{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T18:58:55Z","timestamp":1788634735658,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,15]],"date-time":"2020-11-15T00:00:00Z","timestamp":1605398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The objective of this study was to examine the protective effect of phytic acid (PA) in reducing oxidative stress in an animal model for human hereditary hemochromatosis (HH) fed high-fat diets. Sixty-four \u00df2 microglobulin knockout (\u03b22m KO) mice were randomly assigned to three treatments by feeding: control (basal), atherogenic (AT), and polyunsaturated fatty acid (PUFA) diets. One-half of the mice in each treatment group were fed 2% (wt\/wt) PA. The \u00df2m+\/+ mice (wild type (WT)) were fed a basal diet. All seven groups were fed for 10 weeks with a 50-ppm iron-containing diet (AIN-93G). Free iron and lipids were measured in serum samples. Nonheme iron, thiobarbituric acid-reactive substances (TBARS), superoxide dismutase (SOD), and catalase concentrations were measured in the liver tissue. Nonheme iron concentration in \u00df2m KO mice (on the basal diet) was 20\u00d7 higher (p &lt; 0.0001) than in the WT mice. Compared to the WT mice, \u00df2m KO mice had a significantly higher concentration of free iron in the serum (p &lt; 0.0001), six-fold higher hepatic TBARs (p &lt; 0.0001), and 18% lower hepatic SOD level. When PA was added to the \u03b22m KO basal diet, a reduction (26 to 50%) of iron concentration was seen in the liver and heart. The addition of PA also significantly reduced TBARs in all three dietary groups of the iron-overloaded group, but most effectively in the control group. An increase in SOD concentration was seen only in the PUFA group, but serum triacylglycerol (TG) concentration was reduced in both dietary fat groups. In conclusion, our results suggest that PA protects against oxidative stress-induced by genetic iron overload alone or when fed high fat.<\/jats:p>","DOI":"10.3390\/molecules25225331","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T22:53:52Z","timestamp":1605567232000},"page":"5331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Phytic Acid Protects from Oxidative Stress Induced by Iron-Overload and High-Fat Diets in \u00df2-Microglobulin Knockout Mice"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2374-4462","authenticated-orcid":false,"given":"Sixtus","family":"Aguree","sequence":"first","affiliation":[{"name":"Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011, USA"},{"name":"Corteva Agriscience, Johnston, IA 50131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2294-0701","authenticated-orcid":false,"given":"Manju B.","family":"Reddy","sequence":"additional","affiliation":[{"name":"Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"568S","DOI":"10.1093\/jn\/131.2.568S","article-title":"Iron biology in immune function, muscle metabolism and neuronal functioning","volume":"131","author":"Beard","year":"2001","journal-title":"J. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1559S","DOI":"10.3945\/ajcn.117.155804","article-title":"Current understanding of iron homeostasis","volume":"106","author":"Anderson","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1016\/j.bbamcr.2012.01.014","article-title":"Hepcidin and iron homeostasis","volume":"1823","author":"Ganz","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/ng0896-399","article-title":"A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis","volume":"13","author":"Feder","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1146\/annurev.physiol.64.081501.155838","article-title":"Mechanisms of iron accumulation in hereditary hemochromatosis","volume":"64","author":"Fleming","year":"2002","journal-title":"Annu. Rev. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1084\/jem.184.5.1975","article-title":"Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man","volume":"184","author":"Santos","year":"1996","journal-title":"J. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s10534-005-6687-x","article-title":"Apical distribution of HFE-beta2-microglobulin is associated with inhibition of apical iron uptake in intestinal epithelia cells","volume":"19","author":"Arredondo","year":"2006","journal-title":"Biometals"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1182\/blood.V92.6.1845","article-title":"Iron is hot: An update on the pathophysiology of hemochromatosis","volume":"92","author":"Andrews","year":"1998","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10282","DOI":"10.1016\/S0021-9258(18)67521-0","article-title":"The involvement of iron in lipid peroxidation","volume":"261","author":"Braughler","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/0748-5514(85)90025-X","article-title":"Role of metals in oxygen radical reactions","volume":"1","author":"Aust","year":"1986","journal-title":"Free Radic. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1042\/bj3000799","article-title":"The effect of iron overload on rat plasma and liver oxidant status in vivo","volume":"300","author":"Dabbagh","year":"1994","journal-title":"Biochem. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"808","DOI":"10.3390\/biom5020808","article-title":"Oxidative stress and the homeodynamics of iron metabolism","volume":"5","author":"Bresgen","year":"2015","journal-title":"Biomolecules"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0753-3322(01)00068-3","article-title":"Iron metabolism, free radicals, and oxidative injury","volume":"55","author":"Emerit","year":"2001","journal-title":"Biomed. Pharmacother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/j.bbadis.2015.03.011","article-title":"An overview of molecular basis of iron metabolism regulation and the associated pathologies","volume":"1852","author":"Silva","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Petroski, W., and Minich, D.M. (2020). Is there such a thing as \"anti-nutrients\"? A narrative review of perceived problematic plant compounds. Nutrients, 12.","DOI":"10.3390\/nu12102929"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1093\/ajcn\/63.2.203","article-title":"The influence of different protein sources on phytate inhibition of nonheme-iron absorption in humans","volume":"63","author":"Reddy","year":"1996","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1207\/s15327914nc5502_1","article-title":"Protection against cancer by dietary IP6 and inositol","volume":"55","author":"Vucenik","year":"2006","journal-title":"Nutr. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/0891-5849(90)90146-A","article-title":"Antioxidant functions of phytic acid","volume":"8","author":"Graf","year":"1990","journal-title":"Free Radic. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/0003-4975(91)91254-S","article-title":"Protection of ischemic heart from reperfusion injury by myo-inositol hexaphosphate, a natural antioxidant","volume":"52","author":"Rao","year":"1991","journal-title":"Ann. Thorac. Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1016\/j.ccr.2007.09.008","article-title":"Formation and stability of phytate complexes in solution","volume":"252","author":"Crea","year":"2008","journal-title":"Coord. Chem. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kremer, C., Torres, J., Bianchi, A., Savastano, M., and Bazzicalupi, C. (2020). Myo-inositol hexakisphosphate: Coordinative versatility of a natural product. Coord. Chem. Rev., 419.","DOI":"10.1016\/j.ccr.2020.213403"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1631\/jzus.B0710640","article-title":"Phytate: Impact on environment and human nutrition. A challenge for molecular breeding","volume":"9","author":"Bohn","year":"2008","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3923\/ajpnft.2011.1.22","article-title":"Phytic acid in cereal grains: Structure, healthy or harmful ways to reduce phytic acid in cereal grains and their effects on nutritional quality","volume":"1","author":"Coulibaly","year":"2011","journal-title":"Am. J. Plant Nutr. Fertil. Technol."},{"key":"ref_24","first-page":"1554","article-title":"A review phytic acid: As antinutrient or nutraceutical","volume":"6","author":"Nissar","year":"2017","journal-title":"J. Pharmacogn. Phytochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/S0024-3205(97)00092-1","article-title":"IP6: A novel anti-cancer agent","volume":"61","author":"Shamsuddin","year":"1997","journal-title":"Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/BF02537090","article-title":"Lipid peroxidation and antioxidant status is affected by different vitamin E levels when feeding fish oil","volume":"29","author":"Cho","year":"1994","journal-title":"Lipids"},{"key":"ref_27","unstructured":"Cook, J.D. (1980). Tissue iron stores. Methods in Hematology, Churchill Livingston Press."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/S0076-6879(94)33010-7","article-title":"Measurement of iron and copper in biological systems: Bleomycin and copper-phenanthroline assays","volume":"233","author":"Evans","year":"1994","journal-title":"Methods Enzym."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7","DOI":"10.5487\/TR.2014.30.1.007","article-title":"A rapid method for estimating the levels of urinary thiobarbituric acid reactive substances for environmental epidemiologic survey","volume":"30","author":"Kil","year":"2014","journal-title":"Toxicol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0076-6879(84)05016-3","article-title":"Catalase in vitro","volume":"105","author":"Aebi","year":"1984","journal-title":"Methods Enzym."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1024\/0300-9831.74.6.445","article-title":"Phytic acid degradation as a means of improving iron absorption","volume":"74","author":"Hurrell","year":"2004","journal-title":"Int. J. Vitam. Nutr. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1093\/ajcn\/56.3.573","article-title":"Soy protein, phytate, and iron absorption in humans","volume":"56","author":"Hurrell","year":"1992","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2013\/147307","article-title":"Phytic acid inhibits lipid peroxidation in vitro","volume":"2013","author":"Zajdel","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.biopha.2016.12.125","article-title":"Inositol hexa phosphoric acid (phytic acid), a nutraceuticals, attenuates iron-induced oxidative stress and alleviates liver injury in iron overloaded mice","volume":"87","author":"Bhowmik","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_35","first-page":"172494","article-title":"The potential benefits and adverse effects of phytic acid supplement in streptozotocin-induced diabetic rats","volume":"2013","author":"Omoruyi","year":"2013","journal-title":"Adv. Pharmacol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4061\/2011\/431068","article-title":"Phytic acid protects against 6-hydroxydopamine-induced dopaminergic neuron apoptosis in normal and iron excess conditions in a cell culture model","volume":"2011","author":"Xu","year":"2011","journal-title":"Parkinson\u2019s Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.tox.2007.12.017","article-title":"Neuroprotective effect of the natural iron chelator, phytic acid in a cell culture model of Parkinson\u2019s disease","volume":"245","author":"Xu","year":"2008","journal-title":"Toxicology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1007\/s11745-010-3408-1","article-title":"Atherogenic dyslipidemia: Cardiovascular risk and dietary intervention","volume":"45","author":"Musunuru","year":"2010","journal-title":"Lipids"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.freeradbiomed.2019.03.036","article-title":"An update on lipid oxidation and inflammation in cardiovascular diseases","volume":"144","author":"Zhong","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.joca.2015.09.007","article-title":"Iron overload in a murine model of hereditary hemochromatosis is associated with accelerated progression of osteoarthritis under mechanical stress","volume":"24","author":"Camacho","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5756","DOI":"10.1038\/s41598-017-05810-2","article-title":"Iron overload exacerbates age-associated cardiac hypertrophy in a mouse model of hemochromatosis","volume":"7","author":"Sukumaran","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0165-2478(94)90094-9","article-title":"Iron overload in Beta-2-microglobulin-deficient mice","volume":"39","author":"Reimao","year":"1994","journal-title":"Immunol. Let\u00cders"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/hep.1840110122","article-title":"The pathology of hepatic iron overload: A free radical mediated processes?","volume":"11","author":"Bacon","year":"1990","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1046\/j.1365-2362.2000.00628.x","article-title":"Non-transferrin-bound iron is present in serum of hereditary haemochromatosis heterozygotes","volume":"30","author":"Valk","year":"2000","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.freeradbiomed.2018.10.413","article-title":"Non-transferrin-bound iron transporters","volume":"133","author":"Knutson","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"G251","DOI":"10.1152\/ajpgi.00137.2014","article-title":"A high-fat diet modulates iron metabolism but does not promote liver fibrosis in hemochromatotic Hjv(-)\/(-) mice","volume":"308","author":"Padda","year":"2015","journal-title":"Am. J. Physiol. Gastrointest Liver Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1093\/jn\/132.8.2263","article-title":"High dietary iron concentrations enhance the formation of cholesterol oxidation products in the liver of adult rats fed salmon oil with minimal effects on antioxidant status","volume":"132","author":"Brandsch","year":"2002","journal-title":"J. Nutr."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Imam, M.U., Zhang, S., Ma, J., Wang, H., and Wang, F. (2017). Antioxidants mediate both iron homeostasis and oxidative stress. Nutrients, 9.","DOI":"10.3390\/nu9070671"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2917","DOI":"10.1002\/j.1460-2075.1995.tb07291.x","article-title":"Rapid responses to oxidative stress mediated by iron regulatory protein","volume":"14","author":"Pantopoulos","year":"1995","journal-title":"EMBO J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.1002\/j.1460-2075.1993.tb06039.x","article-title":"Translational regulation via iron-responsive elements by the nitric oxide\/NO-synthase pathway","volume":"12","author":"Weiss","year":"1993","journal-title":"EMBO J."},{"key":"ref_51","first-page":"18","article-title":"Lowering of serum cholesterol and triglycerides and modulation of divalent cations by dietary phytate","volume":"42","author":"Jariwalla","year":"1990","journal-title":"J. Appl. Nutr."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1093\/jn\/128.11.1950","article-title":"Phytic acid inhibits free radical formation in vitro but does not affect liver oxidant or antioxidant status in growing rats","volume":"128","author":"Rimbach","year":"1998","journal-title":"J. Nutr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3620","DOI":"10.1016\/S0021-9258(17)43139-5","article-title":"Iron-catalyzed hydroxyl radical formation. Stringent requirement for free iron coordination site","volume":"259","author":"Graf","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_54","first-page":"3699","article-title":"Inositol hexaphosphate (IP6) as an anti-neoplastic and lipid-lowering agent","volume":"19","author":"Jariwalla","year":"1999","journal-title":"Anticancer Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/22\/5331\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:33:44Z","timestamp":1760178824000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/22\/5331"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,15]]},"references-count":54,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["molecules25225331"],"URL":"https:\/\/doi.org\/10.3390\/molecules25225331","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,15]]}}}