Hypoxia-Inducible Factor Augments Experimental Colitis Through an MIF–Dependent Inflammatory Signaling Cascade
Open accessAbstract
Background & aims Colon epithelial cells are critical for barrier function and contain a highly developed immune response. A previous study has shown hypoxia-inducible factor (HIF) as a critical regulator of barrier protection during colon epithelial injury. However, the role of HIF signaling in colon mucosal immunity is not known.Methods With the use of cre/loxP technology, intestinal-specific disruption of von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (Hif)-1alpha, and aryl hydrocarbon nuclear translocator (Arnt) was generated. Colon inflammation was induced using a dextran sulfate sodium (DSS)-induced colitis model, and the mice were analyzed by histologic analysis, Western blot analysis, and quantitative polymerase chain reaction.Results In mice, colonic epithelium disruption of Vhl resulted in constitutive expression of HIF, which initiated an increase in inflammatory infiltrates and edema in the colon. These effects were ameliorated in mice by disruption of both Vhl and Arnt/Hif1beta (which inactivates HIF). In a DSS-induced colitis model, increased HIF expression correlated with more severe clinical symptoms and an increase in histologic damage, while disruption of both Vhl and Arnt in the colon epithelium inhibited these effects. Furthermore, colons with constitutive activation of HIF displayed increased expression of proinflammatory mediators that were synergistically potentiated following DSS administration and reduced by inhibition of the proinflammatory and direct HIF target gene macrophage migration inhibitory factor.Conclusions The present study shows that a chronic increase in HIF signaling in the colon epithelial cells initiates a hyperinflammatory reaction that may have important implications in developing therapeutic strategies for inflammatory bowel disease.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
These findings may be somewhat model-dependent, since epithelial HIF-based signaling has also been shown to promote inflammation in another study.
“These findings may be somewhat model-dependent, since epithelial HIF-based signaling has also been shown to promote inflammation in another study27.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [27]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717 · see citing works
Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212 · see citing works
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · see citing works
Semenza, G. L., & Wang, G. L. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.12.5447 · Cited by 2,617 · see citing works
Regulation of angiogenesis by hypoxia: role of the HIF system
Pugh, C. W., & Ratcliffe, P. J. (2003) · Nature Medicine · doi:10.1038/nm0603-677 · Cited by 2,520 · see citing works
Cellular and developmental control of O <sub>2</sub> homeostasis by hypoxia-inducible factor 1α
Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., et al. (1998) · Genes & Development · doi:10.1101/gad.12.2.149 · Cited by 2,476 · see citing works
HIF-1α is essential for myeloid cell-mediated inflammation
Cramer, T., Yamanishi, Y., Clausen, B. E., Förster, I., Pawlinski, R., Mackman, N., Haase, V. H., Jaenisch, R., Corr, M., Nizet, V., et al. (2003) · Cell · doi:10.1016/s0092-8674(03)00154-5 · Cited by 2,046 · see citing works
Self-citationChemically induced mouse models of intestinal inflammation
Wirtz, S., Neufert, C., Weigmann, B., & Neurath, M. F. (2007) · Nature Protocols · doi:10.1038/nprot.2007.41 · Cited by 1,567 · see citing works
General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia.
Wang, G. L., & Semenza, G. L. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.9.4304 · Cited by 1,468 · see citing works
Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation
Hu, C.-J., Wang, L.-Y., Chodosh, L. A., Keith, B., & Simon, M. C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.9361-9374.2003 · Cited by 1,386 · see citing works
Tian, H., McKnight, S. L., & Russell, D. W. (1997) · Genes & Development · doi:10.1101/gad.11.1.72 · Cited by 1,351 · see citing works
The fundamental basis of inflammatory bowel disease
Strober, W., Fuss, I. J., & Mannon, P. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30587 · Cited by 1,310 · see citing works
Tissue‐specific and inducible Cre‐mediated recombination in the gut epithelium
Marjou, F. E., Janssen, K., Chang, B. H., Li, M., Hindie, V., Chan, L., Louvard, D., Chambon, P., METZGER, D., & Robine, S. (2004) · genesis · doi:10.1002/gene.20042 · Cited by 1,044 · see citing works
Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia.
Wang, G. L., & Semenza, G. L. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80571-7 · Cited by 863 · see citing works
(2002) · PubMed · Cited by 840 · see citing works
Maltepe, E., Schmidt, J. V., Baunoch, D., Bradfield, C. A., & Simon, M. C. (1997) · Nature · doi:10.1038/386403a0 · Cited by 781 · see citing works
HIF-2α Promotes Hypoxic Cell Proliferation by Enhancing c-Myc Transcriptional Activity
Gordan, J. D., Bertout, J. A., Hu, C.-J., Diehl, J. A., & Simon, M. C. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.02.006 · Cited by 781 · see citing works
Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression
Makino, Y., Cao, R., Svensson, K., Bertilsson, G., Asman, M., Tanaka, H., Cao, Y., Berkenstam, A., & Poellinger, L. (2001) · Nature · doi:10.1038/35107085 · Cited by 705 · see citing works
Synnestvedt, K., Furuta, G. T., Comerford, K. M., Louis, N. A., Karhausen, J., Eltzschig, H. K., Hansen, K. R., Thompson, L. F., & Colgan, S. P. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15337 · Cited by 679 · see citing works
Synnestvedt, K., Furuta, G. T., Comerford, K. M., Louis, N., Karhausen, J., Eltzschig, H. K., Hansen, K. R., Thompson, L. F., & Colgan, S. P. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215337 · Cited by 660 · see citing works
Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis
Karhausen, J., Furuta, G. T., Tomaszewski, J. E., Johnson, R. S., Colgan, S. P., & Haase, V. H. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200421086 · Cited by 655 · see citing works
Self-citationTian, H., Hammer, R. E., Matsumoto, A. M., Russell, D. W., & McKnight, S. L. (1998) · Genes & Development · doi:10.1101/gad.12.21.3320 · Cited by 647 · see citing works
Yu, A. Y., Shimoda, L. A., Iyer, N. V., Huso, D. L., Sun, X., McWilliams, R. M., Beaty, T. H., Sham, J. S. K., Wiener, C. M., Sylvester, J. T., et al. (1999) · Journal of Clinical Investigation · doi:10.1172/jci5912 · Cited by 645 · see citing works
Wiesener, M. S., Turley, H., Allen, W. E., Willam, C., Eckardt, K., Talks, K., Wood, S. M., Gatter, K. C., Harris, A. L., Pugh, C. W., et al. (1998) · Blood · doi:10.1182/blood.v92.7.2260 · Cited by 629 · see citing works
Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic
Warner, T. D., & Mitchell, J. A. (2004) · The FASEB Journal · doi:10.1096/fj.03-0645rev · Cited by 613 · see citing works
Furuta, G. T., Turner, J. R., Taylor, C. T., Hershberg, R. M., Comerford, K., Narravula, S., Podolsky, D. K., & Colgan, S. P. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.9.1027 · Cited by 449 · see citing works
Uchida, T., Rossignol, F., Matthay, M. A., Mounier, R., Couette, S., Clottes, E., & Clérici, C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400461200 · Cited by 429 · see citing works
Vascular tumors in livers with targeted inactivation of the von Hippel–Lindau tumor suppressor
Haase, V. H., Glickman, J. N., Socolovsky, M., & Jaenisch, R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.4.1583 · Cited by 421 · see citing works
Self-citationThe Hydroxylase Inhibitor Dimethyloxalylglycine Is Protective in a Murine Model of Colitis
Cummins, E. P., Seeballuck, F., Keely, S. J., Mangan, N. E., Callanan, J. J., Fallon, P. G., & Taylor, C. T. (2008) · Gastroenterology · doi:10.1053/j.gastro.2007.10.012 · Cited by 407 · see citing works
Mucosal Protection by Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition
Robinson, A., Keely, S., Karhausen, J., Gerich, M. E., Furuta, G. T., & Colgan, S. P. (2008) · Gastroenterology · doi:10.1053/j.gastro.2007.09.033 · Cited by 368 · see citing works
Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice
Gnarra, J. R., Ward, J. M., Porter, F. D., WAGNER, J. R., Devor, D. E., Grinberg, A., Emmert‐Buck, M. R., Westphal, H., Klausner, R. D., & Linehan, W. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.17.9102 · Cited by 362 · see citing works
Al‐Abed, Y., Dabideen, D. R., Aljabari, B., Valster, A. H., Messmer, D., Ochani, M., Tanovic, M., Ochani, K., Bacher, M., Nicoletti, F., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c500243200 · Cited by 309 · see citing works
Development of chronic colitis is dependent on the cytokine MIF
de Jong, Y. P., Abadía‐Molina, A. C., Satoskar, A. R., Clarke, K., Rietdijk, S. T., Faubion, W. A., Mizoguchi, E., Metz, C. N., Sahli, M. A., ten Hove, T., et al. (2001) · Nature Immunology · doi:10.1038/ni720 · Cited by 305 · see citing works
Kaidi, A., Qualtrough, D., Williams, A. C., & Paraskeva, C. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0425 · Cited by 300 · see citing works
Thoracic Manifestations of Inflammatory Bowel Disease
Black, H. R., Mendoza, M. D., & Murin, S. (2007) · CHEST Journal · doi:10.1378/chest.06-1074 · Cited by 266 · see citing works
Local and Systemic Inflammation in Chronic Obstructive Pulmonary Disease
Wouters, E. F. �. (2005) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200408-039ms · Cited by 253 · see citing works
Defective Brain Development in Mice Lacking the Hif-1 α Gene in Neural Cells
Tomita, S., Ueno, M., Sakamoto, M., Kitahama, Y., Ueki, M., Nobuhiro Maekawa, A., Sakamoto, H., Gassmann, M., Kageyama, R., Ueda, N., et al. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.19.6739-6749.2003 · Cited by 250 · see citing works
Self-citationNeurath, M. F., Fuss, I. J., & Strober, W. (2000) · International Reviews of Immunology · doi:10.3109/08830180009048389 · Cited by 192 · see citing works
Crystal structure of the macrophage migration inhibitory factor from rat liver
Suzuki, M., Sugimoto, H., Nakagawa, A., Tanaka, I., Nishihira, J., & Sakai, M. (1996) · Nature Structural Biology · doi:10.1038/nsb0396-259 · Cited by 190 · see citing works
Ohkawara, T., Nishihira, J., Takeda, H., Hige, S., Kato, M., Sugiyama, T., Iwanaga, T., Nakamura, H., Mizue, Y., & Asaka, M. (2002) · Gastroenterology · doi:10.1053/gast.2002.34236 · Cited by 152 · see citing works
Scortegagna, M., Cataisson, C., Martin, R. J., Hicklin, D. J., Schreiber, R. D., Yuspa, S. H., & Arbeit, J. M. (2008) · Blood · doi:10.1182/blood-2007-10-115758 · Cited by 151 · see citing works
The HIF pathway as a therapeutic target
Hewitson, K. S., & Schofield, C. J. (2004) · Drug Discovery Today · doi:10.1016/s1359-6446(04)03202-7 · Cited by 147 · see citing works
Goyette, P., Labbé, C., Trinh, T. T., Xavier, R. J., & Rioux, J. D. (2007) · Annals of Medicine · doi:10.1080/07853890701197615 · Cited by 139 · see citing works
Baugh, J. A., Gantier, M. P., Li, L., Byrne, A., Buckley, A., & Donnelly, S. C. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.06.148 · Cited by 136 · see citing works
Tomita, S., Sinal, C. J., Yim, S. H., & Gonzalez, F. J. (2000) · Molecular Endocrinology · doi:10.1210/mend.14.10.0533 · Cited by 121 · see citing works
Self-citationShah, Y. M., Morimura, K., & Gonzalez, F. J. (2006) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00381.2006 · Cited by 120 · see citing works
Self-citationIto, S., Chen, C., Satoh, J., Yim, S., & Gonzalez, F. J. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31647 · Cited by 96 · see citing works
Self-citationHyperbaric oxygen: a novel modality to ameliorate experimental colitis
Rachmilewitz, D., Karmeli, F., Okon, E., Rubenstein, I. D., & Better, O. S. (1998) · Gut · doi:10.1136/gut.43.4.512 · Cited by 55 · see citing works
Role of HIF-1 in Iron Regulation: Potential Therapeutic Strategy for Neurodegenerative Disorders
Lee, D. W., & Andersen, J. K. (2006) · Current Molecular Medicine · doi:10.2174/156652406779010849 · Cited by 51 · see citing works
Ohkawara, T., Miyashita, K., Nishihira, J., Mitsuyama, K., Takeda, H., Kato, M., Kondo, N., Yamasaki, Y., Sata, M., Yoshiki, T., et al. (2005) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2005.02771.x · Cited by 37 · see citing works
HIF-2α regulates glyceraldehyde-3-phosphate dehydrogenase expression in endothelial cells
Graven, K. K., Bellur, D. L., Klahn, B. D., Lowrey, S. L., & Amberger, E. (2003) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(03)00049-6 · Cited by 36 · see citing works
Ohkawara, T., Nishihira, J., Ishiguro, Y., Otsubo, E., Nagai, K., Takeda, H., Kato, M., Yoshiki, T., Iwanaga, T., & Asaka, M. (2006) · Immunology Letters · doi:10.1016/j.imlet.2006.09.002 · Cited by 26 · see citing works
Mucosal Epithelium in Health and Disease
Ponda, P., & Mayer, L. (2005) · Current Molecular Medicine · doi:10.2174/1566524054863933 · Cited by 22 · see citing works
Flagged first, then by citations
1 of the 55 references couldn’t be matched to a known paper.
Research works printed but not linked: 3
- Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHL- mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001;292:464 -468.
- Iyer NV, Kotch LE, Agani F, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 1998;12:149 -162.
- Graven KK, Bellur D, Klahn BD, et al. HIF-2alpha regulates glyc- eraldehyde-3-phosphate dehydrogenase expression in endothe- lial cells. Biochim Biophys Acta 2003;1626:10 -18.
Cited by
Sorted by citations
Dextran Sodium Sulphate Colitis Mouse Model: Traps and Tricks
Perše, M., & Cerar, A. (2012) · BioMed Research International · doi:10.1155/2012/718617 · Cited by 886 · see citing works
Interdependence of hypoxic and innate immune responses
Nizet, V., & Johnson, R. S. (2009) · Nature Reviews Immunology · doi:10.1038/nri2607 · Cited by 708 · see citing works
HIF ‐1 at the crossroads of hypoxia, inflammation, and cancer
Balamurugan, K. (2015) · International Journal of Cancer · doi:10.1002/ijc.29519 · Cited by 571 · see citing works
Hypoxia: an alarm signal during intestinal inflammation
Colgan, S. P., & Taylor, C. T. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.39 · Cited by 461 · see citing works
Shah, Y. M., Matsubara, T., Ito, S., Yim, S.-H., & Gonzalez, F. J. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2008.12.012 · Cited by 431 · see citing works
Self-citationMetabolic Shifts in Immunity and Inflammation
Kominsky, D. J., Campbell, E. L., & Colgan, S. P. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903002 · Cited by 413 · see citing works
Espey, M. G. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.10.554 · Cited by 396 · see citing works
Redox control of inflammation in macrophages
Brüne, B., Dehne, N., Grossmann, N., Jung, M., Namgaladze, D., Schmid, T., von Knethen, A., & Weigert, A. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4785 · Cited by 377 · see citing works
Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases
Eltzschig, H. K., Bratton, D. L., & Colgan, S. P. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4422 · Cited by 363 · see citing works
Mammalian Per-Arnt-Sim Proteins in Environmental Adaptation
McIntosh, B. E., Hogenesch, J. B., & Bradfield, C. A. (2010) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021909-135922 · Cited by 352 · see citing works
Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives
Milagro, F. I., Mansego, M. L., de Miguel, C., & Martínez, J. A. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.06.010 · Cited by 310 · see citing works
Taylor, M., Qu, A., Anderson, E. R., Matsubara, T., Martin, A., Gonzalez, F. J., & Shah, Y. M. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.03.007 · Cited by 265 · see citing works
Self-citationControl and dysregulation of redox signalling in the gastrointestinal tract
Campbell, E. L., & Colgan, S. P. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0079-5 · Cited by 258 · see citing works
Metabolic control of the Treg/Th17 axis
Barbi, J. J., Pardoll, D. M., & Pan, F. (2013) · Immunological Reviews · doi:10.1111/imr.12029 · Cited by 215 · see citing works
Dashdorj, A., Jyothi, K. R., Lim, S., Jo, A., Nguyen, M. N., Ha, J., Yoon, K., Kim, H. J., Park, J., Murphy, M. P., et al. (2013) · BMC Medicine · doi:10.1186/1741-7015-11-178 · Cited by 206 · see citing works
Holden, V. I., Breen, P., Houle, S., Dozois, C. M., & Bachman, M. A. (2016) · mBio · doi:10.1128/mbio.01397-16 · Cited by 204 · see citing works
Long-Term Culture Captures Injury-Repair Cycles of Colonic Stem Cells
Wang, Y., Chiang, I.-L., Ohara, T. E., Fujii, S., Cheng, J., Muegge, B. D., Heul, A. V., Han, N. D., Lu, Q., Xiong, S., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.015 · Cited by 196 · see citing works
Dong, L., Du, H., Zhang, M., Xu, H., Pu, X., Chen, Q., Luo, R., Hu, Y., Wang, Y., Tu, H., et al. (2022) · Phytotherapy Research · doi:10.1002/ptr.7429 · Cited by 199 · see citing works
MIF-Dependent Control of Tumor Immunity
Noe, J. T., & Mitchell, R. A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.609948 · Cited by 198 · see citing works
Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines
Malkov, M. I., Lee, C. T., & Taylor, C. T. (2021) · Cells · doi:10.3390/cells10092340 · Cited by 185 · see citing works
The role of hypoxia in inflammatory disease (Review)
Biddlestone, J., Bandarra, D., & Rocha, S. (2015) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2015.2079 · Cited by 178 · see citing works
Xue, X., Ramakrishnan, S. K., Anderson, E. R., Taylor, M. J., Zimmermann, E. M., Spence, J. R., Huang, S., Greenson, J. K., & Shah, Y. M. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.07.010 · Cited by 171 · see citing works
Self-citationActivation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis
Xie, C., Yagai, T., Luo, Y., Liang, X., Chen, T., Wang, Q., Sun, D., Zhao, J., Ramakrishnan, S. K., Sun, L., et al. (2017) · Nature Medicine · doi:10.1038/nm.4412 · Cited by 161 · see citing works
Self-citationControl of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis
Glover, L. E., Bowers, B. E., Saeedi, B., Ehrentraut, S. F., Campbell, E. L., Bayless, A. J., Dobrinskikh, E., Kendrick, A. A., Kelly, C. J., Burgess, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1302840110 · Cited by 155 · see citing works
The role of HIF in immunity and inflammation
Cummins, E. P., Keogh, C. E., Crean, D., & Taylor, C. T. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2015.12.004 · Cited by 153 · see citing works
Iron in the Tumor Microenvironment-Connecting the Dots
Pfeifhofer-Obermair, C., Tymoszuk, P., Petzer, V., Weiss, G., & Nairz, M. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00549 · Cited by 151 · see citing works
Xue, X., Taylor, M. J., Anderson, E. R., Hao, C., Qu, A., Greenson, J. K., Zimmermann, E. M., Gonzalez, F. J., & Shah, Y. M. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3836 · Cited by 146 · see citing works
Self-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 136 · see citing works
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 133 · see citing works
Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD
Welden, S. V., Selfridge, A. C., & Hindryckx, P. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.101 · Cited by 124 · see citing works
Hypoxia and Metabolic Factors That Influence Inflammatory Bowel Disease Pathogenesis
Glover, L. E., & Colgan, S. P. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.01.056 · Cited by 124 · see citing works
Adenosine and Hypoxia-Inducible Factor Signaling in Intestinal Injury and Recovery
Colgan, S. P., & Eltzschig, H. K. (2011) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020911-153230 · Cited by 121 · see citing works
Kim, H., Banerjee, N., Barnes, R. C., Pfent, C. M., Talcott, S. T., Dashwood, R. H., & Mertens‐Talcott, S. U. (2016) · Molecular Carcinogenesis · doi:10.1002/mc.22484 · Cited by 117 · see citing works
Verma, A., Pittala, S., Alhozeel, B., Shteinfer‐Kuzmine, A., Ohana, E., Gupta, R., Chung, J. H., & Shoshan‐Barmatz, V. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.06.024 · Cited by 116 · see citing works
MIF as a Disease Target: ISO-1 as a Proof-of-Concept Therapeutic
Al‐Abed, Y., & VanPatten, S. (2010) · Future Medicinal Chemistry · doi:10.4155/fmc.10.281 · Cited by 108 · see citing works
Hypoxia 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 106 · see citing works
Mucosal pathogenesis in gastro‐esophageal reflux disease
Ustaoglu, A., Nguyen, A. D., Spechler, S. J., Sifrim, D. A., Souza, R. F., & Woodland, P. J. (2020) · Neurogastroenterology & Motility · doi:10.1111/nmo.14022 · Cited by 105 · see citing works
Hypoxia-Induced Inflammation in the Lung
Fröhlich, S., Boylan, J. F., & McLoughlin, P. (2013) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2012-0137tr · Cited by 99 · see citing works
Bourgonje, A. R., Klóska, D., Grochot‐Przeczek, A., Feelisch, M., Cuadrado, A., & van Goor, H. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102603 · Cited by 95 · see citing works
Hypoxia. Regulation of NFκB signalling during inflammation: the role of hydroxylases
Oliver, K. M., Taylor, C. T., & Cummins, E. P. (2009) · Arthritis Research & Therapy · doi:10.1186/ar2575 · Cited by 91 · see citing works
Kim, 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 · see citing works
Hypoxia and inflammatory bowel disease
Cummins, E. P., & Crean, D. (2016) · Microbes and Infection · doi:10.1016/j.micinf.2016.09.004 · Cited by 83 · see citing works
Cane, 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 82 · see citing works
Reflux esophagitis and its role in the pathogenesis of Barrett’s metaplasia
Souza, R. F. (2017) · Journal of Gastroenterology · doi:10.1007/s00535-017-1342-1 · Cited by 79 · see citing works
Creatine maintains intestinal homeostasis and protects against colitis
Turer, E. E., McAlpine, W., Wang, K.-W., Lu, T., Li, X., Tang, M., Zhan, X., Wang, T., Zhan, X., Bu, C.-H., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1621400114 · Cited by 76 · see citing works
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 75 · see citing works
Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury
Kannan, K. B., Colorado, I., Reino, D. C., Palange, D., Lu, Q., Qin, X., Abungu, B., Watkins, A. C., Caputo, F. J., Xu, D.-Z., et al. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00459.2010 · Cited by 73 · see citing works
Triner, D. A., Xue, X., Schwartz, A. J., Jung, I., Colacino, J. A., & Shah, Y. M. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00481-16 · Cited by 72 · see citing works
Self-citationKim, H., Banerjee, N., Sirven, M. A., Minamoto, Y., Markel, M. E., Suchodolski, J. S., Talcott, S. T., & Mertens‐Talcott, S. U. (2017) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2017.02.005 · Cited by 70 · see citing works
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 69 · see citing works
Self-citationRees, W. D., Tandun, R., Yau, E., Zachos, N. C., & Steiner, T. S. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.583919 · Cited by 69 · see citing works
Chen, 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 · see citing works
Souza, R. F., Bayeh, L., Spechler, S. J., Tambar, U. K., & Bruick, R. K. (2017) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2017.10.004 · Cited by 66 · see citing works
Results of the 2nd Scientific Workshop of the ECCO (III): Basic mechanisms of intestinal healing
Rieder, F., Karrasch, T., Ben‐Horin, S., Schirbel, A., Ehehalt, R., Wehkamp, J., de Haar, C. G., Velin, D., Latella, G., Scaldaferri, F., et al. (2011) · Journal of Crohn s and Colitis · doi:10.1016/j.crohns.2011.11.009 · Cited by 64 · see citing works
Ma, X., Zhang, H., Xue, X., & Shah, Y. M. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.805655 · Cited by 62 · see citing works
Self-citationHypoxia-inducible factor-2α plays a role in mediating oesophagitis in GORD
Huo, X., Agoston, A. T., Dunbar, K. B., Cipher, D. J., Zhang, X., Yu, C., Cheng, E., Zhang, Q., Pham, T. H., Tambar, U. K., et al. (2016) · Gut · doi:10.1136/gutjnl-2016-312595 · Cited by 59 · see citing works
Intestinal Hypoxia-inducible Factor-2α (HIF-2α) Is Critical for Efficient Erythropoiesis
Anderson, E. R., Xue, X., & Shah, Y. M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.238667 · Cited by 57 · see citing works
Self-citationMimouna, 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 · see citing works
Nix-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 57 · see citing works
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 · see citing works
The Therapeutic Effect of Chelidonic Acid on Ulcerative Colitis
Kim, D., Kim, S. J., Kim, M.-C., Jeon, Y., Um, J., & Hong, S. (2012) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.35.666 · Cited by 55 · see citing works
The absence of LPA receptor 2 reduces the tumorigenesis by ApcMin mutation in the intestine
Lin, S., Lee, S., Shim, H., Chun, J. J. M., & Yun, C. C. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00321.2010 · Cited by 54 · see citing works
The 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 51 · see citing works
Elevated d -2-hydroxyglutarate during colitis drives progression to colorectal cancer
Han, J., Jackson, D. N., Holm, J., Turner, K., Ashcraft, P., Wang, X., Cook, B. N., Arning, E., Genta, R. M., Venuprasad, K., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1712625115 · Cited by 52 · see citing works
Metabolic 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 49 · see citing works
Garai, J., & Lóránd, T. (2009) · Current Medicinal Chemistry · doi:10.2174/092986709787581842 · Cited by 51 · see citing works
Ramakrishnan, S. K., Zhang, H., Takahashi, S., Centofanti, B., Periyasamy, S., Weisz, K. M., Chen, Z., Uhler, M. D., Rui, L., Gonzalez, F. J., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.01.004 · Cited by 50 · see citing works
Self-citationKeely, S., Glover, L. E., Weissmüller, T., MacManus, C. F., Fillon, S., Fennimore, B. P., & Colgan, S. P. (2009) · Molecular Biology of the Cell · doi:10.1091/mbc.e09-07-0573 · Cited by 50 · see citing works
Vavricka, S. R., Rogler, G., Maetzler, S., Misselwitz, B., Safroneeva, E., Frei, P., Manser, C. N., Biedermann, L., Fried, M., Higgins, P., et al. (2013) · Journal of Crohn s and Colitis · doi:10.1016/j.crohns.2013.07.011 · Cited by 49 · see citing works
Hirota, S. A., Beck, P. L., & MacDonald, J. A. (2009) · Recent Patents on Inflammation & Allergy Drug Discovery · doi:10.2174/187221309787158434 · Cited by 48 · see citing works
Neutrophils and inflammatory resolution in the mucosa
Colgan, S. P. (2015) · Seminars in Immunology · doi:10.1016/j.smim.2015.03.007 · Cited by 48 · see citing works
Gao, H., Ren, F., Wen, P., Xie, L. X., Wang, R., Yang, Z. N., & Li, Y. X. (2020) · Journal of Dairy Science · doi:10.3168/jds.2020-19063 · Cited by 48 · see citing works
Hypoxia-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 46 · see citing works
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 44 · see citing works
Jo, Y., Kim, D. W., Choi, J., & Kim, S. (2019) · Scientific Reports · doi:10.1038/s41598-019-40027-5 · Cited by 44 · see citing works
Activation 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 44 · see citing works
Self-citationNeutrophils 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 · see citing works
Fruehauf, H., Vavricka, S. R., Lutz, T. A., Gassmann, M., Wojtal, K. A., Erb, A., Maggiorini, M., Schwizer, W., Fried, M., Fox, M. R., et al. (2019) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2019.11.036 · Cited by 43 · see citing works
Yin, J., Zhou, C., Yang, K., Ren, Y., Qiu, Y., Xu, P., Xiao, W., & Yang, H. (2020) · Cell Biology International · doi:10.1002/cbin.11336 · Cited by 44 · see citing works
Seike, K., Kiledal, E. A., Fujiwara, H., Henig, I. J., da Silva, M. B., van den Brink, M. R. M., Hein, R., Hoostal, M. J., Liu, C., Oravecz-Wilson, K. I., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.01.007 · Cited by 42 · see citing works
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 · see citing works
Toullec, A., Buard, V., Rannou, E., Tarlet, G., Guipaud, O., Robine, S., Iruela‐Arispe, M. L., François, A., & Milliat, F. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.08.001 · Cited by 40 · see citing works
Oh, S., Ok, S., Jung, T.-S., Jeon, S.-O., Park, J.-M., Jung, J.-W., & Ryu, D. (2017) · Asian Pacific Journal of Tropical Medicine · doi:10.1016/j.apjtm.2017.08.017 · Cited by 39 · see citing works
HIF-1α alleviates ferroptosis in ulcerative colitis by regulation of GPX4
Hu, W., Cai, Y., Cai, D., Chen, Z., Huang, S., Zhang, S., Zhuang, H., Fang, T., & Chen, X. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07883-8 · Cited by 41 · see citing works
Non-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 · see citing works
Oxygen sensing in intestinal mucosal inflammation
Flück, K., & Fandrey, J. (2015) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-015-1722-4 · Cited by 35 · see citing works
Long, G., Chen, H., Wu, M., Li, Y., Gao, L., Huang, S., Zhang, Y., Jia, Z., & Xia, W. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01191 · Cited by 36 · see citing works
Liu, H., Li, M., Wang, P., & Wang, F. (2011) · Cytokine · doi:10.1016/j.cyto.2011.08.023 · Cited by 36 · see citing works
Ramakrishnan, S. K., Taylor, M. J., Qu, A., Ahn, S.-H., Suresh, M. V., Raghavendran, K., Gonzalez, F. J., & Shah, Y. M. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.01441-13 · Cited by 35 · see citing works
Self-citationLiu, H., Wang, P., Cao, M., Li, M., & Wang, F. (2012) · Cellular Physiology and Biochemistry · doi:10.1159/000188076 · Cited by 34 · see citing works
Iron and colorectal cancer: evidence from in vitro and animal studies
Padmanabhan, H., Brookes, M., & Iqbal, T. H. (2015) · Nutrition Reviews · doi:10.1093/nutrit/nuu015 · Cited by 35 · see citing works
Youness, R. A., Elemam, N. M., Abdelhamid, A. M., Mohamed, A. H., Elsherbiny, L. M., Ramzy, A., & Assal, R. A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1636839 · Cited by 34 · see citing works
Bakirtzi, K., West, G. A., Fiocchi, C., Law, I. K. M., Iliopoulos, D., & Pothoulakis, C. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2014.08.015 · Cited by 36 · see citing works
Inflammation, HIF-1, and the Epigenetics That Follows
Brigati, C., Banelli, B., Vinci, A. D., Casciano, I., Allemanni, G., Forlani, A., Borzì, L., & Romani, M. (2010) · Mediators of Inflammation · doi:10.1155/2010/263914 · Cited by 34 · see citing works
Hyperbaric oxygen therapy ameliorates TNBS-induced acute distal colitis in rats
Parra, R. S., Lopes, A. H., Carreira, E. U., Feitosa, M. R., Cunha, F. Q., Garcia, S. B., Cunha, T. M., da Rocha, J. J. R., & Féres, O. (2015) · Medical Gas Research · doi:10.1186/s13618-015-0026-2 · Cited by 33 · see citing works
Mladenova, D. N., Daniel, J. J., Dahlstrom, J. E., Bean, E. G., Gupta, R., Pickford, R., Currey, N., Musgrove, E. A., & Kohonen‐Corish, M. R. J. (2010) · Gut · doi:10.1136/gut.2010.208314 · Cited by 33 · see citing works
Barrier integrity and chronic inflammation mediated by HIF-1 impact on intestinal tumorigenesis
Robrahn, L., Jiao, L. R., & Cramer, T. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.07.002 · Cited by 32 · see citing works
Xue, G., Gao, R., Liu, Z., Xu, N., Cao, Y., Zhao, B., & Du, J. (2021) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00061.2021 · Cited by 32 · see citing works
Hypoxia-Induced Signaling in Gut and Liver Pathobiology
Solanki, S. A., & Shah, Y. M. (2023) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-051122-094743 · Cited by 32 · see citing works
Self-citationGale, D. P., & Maxwell, P. H. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.10.012 · Cited by 32 · see citing works
- Authors
- Shah, Y. M., Ito, S., Morimura, K., Chen, C., Yim, S., Haase, V. H., & Gonzalez, F. J.
- Affiliations
- National Institutes of Health (US)
- University of Pennsylvania (US)
- Corresponding author
- Gonzalez, Frank J.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 134
- Issue
- 7
- Pages
- 2036-2048.e3
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC2533811
- OpenAlex
- W1989538067
- Cited by
- 168
- References
- 55
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 5 · 2023: 8 · 2022: 7 · 2021: 10 · 2020: 11 · 2019: 8 · 2018: 5 · 2017: 11 · 2016: 11 · 2015: 12 · 2014: 10 · 2013: 14 · 2012: 12
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01BC005561, R01CA100787)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
- Health Sciences › Medicine › Epidemiology › Microscopic Colitis
- Keywords
- hypoxia-inducible factor, HIF-1α, ARNT, VHL, macrophage migration inhibitory factor, DSS-induced colitis, experimental colitis, colonic epithelium, mucosal immunity, inflammatory bowel disease, intestinal inflammation, pro-inflammatory mediators
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Colitis, Colon, Disease Models, Animal, Enzyme Inhibitors, Gene Expression Regulation, Intestinal Mucosa, Isoxazoles, Macrophage Migration-Inhibitory Factors, Mice, Transgenic, Recombination, Genetic, Time Factors, Signal Transduction, Dextran Sulfate, Inflammation Mediators, Integrases, Intramolecular Oxidoreductases, Mice, Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Proteins, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
