57
Self-citationKominsky, D. J., Keely, S., MacManus, C. F., Glover, L. E., Scully, M. M., Collins, C. B., Bowers, B., Campbell, E. L., & Colgan, S. P. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002805 · Cited by 57
“However, the results do corroborate our findings and those of others indicating that NF-kB is protective within the intestinal epithelium (40, 41, 48) and suggest that the endogenously protective effect of methylation may be due, at least in part, to epithelial NF-kB activation.”
ResultSelf-citationNix-Mediated Mitophagy Modulates Mitochondrial Damage During Intestinal Inflammation
Vincent, G., Novak, E. A., Siow, V. S., Cunningham, K. E., Griffith, B. D., Comerford, T. E., Mentrup, H. L., Stolz, D. B., Loughran, P., Ranganathan, S., et al. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7702 · Cited by 60
“Likewise, PHD inhibition via the hydroxylase inhibitor dimethyloxalylglycine, or genetic deletion of PHD1 protected mice from DSS colitis (12, 57).”
BackgroundMethodTojo, K., Tamada, N., Nagamine, Y., Yazawa, T., Ota, S., & Goto, T. (2017) · The FASEB Journal · doi:10.1096/fj.201700888r · Cited by 57
“PHD inhibition is potentially applicable for anemia (45, 46), ischemia-reperfusion (47–49), colitis (50, 51), sepsis (43, 52), lactic acidosis (53), and lung injury (13, 15), and several PHD inhibitors have been developed (30, 54).”
BackgroundDowdell, A. S., & Colgan, S. P. (2021) · Pharmaceuticals · doi:10.3390/ph14080708 · Cited by 55
Fang, X., Liu, H., Du, Y., Jiang, L., Gao, F., Wang, Z., Chi, Z., Shi, B., & Zhao, X. (2024) · Research · doi:10.34133/research.0415 · Cited by 56
“To validate this hypothesis, we established a DSS-induced colitis model in conventional or micro-biota-depleted mice [49].”
MethodTargeting the A2B adenosine receptor during gastrointestinal ischemia and inflammation
Eltzschig, H. K., Rivera–Nieves, J., & Colgan, S. P. (2009) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728220903241666 · Cited by 57
“Targets (2009) 13(11) 1273 and tissue protective role of HIF-1α signaling during acute inflammation [6,8,12,13,52,54,65,91,93] or bacterial infections [91,94].”
BackgroundHypoxia and hypoxia-inducible factors in myeloid cell-driven host defense and tissue homeostasis
Jantsch, J., & Schödel, J. (2015) · Immunobiology · doi:10.1016/j.imbio.2014.09.009 · Cited by 46
Kim, Y., Yi, E.-J., Kim, Y., Lee, A. R., Chung, J., Ha, H. C., Cho, J. M., Kim, S.-R., Ko, H., Cheon, J. H., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.609689 · Cited by 57
“The pan-hydroxylase inhibitors such as dimethyloxalylglycine (DMOG) and FG-4497 have protective effects in experimental murine colitis (20, 21).”
BackgroundRoxadustat: Not just for anemia
Zhu, X., Jiang, L., Wei, X. S., Long, M., & Du, Y. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.971795 · Cited by 64
“Another study of a mouse model of dextran sulfate sodium (DSS)-induced colitis showed that activation of HIF-1 had a protective effect, and suggested that PHIs have potential as a novel treatment for inflammatory bowel disease (Cummins et al., 2008).”
BackgroundHlaing, S. P., Cao, J., Lee, J., Kim, J., Saparbayeva, A., Kwak, D., Kim, H., Hwang, S., Yun, H., Moon, H. R., et al. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14102118 · Cited by 54
“Colitis severity was also evaluated by histological examinations [45].”
BackgroundWang, P., Li, T., Niu, C., Sun, S., & Liu, D. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.109763 · Cited by 57
The hypoxia–inflammation link and potential drug targets
Koeppen, M., Eckle, T. D. L. G., & Eltzschig, H. K. (2011) · Current Opinion in Anaesthesiology · doi:10.1097/aco.0b013e32834873fd · Cited by 54
C-Type Lectin SIGN-R1 Has a Role in Experimental Colitis and Responsiveness to Lipopolysaccharide
Saunders, S. P., Barlow, J. L., Walsh, C. M., Bellsoi, A., Smith, P., McKenzie, A. N. J., & Fallon, P. G. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901970 · Cited by 53
“Colitis was induced byDSS treatment ofmice (18, 19).”
MethodSelf-citationThe Inflammatory Tissue Microenvironment in IBD
Colgan, S. P., Curtis, V. F., & Campbell, E. L. (2013) · Inflammatory Bowel Diseases · doi:10.1097/mib.0b013e31828dcaaf · Cited by 52
“It is now appreciated that NF-kB–dependent pathways are also regulated by the enzymes that promote the degradation of HIF-a subunits (namely HIF prolyl hydroxylases [PHDs]) and that the usefulness of PHD inhibitors in murine colitis models also target the NF-kB pathway.(26) Indeed, hypoxia has been shown to activate N…”
BackgroundMetabolic regulation of intestinal epithelial barrier during inflammation
Colgan, S. P., Curtis, V. F., Lanis, J. M., & Glover, L. E. (2014) · Tissue Barriers · doi:10.4161/21688362.2014.970936 · Cited by 51
“These results show that the PHD inhibition provides an overall beneficial influence on clinical symptoms (weight loss, colon length, tissue TNF a / IFNg) in murine TNBS or DSS colitis models, most likely due to their barrier protective function.(23,27) More recently, we and others have utilized a AKB-4924, a relativel…”
BackgroundAnti‐inflammatory actions of adrenomedullin through fine tuning of HIF stabilization
MacManus, C. F., Campbell, E. L., Keely, S., Burgess, A., Kominsky, D. J., & Colgan, S. P. (2011) · The FASEB Journal · doi:10.1096/fj.10-170316 · Cited by 50
“A number of studies have indicated that stabilization of endogenous HIF-1 is protective in mucosal inflammation (2, 16, 17).”
BackgroundSelf-citationPrados, M. E., García‐Martín, A., Unciti-Broceta, J. D., Palomares, B., Collado, J. A., Minassi, A., Calzado, M. A., Appendino, G., & Muñóz, E. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-0497-0 · Cited by 50
Hypoxia‐inducible factors in metabolic reprogramming during sepsis
Vanderhaeghen, T., Vandewalle, J., & Libert, C. (2020) · FEBS Journal · doi:10.1111/febs.15222 · Cited by 47
Hirota, S. A., Beck, P. L., & MacDonald, J. A. (2009) · Recent Patents on Inflammation & Allergy Drug Discovery · doi:10.2174/187221309787158434 · Cited by 48
“However, data from the literature suggests that HIF1 plays a protective and regulatory role in the gastrointestinal tract through maintenance of intestinal barrier function and colonic inflammation [10-14,111,112].”
BackgroundInfluentialNeutrophils and inflammatory resolution in the mucosa
Colgan, S. P. (2015) · Seminars in Immunology · doi:10.1016/j.smim.2015.03.007 · Cited by 48
Hydroxylase-dependent regulation of the NF-κB pathway
Scholz, C. C., & Taylor, C. T. (2013) · Biological Chemistry · doi:10.1515/hsz-2012-0338 · Cited by 46
Self-citationShang, L., Wang, T., Tong, D., Kang, W., Liang, Q., & Ge, S. (2018) · Cell Proliferation · doi:10.1111/cpr.12516 · Cited by 46
Sun, L., Li, T., Tang, H., Yu, K., Ma, Y., Yu, M., Qiu, Y., Xu, P., Xiao, W., & Yang, H. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00806 · Cited by 47
“reported that HIF1α inhibited epithelial cell apoptosis by suppression of HIF-1α degradation in murine colitis (27).”
BackgroundHypoxia-adaptive pathways: A pharmacological target in fibrotic disease?
Strowitzki, M. J., Ritter, A. S., Kimmer, G., & Schneider, M. A. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104364 · Cited by 47
Hydroxylases as therapeutic targets in inflammatory bowel disease
Cummins, E. P., Doherty, G. A., & Taylor, C. T. (2013) · Laboratory Investigation · doi:10.1038/labinvest.2013.9 · Cited by 45
Self-citationSelvaraju, V., Parinandi, N. L., Adluri, R. S., Goldman, J. W., Hussain, N., Sánchez, J. A., & Maulik, N. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5186 · Cited by 44
“(40) induced colitis in mice through oral administration of dextran-sodium sulfate to closely mimic human UC.”
BackgroundActivation of HIF-1α does not increase intestinal tumorigenesis
Xue, X., Ramakrishnan, S. K., & Shah, Y. M. (2014) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00112.2014 · Cited by 46
Neutrophils as Components of Mucosal Homeostasis
Hall, C. H. T., Campbell, E. L., & Colgan, S. P. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.07.001 · Cited by 44
“In both studies, HIF-stabilizer treatment was associated with profound pro-resolving functions, particularly related to mucosal barrier function.(36,39) It is notable PHD inhibitors are currently in development for renal anemia (erythropoietin induction)(45) and that the use of local oral delivery of an extended-relea…”
BackgroundChallenges in IBD Research 2024: Preclinical Human IBD Mechanisms
Ciorba, M. A., Konnikova, L., Hirota, S. A., Lucchetta, E. M., Turner, J. R., Slavin, A., Johnson, K., Condray, C. D., Hong, S., Cressall, B. K., et al. (2024) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izae081 · Cited by 44
Hypoxia-inducible factor as a bridge between healthy barrier function, wound healing, and fibrosis
Steiner, C. A., Cartwright, I. M., Taylor, C. T., & Colgan, S. P. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00227.2022 · Cited by 45
Self-citationInvolvement of HIF-1α in MLCK-dependent Endothelial Barrier Dysfunction in Hypoxia
Qi, H., Wang, P., Liu, C., Li, M., Wang, S., Huang, Y., & Wang, F. (2011) · Cellular Physiology and Biochemistry · doi:10.1159/000327951 · Cited by 42
Natarajan, R., Salloum, F. N., Fisher, B. J., Smithson, L. A., Almenara, J. A., & Fowler, A. A. (2009) · Vascular Pharmacology · doi:10.1016/j.vph.2009.05.007 · Cited by 41
Hypoxia‐sensitive pathways in intestinal inflammation
Brown, E., & Taylor, C. T. (2017) · The Journal of Physiology · doi:10.1113/jp274350 · Cited by 41
“In support of the concept that PHD inhibition may be of therapeutic benefit in human colitis, it was demonstrated that the pan-hydroxylase inhibitor dimethyloxalylglycine (DMOG) is protective against DSS-induced colitis (Cummins et al. 2008).”
BackgroundSelf-citationBrown, E., Rowan, C. R., Strowitzki, M. J., Fagundes, R. R., Faber, K. N., Güntsch, A., Halligan, D. N., Kugler, J., Jones, F., Lee, C. T., et al. (2020) · The FASEB Journal · doi:10.1096/fj.201902103r · Cited by 43
Self-citationAyrapetov, M. K., Xu, C., Sun, Y., Zhu, K., Parmar, K., D'Andrea, A. D., & Price, B. D. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026064 · Cited by 41
“Previous studies using DMOG and related prolylhydroxylase inhibitors in whole animal models have indicated protection from ischemic injury [51], protection in a murine model of colitis [47] and the development of hypoxia tolerance [29].”
ResultYan, Z., & Xu, G. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00393 · Cited by 40
“In addition, it has been found that T cells or dendritic cells lacking HIF-1 cause aggravation of intestinal inflammation (84), especially in inflammatory bowel diseases, and the treatment of inflammatory bowel disease with PHIs has become a new approach (85).”
BackgroundTakaku, M., Tomita, S., Kurobe, H., Kihira, Y., Morimoto, A., Higashida, M., Ikeda, Y., Ushiyama, A., Hashimoto, I., Nakanishi, H., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042964 · Cited by 40
“The HIF-mediated effects of PHD inhibitors on apoptosis in ischemia have been studied in acute renal failure [21] and a colitis model in vitro [22].”
Katschinski, D. M. (2008) · Acta Physiologica · doi:10.1111/j.1748-1716.2008.01952.x · Cited by 38
The role of hypoxia‐inducible factor 1‐alpha in inflammatory bowel disease
Yin, J., Ren, Y., Yang, K., Wang, W., Wang, T., Xiao, W., & Yang, H. (2021) · Cell Biology International · doi:10.1002/cbin.11712 · Cited by 38
“HIF‐1α, activated by DMOG also ameliorates DSS‐ induced colitis via reducing epithelial cell apoptosis (Cummins et al., 2008).”
BackgroundNon-canonical HIF-1 stabilization contributes to intestinal tumorigenesis
Rohwer, N., Jumpertz, S., Erdem, M., Egners, A., Warzecha, K. T., Fragoulis, A., Kühl, A. A., Kramann, R., Neuß, S., Rudolph, I., et al. (2019) · Oncogene · doi:10.1038/s41388-019-0816-4 · Cited by 37
Liu, Y., Zhu, F., Li, H., Fan, H., Wu, H., Dong, Y., Chu, S., Tan, C., Wang, Q., He, H., et al. (2020) · Aging · doi:10.18632/aging.103555 · Cited by 38
“com 14973 AGING cells, and is strongly reduces epithelial barrier dysfunction in DSS-induced colitis [18].”
Background
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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