{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T03:44:38Z","timestamp":1783655078776,"version":"3.55.0"},"reference-count":45,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,15]],"date-time":"2021-05-15T00:00:00Z","timestamp":1621036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK074867"],"award-info":[{"award-number":["DK074867"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK109717"],"award-info":[{"award-number":["DK109717"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000063","name":"Office of Dietary Supplements","doi-asserted-by":"publisher","award":["DK109717"],"award-info":[{"award-number":["DK109717"]}],"id":[{"id":"10.13039\/100000063","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and &gt;85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40\u201350%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH.<\/jats:p>","DOI":"10.3390\/nu13051686","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T02:31:34Z","timestamp":1621218694000},"page":"1686","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Oral Administration of Ginger-Derived Lipid Nanoparticles and Dmt1 siRNA Potentiates the Effect of Dietary Iron Restriction and Mitigates Pre-Existing Iron Overload in Hamp KO Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Xiaoyu","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China"},{"name":"Food Science &amp; Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4686-6526","authenticated-orcid":false,"given":"Mingzhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Georgia State University, Atlanta, GA 30303, USA"},{"name":"School of Basic Medical Science, Health Science Center, Institute of Medical Engineering, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina R.","family":"Woloshun","sequence":"additional","affiliation":[{"name":"Food Science &amp; Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7956-9245","authenticated-orcid":false,"given":"Yang","family":"Yu","sequence":"additional","affiliation":[{"name":"Food Science &amp; Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2282-2131","authenticated-orcid":false,"given":"Jennifer K.","family":"Lee","sequence":"additional","affiliation":[{"name":"Food Science &amp; Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shireen R. L.","family":"Flores","sequence":"additional","affiliation":[{"name":"Food Science &amp; Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Merlin","sequence":"additional","affiliation":[{"name":"Center for Diagnostics and Therapeutics, Institute for Biomedical Science, Georgia State University, Atlanta, GA 30303, USA"},{"name":"Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8765-0297","authenticated-orcid":false,"given":"James F.","family":"Collins","sequence":"additional","affiliation":[{"name":"Food Science &amp; Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"G397","DOI":"10.1152\/ajpgi.00348.2013","article-title":"Mechanistic and regulatory aspects of intestinal iron absorption","volume":"307","author":"Gulec","year":"2014","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1126\/science.1104742","article-title":"Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization","volume":"306","author":"Nemeth","year":"2004","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"18016","DOI":"10.1038\/nrdp.2018.16","article-title":"Haemochromatosis","volume":"4","author":"Brissot","year":"2018","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.jhep.2004.01.020","article-title":"Intestinal absorption of iron in HFE-1 hemochromatosis: Local or systemic process?","volume":"40","author":"Brissot","year":"2004","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.14309\/ajg.0000000000000315","article-title":"ACG Clinical guideline: Hereditary hemochromatosis","volume":"114","author":"Kowdley","year":"2019","journal-title":"Am. J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"468","DOI":"10.3945\/ajcn.112.048264","article-title":"Relevance of dietary iron intake and bioavailability in the management of HFE hemochromatosis: A systematic review","volume":"98","author":"Moretti","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1053\/gast.2001.24050","article-title":"Intestinal iron uptake determined by divalent metal transporter is enhanced in HFE-deficient mice with hemochromatosis","volume":"120","author":"Griffiths","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1073\/pnas.96.6.3143","article-title":"Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increased duodenal expression of the iron transporter DMT1","volume":"96","author":"Fleming","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1136\/gut.52.7.953","article-title":"Duodenal expression of iron transport molecules in untreated haemochromatosis subjects","volume":"52","author":"Stuart","year":"2003","journal-title":"Gut"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12345","DOI":"10.1073\/pnas.192423399","article-title":"Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function","volume":"99","author":"Hubert","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.ymthe.2019.01.003","article-title":"Oral gavage of ginger nanoparticle-derived lipid vectors carrying Dmt1 siRNA blunts iron loading in murine hereditary hemochromatosis","volume":"27","author":"Wang","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.2217\/nnm-2017-0196","article-title":"Oral administration of ginger-derived nanolipids loaded with siRNA as a novel approach for efficient siRNA drug delivery to treat ulcerative colitis","volume":"12","author":"Zhang","year":"2017","journal-title":"Nanomedicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e3685","DOI":"10.21769\/BioProtoc.3685","article-title":"Preparation and characterization of ginger lipid-derived nanoparticles for colon-targeted siRNA delivery","volume":"10","author":"Sung","year":"2020","journal-title":"Bio-Protocol"},{"key":"ref_14","first-page":"e3390","article-title":"Isolation, purification, and characterization of ginger-derived nanoparticles (GDNPs) from ginger, rhizome of zingiber officinale","volume":"9","author":"Sung","year":"2019","journal-title":"Bio-Protocol"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.cell.2005.06.025","article-title":"Identification of an intestinal heme transporter","volume":"122","author":"Shayeghi","year":"2005","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.cell.2006.09.041","article-title":"Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption","volume":"127","author":"Qiu","year":"2006","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3035","DOI":"10.2217\/nnm-2016-0353","article-title":"Do ginger-derived nanoparticles represent an attractive treatment strategy for inflammatory bowel diseases?","volume":"11","author":"Zhang","year":"2016","journal-title":"Nanomedicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1182\/bloodadvances.2017008359","article-title":"Intestinal hephaestin potentiates iron absorption in weanling, adult, and pregnant mice under physiological conditions","volume":"1","author":"Doguer","year":"2017","journal-title":"Blood Adv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"G535","DOI":"10.1152\/ajpgi.00169.2017","article-title":"Consumption of a high-iron diet disrupts homeostatic regulation of intestinal copper absorption in adolescent mice","volume":"313","author":"Ha","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gulec, S., and Collins, J.F. (2013). Investigation of iron metabolism in mice expressing a mutant Menke\u2019s copper transporting ATPase (Atp7a) protein with diminished activity (Brindled; Mo (Br) (\/y)). PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066010"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1172\/JCI105019","article-title":"Studies on iron absorption. Intestinal regulatory mechanisms","volume":"43","author":"Wheby","year":"1964","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"G877","DOI":"10.1152\/ajpgi.00261.2011","article-title":"Exploration of the copper-related compensatory response in the Belgrade rat model of genetic iron deficiency","volume":"301","author":"Jiang","year":"2011","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3945\/jn.113.183160","article-title":"Silencing the Menkes copper-transporting ATPase (Atp7a) gene in rat intestinal epithelial (IEC-6) cells increases iron flux via transcriptional induction of ferroportin 1 (Fpn1)","volume":"144","author":"Gulec","year":"2014","journal-title":"J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23943","DOI":"10.1074\/jbc.M113.489500","article-title":"Transcription factors Sp1 and Hif2alpha mediate induction of the copper-transporting ATPase (Atp7a) gene in intestinal epithelial cells during hypoxia","volume":"288","author":"Xie","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.biomaterials.2016.06.018","article-title":"Edible ginger-derived nanoparticles: A novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer","volume":"101","author":"Zhang","year":"2016","journal-title":"Biomaterials"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1038\/mt.2016.159","article-title":"Edible ginger-derived nano-lipids loaded with doxorubicin as a novel drug-delivery approach for colon cancer therapy","volume":"24","author":"Zhang","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/ng.2996","article-title":"Identification of erythroferrone as an erythroid regulator of iron metabolism","volume":"46","author":"Kautz","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cell.2012.01.021","article-title":"Hypoxia-inducible factors in physiology and medicine","volume":"148","author":"Semenza","year":"2012","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.cell.2009.01.035","article-title":"Origins and mechanisms of miRNAs and siRNAs","volume":"136","author":"Carthew","year":"2009","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"G635","DOI":"10.1152\/ajpgi.00160.2015","article-title":"Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese","volume":"309","author":"Shawki","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4406","DOI":"10.1182\/blood.V93.12.4406","article-title":"Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron","volume":"93","author":"Gruenheid","year":"1999","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1084\/jem.189.5.831","article-title":"The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes","volume":"189","author":"Gruenheid","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1073\/pnas.0409409102","article-title":"Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin","volume":"102","author":"Knutson","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1182\/blood-2006-02-003376","article-title":"Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis","volume":"108","author":"Viatte","year":"2006","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Mao, Q.Q., Xu, X.Y., Cao, S.Y., Gan, R.Y., Corke, H., Beta, T., and Li, H.B. (2019). Bioactive compounds and bioactivities of ginger (Zingiber officinale Roscoe). Foods, 8.","DOI":"10.3390\/foods8060185"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.bbagen.2010.03.011","article-title":"Serum ferritin: Past, present and future","volume":"1800","author":"Wang","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1017\/S0007114510005507","article-title":"Iron absorption in hepcidin1 knockout mice","volume":"105","author":"Masaratana","year":"2011","journal-title":"Br. J. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.bbagen.2011.07.014","article-title":"Non-transferrin bound iron: A key role in iron overload and iron toxicity","volume":"1820","author":"Brissot","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.bmcl.2011.11.069","article-title":"Synthesis and biological evaluation of substituted pyrazoles as blockers of divalent metal transporter 1 (DMT1)","volume":"22","author":"Cadieux","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.chembiol.2006.08.005","article-title":"Small-molecule screening identifies the selanazal drug ebselen as a potent inhibitor of DMT1-mediated iron uptake","volume":"13","author":"Wetli","year":"2006","journal-title":"Chem. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5108","DOI":"10.1016\/j.bmcl.2012.05.129","article-title":"Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors","volume":"22","author":"Zhang","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.bcp.2015.05.002","article-title":"Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1\/SLC11A2","volume":"96","author":"Montalbetti","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7369","DOI":"10.1002\/chem.202000159","article-title":"DMT1 inhibitors kill cancer stem cells by blocking lysosomal iron translocation","volume":"26","author":"Turcu","year":"2020","journal-title":"Chemistry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e51913","DOI":"10.7554\/eLife.51913","article-title":"Mechanistic basis of the inhibition of SLC11\/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds","volume":"8","author":"Manatschal","year":"2019","journal-title":"Elife"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Pulli, B., Ali, M., Forghani, R., Schob, S., Hsieh, K.L., Wojtkiewicz, G., Linnoila, J.J., and Chen, J.W. (2013). Measuring myeloperoxidase activity in biological samples. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0067976"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/5\/1686\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:01:54Z","timestamp":1760162514000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/5\/1686"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,15]]},"references-count":45,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["nu13051686"],"URL":"https:\/\/doi.org\/10.3390\/nu13051686","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,15]]}}}