{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:26:49Z","timestamp":1787635609141,"version":"build-2736575974"},"reference-count":59,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T00:00:00Z","timestamp":1633478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The vaso-occlusive crisis (VOC) is a major complication of sickle cell disease (SCD); thus, strategies to ameliorate vaso-occlusive episodes are greatly needed. We evaluated the therapeutic benefits of quercetin in a SCD transgenic sickle mouse model. This disease model exhibited very mild disease pathophysiology in the steady state. The severity of the disease in the NY1DD mouse was amplified by subjecting mice to 18 h of hypoxia followed by 3 h of reoxygenation. Quercetin (200 mg\/kg body weight) administered to hypoxia challenged NY1DD mice in a single intraperitoneal (i.p.) dose at the onset of reoxygenation completely ameliorated all hypoxia reoxygenation (H\/R)-induced pathophysiology. Additionally, it ameliorated the mild intrinsic steady state pathophysiology. These results are comparable with those seen with semisynthetic supra plasma expanders. In control mice, C57BL\/6J, hypoxia reoxygenation-induced vaso-occlusion was at significantly lower levels than in NY1DD mice, reflecting the role of sickle hemoglobin (HbS) in inducing vaso-occlusion; however, the therapeutic benefits from quercetin were significantly muted. We suggest that these findings represent a unique genotype of the NY1DD mice, i.e., the presence of high oxygen affinity red blood cells (RBCs) with chimeric HbS, composed of mouse \u03b1-chain and human \u03b2S-chain, as well as human \u03b1-chain and mouse \u03b2-chain (besides HbS). The anti-anemia therapeutic benefits from high oxygen affinity RBCs in these mice exert disease severity modifications that synergize with the therapeutic benefits of quercetin. Combining the therapeutic benefits of high oxygen affinity RBCs generated in situ by chemical or genetic manipulation with the therapeutic benefits of antiadhesive therapies is a novel approach to treat sickle cell patients with severe pathophysiology.<\/jats:p>","DOI":"10.3390\/biom11101473","type":"journal-article","created":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T10:36:57Z","timestamp":1633516617000},"page":"1473","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Quercetin Completely Ameliorates Hypoxia\u2013Reoxygenation-Induced Pathophysiology Severity in NY1DD Transgenic Sickle Mice: Intrinsic Mild Steady State Pathophysiology of the Disease in NY1DD Is Also Reversed"],"prefix":"10.3390","volume":"11","author":[{"given":"Sangeetha","family":"Thangaswamy","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig A.","family":"Branch","sequence":"additional","affiliation":[{"name":"Magnetic Resonance Research Center, Department of Radiology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4219-7852","authenticated-orcid":false,"given":"Kamalakar","family":"Ambadipudi","sequence":"additional","affiliation":[{"name":"Magnetic Resonance Research Center, Department of Radiology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seetharama A.","family":"Acharya","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1016\/j.clinbiochem.2009.06.024","article-title":"Hemoglobin disorders and endothelial cell interactions","volume":"42","author":"Conran","year":"2009","journal-title":"Clin. Biochem."},{"key":"ref_2","first-page":"542","article-title":"Abnormal vitamin E and glutathione peroxidase levels in sickle cell anemia: Evidence for increased susceptibility to lipid peroxidation in vivo","volume":"94","author":"Chiu","year":"1979","journal-title":"J. Lab. Clin. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1172\/JCI110724","article-title":"Spontaneous oxygen radical generation by sickle erythrocytes","volume":"70","author":"Hebbel","year":"1982","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1182\/blood.V63.2.362.362","article-title":"A novel phospholipid in irreversibly sickled cells: Evidence for in vivo peroxidative membrane damage in sickle cell disease","volume":"63","author":"Jain","year":"1984","journal-title":"Blood."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ajh.2830150102","article-title":"Impaired pentose phosphate shunt function in sickle cell disease: A potential mechanism for increased Heinz body formation and membrane lipid peroxidation","volume":"15","author":"Lachant","year":"1983","journal-title":"Am. J. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1172\/JCI111857","article-title":"Abnormal redox status of membrane-protein thiols in sickle erythrocytes","volume":"75","author":"Rank","year":"1985","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1042\/bj2370265","article-title":"Sickle cell membranes and oxidative damage","volume":"237","author":"Omorphos","year":"1986","journal-title":"J. Biochem."},{"key":"ref_8","first-page":"589","article-title":"Relationship of glutathione levels and Heinz body formation to irreversibly sickled cells in sickle cell anemia","volume":"103","author":"Wetterstroem","year":"1984","journal-title":"J. Lab. Clin. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Rifkind, J.M., Mohanty, J.G., and Nagababu, E. (2015). The pathophysiology of extracellular hemoglobin associated with enhanced oxidative reactions. Front Physiol., 5.","DOI":"10.3389\/fphys.2014.00500"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1365-2141.1980.tb01186.x","article-title":"Superoxide dismutase, glutathione peroxidase, catalase and lipid peroxidation of normal and sickled erythrocytes","volume":"44","author":"Das","year":"1980","journal-title":"Br. J. Haematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1089\/ars.2009.2822","article-title":"Heme degradation and vascular injury","volume":"12","author":"Belcher","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1172\/JCI9225","article-title":"Hypoxia\/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice","volume":"106","author":"Kaul","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1358\/dot.2020.56.4.3110575","article-title":"L-Glutamine in sickle cell disease","volume":"56","author":"Cox","year":"2020","journal-title":"Drugs of Today."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1093\/carcin\/bgr022","article-title":"Coffee phenolic phytochemicals suppress colon cancer metastasis by targeting MEK and TOPK","volume":"32","author":"Kang","year":"2011","journal-title":"Carcinogenesis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"81","DOI":"10.4103\/0973-7847.99898","article-title":"Neuroprotective potential of phytochemicals","volume":"6","author":"Kumar","year":"2012","journal-title":"Pharmacogn. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1021\/jf00052a008","article-title":"Principal Phenolic Phytochemicals in Selected California Wines and Their Antioxidant Activity in Inhibiting Oxidation of Human Low-Density Lipoproteins","volume":"43","author":"Frankel","year":"1995","journal-title":"J. Agric. Food. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/S0006-8993(03)03009-9","article-title":"Quercetin, a natural flavonoid, attenuates vacuolar formation in the optic tract in rat chronic cerebral hypoperfusion model","volume":"980","author":"Takizawa","year":"2003","journal-title":"Brain Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7514","DOI":"10.1021\/jf049243r","article-title":"Protective effects of quercetin and vitamin C against oxidative stress-induced neurodegeneration","volume":"15","author":"Heo","year":"2004","journal-title":"J. Agric. Food. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.atherosclerosis.2011.04.023","article-title":"Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models","volume":"218","author":"Kleemann","year":"2011","journal-title":"Atherosclerosis."},{"key":"ref_20","first-page":"448","article-title":"Protective effects of quercetin against phenylhydrazine-induced vascular dysfunction and oxidative stress in rats. Food. Chem","volume":"45","author":"Luangaram","year":"2007","journal-title":"Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12150","DOI":"10.1073\/pnas.89.24.12150","article-title":"High expression of human beta S- and alpha-globins in transgenic mice: Hemoglobin composition and hematological consequences","volume":"89","author":"Fabry","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16406","DOI":"10.1016\/S0021-9258(19)85435-2","article-title":"Molecular basis of the inhibition of beta s-chain-dependent polymerization by mouse alpha-chain. Semisynthesis of chimeras of human and mouse alpha-chains","volume":"22","author":"Roy","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"H293","DOI":"10.1152\/ajpheart.01150.2003","article-title":"Anti-inflammatory therapy ameliorates leukocyte adhesion and microvascular flow abnormalities in transgenic sickle mice","volume":"287","author":"Kaul","year":"2004","journal-title":"Am. J. Physiol. Heart. Circ. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/S0753-3322(03)00018-0","article-title":"t-BOOH-induced oxidative damage in sickle red blood cells and the role of flavonoids","volume":"57","author":"Cesquini","year":"2003","journal-title":"Biomed. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1182\/blood.V118.21.848.848","article-title":"Anti-Interleukin-1\u03b2 Antibody-Based Therapy Ameliorates Endothelial Activation and Inflammation in Sickle Mice","volume":"118","author":"Kaul","year":"2011","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/0026-2862(73)90054-X","article-title":"An open cremaster muscle preparation for the study of blood vessels by in vivo microscopy","volume":"5","author":"Baez","year":"1973","journal-title":"Microvas. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1172\/JCI118355","article-title":"In vivo demonstration of red cell-endothelial interaction, sickling and altered microvascular response to oxygen in the sickle transgenic mouse","volume":"96","author":"Kaul","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0026-2862(74)90002-8","article-title":"The correlation of photometric signals derived from in vivo red blood cell flow in microvessels","volume":"7","author":"Silva","year":"1974","journal-title":"Microvas. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1152\/jappl.1967.22.2.333","article-title":"Erythrocyte velocity measurement in microvessels by a two-slit photometric method","volume":"22","author":"Wayland","year":"1967","journal-title":"J. Appl. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0026-2862(74)90043-0","article-title":"On-line volume flow rate and velocity profile measurement for blood in microvessels","volume":"7","author":"Baker","year":"1974","journal-title":"Microvasc. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/0026-2862(80)90050-3","article-title":"In vivo measurements of \"apparent viscosity\" and microvessel hematocrit in the mesentery of the cat","volume":"19","author":"Lipowsky","year":"1980","journal-title":"Microvasc. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2326","DOI":"10.1182\/blood.V106.11.2326.2326","article-title":"Positively Charged Alpha-Chains Can Stimulate K-Cl Cotransport in Transgenic Mouse Red Cells","volume":"106","author":"Romero","year":"2005","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/j.1365-2141.2011.08977.x","article-title":"Mouse models for studying pain in sickle disease: Effects of strain, age, and acuteness","volume":"156","author":"Cain","year":"2012","journal-title":"Br. J. Haematol."},{"key":"ref_34","first-page":"956","article-title":"Chimeric hemoglobins\u2014hybrids of human and swine hemoglobin: Assembly and stability of interspecies hybrids Protein","volume":"5","author":"Rao","year":"1996","journal-title":"Science"},{"key":"ref_35","first-page":"315","article-title":"Disturbed blood flow structuring as critical factor of hemorheological disorders in microcirculation","volume":"19","author":"Mchedlishvili","year":"1998","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1038\/nm1202-799","article-title":"Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease","volume":"8","author":"Reiter","year":"2002","journal-title":"Nat. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.1073\/pnas.88.11.4651","article-title":"Nitric oxide:an endogenous modulator of leukocyte adhesion","volume":"11","author":"Kubes","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1016\/j.bbadis.2011.04.011","article-title":"CURAMA Study Group. Increased efflux of oxidized glutathione (GSSG) causes glutathione depletion and potentially diminishes antioxidant defense in sickle erythrocytes","volume":"1812","author":"Nur","year":"2011","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s11010-006-2494-0","article-title":"Synergistic interactions of ferulic acid with ascorbic acid: Its cardioprotective role during isoproterenol induced myocardial infarction in rats","volume":"283","author":"Yogeeta","year":"2006","journal-title":"Mol. Cell. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1182\/blood.V96.1.314","article-title":"Reperfusion injury pathophysiology in sickle transgenic mice","volume":"96","author":"Osarogiagbon","year":"2000","journal-title":"Blood"},{"key":"ref_41","first-page":"1771","article-title":"Protective Effect of Arginine on Oxidative Stress in Transgenic Sickle Mouse Models. Free Radic","volume":"41","author":"Dasgupta","year":"2006","journal-title":"Biol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"H271","DOI":"10.1152\/ajpheart.00078.2012","article-title":"Increased hemoglobin O2 affinity protects during acute hypoxia","volume":"303","author":"Ozlem","year":"2012","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.clnu.2020.04.036","article-title":"Modulation of Hb-O 2 affinity to improve hypoxemia in COVID-19 patients","volume":"40","author":"Simon","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1093\/ajcn\/62.6.1276","article-title":"Absorption of dietary Quercetin glycosides and Quercetin in healthy ileostomy volunteers","volume":"62","author":"Peter","year":"1995","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0921-8777(99)00074-9","article-title":"Effect of epigallocatechin gallate and Quercetin on oxidative damage to cellular DNA","volume":"459","author":"Johnson","year":"2000","journal-title":"Mutat. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1042\/bst0280022","article-title":"Cytotoxicity, genotoxicity, and oxidative reactions in cell-culture models: Modulatory effects of photochemicals","volume":"28","author":"Wods","year":"2000","journal-title":"Biochem. Soc. Trans."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1002\/jlb.63.6.732","article-title":"Differential regulation of endothelial cell adhesion molecule expression by nitric oxide donors and antioxidants","volume":"63","author":"Spiecker","year":"1998","journal-title":"J. Leukoc. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1159\/000054733","article-title":"Exogenous nitric oxide inhibits VCAM-1 expression in human peritoneal mesothelial cells. Role of cyclic GMP and NF-kappa B","volume":"90","author":"Lee","year":"2000","journal-title":"Nephron"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"H2715","DOI":"10.1152\/ajpheart.00986.2004","article-title":"Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice","volume":"288","author":"Belcher","year":"2005","journal-title":"Am. J. Physiol. Heart. Circ. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"481","DOI":"10.3324\/haematol.12734","article-title":"Adhesion Molecules and Hydroxyurea in the Pathophysiology of Sickle Cell Disease","volume":"93","author":"Clarissa","year":"2008","journal-title":"Haematologica"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1093\/jn\/138.9.1615","article-title":"Daily Quercetin Supplementation Dose-Dependently Increases Plasma Quercetin Concentrations in Healthy Humans","volume":"9","author":"Egert","year":"2008","journal-title":"J. Nutr."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/21691401.2018.1543194","article-title":"Semisynthetic supra plasma expanders: A new class of therapeutics to improve microcircualtion in sickle cell anaemia","volume":"47","author":"Meng","year":"2019","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1097\/SHK.0b013e31818bb98a","article-title":"Microcirculatory effects of changing blood hemoglobin oxygen affinity during hemorrhagic shock resuscitation in an experimental model","volume":"31","author":"Nivaldo","year":"2009","journal-title":"Shock"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Glaros, A.K., Razvi, R., Shah, N., and Zaidi, A.U. (2021). Voxelotor: Alteration of sickle cell disease pathophysiology by a first-in-class polymerization inhibitor. Ther. Adv. Hematol., 12.","DOI":"10.1177\/20406207211001136"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1002\/ajh.24975","article-title":"Sickle hemoglobin oxygen affinity-shifting strategies have unequal cerebrovascular risks","volume":"3","author":"Hebbel","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1182\/blood-2017-02-765891","article-title":"Treating sickle cell disease by targeting HbS polymerization","volume":"129","author":"Eaton","year":"2017","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1182\/blood-2011-03-325258","article-title":"Fetal hemoglobin in sickle cell anemia","volume":"1","author":"Akinsheye","year":"2011","journal-title":"Blood"},{"key":"ref_58","unstructured":"Kaufman, D.P., Khattar, J., and Lappin, S.L. (2021). Physiology, Fetal Hemoglobin, StatPearls Publishing."},{"key":"ref_59","first-page":"146","article-title":"Fetal Hemoglobin is Associated with Peripheral Oxygen Saturation in Sickle Cell Disease in Tanzania","volume":"23","author":"Nkya","year":"2017","journal-title":"Bio Medicine"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/10\/1473\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:09:49Z","timestamp":1760166589000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/10\/1473"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,6]]},"references-count":59,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["biom11101473"],"URL":"https:\/\/doi.org\/10.3390\/biom11101473","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,6]]}}}