{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T08:57:54Z","timestamp":1773824274069,"version":"3.50.1"},"reference-count":68,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T00:00:00Z","timestamp":1677024000000},"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>Acute altitude hypoxia represents the cause of multiple adverse consequences. Current treatments are limited by side effects. Recent studies have shown the protective effects of resveratrol (RSV), but the mechanism remains unknown. To address this, the effects of RSV on the structure and function of hemoglobin of adult (HbA) were preliminarily analyzed using surface plasmon resonance (SPR) and oxygen dissociation assays (ODA). Molecular docking was conducted to specifically analyze the binding regions between RSV and HbA. The thermal stability was characterized to further validate the authenticity and effect of binding. Changes in the oxygen supply efficiency of HbA and rat RBCs incubated with RSV were detected ex vivo. The effect of RSV on the anti-hypoxic capacity under acute hypoxic conditions in vivo was evaluated. We found that RSV binds to the heme region of HbA following a concentration gradient and affects the structural stability and rate of oxygen release of HbA. RSV enhances the oxygen supply efficiency of HbA and rat RBCs ex vivo. RSV prolongs the tolerance times of mice suffering from acute asphyxia. By enhancing the oxygen supply efficiency, it alleviates the detrimental effects of acute severe hypoxia. In conclusion, RSV binds to HbA and regulates its conformation, which enhances oxygen supply efficiency and improves adaption to acute severe hypoxia.<\/jats:p>","DOI":"10.3390\/molecules28052050","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T02:01:25Z","timestamp":1677117685000},"page":"2050","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Resveratrol, a New Allosteric Effector of Hemoglobin, Enhances Oxygen Supply Efficiency and Improves Adaption to Acute Severe Hypoxia"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6227-3555","authenticated-orcid":false,"given":"Zongtang","family":"Chu","sequence":"first","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Academy of Military Science of the Chinese People\u2019s Liberation Army, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8508-4984","authenticated-orcid":false,"given":"Weidan","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Academy of Military Science of the Chinese People\u2019s Liberation Army, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoxing","family":"You","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Academy of Military Science of the Chinese People\u2019s Liberation Army, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuzhi","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Academy of Military Science of the Chinese People\u2019s Liberation Army, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Qin","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Academy of Military Science of the Chinese People\u2019s Liberation Army, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peilin","family":"Shu","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Academy of Military Science of the Chinese People\u2019s Liberation Army, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujing","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Academy of Military Science of the Chinese People\u2019s Liberation Army, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Academy of Military Science of the Chinese People\u2019s Liberation Army, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Academy of Military Science of the Chinese People\u2019s Liberation Army, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2987-7781","authenticated-orcid":false,"given":"Hong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Academy of Military Science of the Chinese People\u2019s Liberation Army, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/cphy.c080113","article-title":"Oxygen transport by hemoglobin","volume":"2","author":"Mairbaurl","year":"2012","journal-title":"Compr. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/vox.12666","article-title":"Rejuvenation of allogenic red cells: Benefits and risks","volume":"113","author":"Aujla","year":"2018","journal-title":"Vox Sang."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lavrinenko, I.A., Vashanov, G.A., C\u00e1ceres, J.L.H., Buchelnikov, A.S., and Nechipurenko, Y.D. (2022). A New Model of Hemoglobin Oxygenation. Entropy, 24.","DOI":"10.3390\/e24091214"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1080\/17474086.2017.1313699","article-title":"Should modulation of p50 be a therapeutic target in the critically ill?","volume":"10","author":"Srinivasan","year":"2017","journal-title":"Expert Rev. Hematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"111949","DOI":"10.1016\/j.biopha.2021.111949","article-title":"Salidroside attenuates acute lung injury via inhibition of inflammatory cytokine production","volume":"142","author":"Song","year":"2021","journal-title":"Biomed Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1001\/archinte.165.3.296","article-title":"Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: A randomized, placebo-controlled trial","volume":"165","author":"Chow","year":"2005","journal-title":"Arch. Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"461","DOI":"10.7326\/0003-4819-116-6-461","article-title":"Acetazolamide in the treatment of acute mountain sickness: Clinical efficacy and effect on gas exchange","volume":"116","author":"Grissom","year":"1992","journal-title":"Ann. Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.wem.2019.04.006","article-title":"Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Acute Altitude Illness: 2019 Update","volume":"30","author":"Luks","year":"2019","journal-title":"Wilderness Environ. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1006\/mvre.1996.0043","article-title":"Low-affinity hemoglobin increases tissue PO2 and decreases arteriolar diameter and flow in the rat cremaster muscle","volume":"52","author":"Kunert","year":"1996","journal-title":"Microvasc. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7419","DOI":"10.4081\/hr.2018.7419","article-title":"GBT440 reverses sickling of sickled red blood cells under hypoxic conditions in vitro","volume":"10","author":"Dufu","year":"2018","journal-title":"Hematol. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"95","DOI":"10.3233\/CH-170340","article-title":"GBT440 improves red blood cell deformability and reduces viscosity of sickle cell blood under deoxygenated conditions","volume":"70","author":"Dufu","year":"2018","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"II351","DOI":"10.1161\/circ.100.suppl_2.Ii-351","article-title":"RSR13, a synthetic allosteric modifier of hemoglobin, improves myocardial recovery following hypothermic cardiopulmonary bypass","volume":"100","author":"Kilgore","year":"1999","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1200\/JCO.1999.17.8.2593","article-title":"Phase I trial to determine the safety, pharmacodynamics, and pharmacokinetics of RSR13, a novel radioenhancer, in newly diagnosed glioblastoma multiforme","volume":"17","author":"Kleinberg","year":"1999","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/978-1-4615-0075-9_30","article-title":"The effect of RSR13, a synthetic allosteric modifier of hemoglobin, on brain tissue pO2 (measured by EPR oximetry) following severe hemorrhagic shock in rats","volume":"530","author":"Miyake","year":"2003","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1097\/00005344-199803000-00005","article-title":"Right-shifting the oxyhemoglobin dissociation curve with RSR13: Effects on high-energy phosphates and myocardial recovery after low-flow ischemia","volume":"31","author":"Woods","year":"1998","journal-title":"J. Cardiovasc. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1182\/blood.2021012070","article-title":"Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin","volume":"138","author":"Henry","year":"2021","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1038\/sj.bjc.6603169","article-title":"Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases","volume":"94","author":"Stea","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"jeb243595","DOI":"10.1242\/jeb.243595","article-title":"Genetic variation in hemoglobin is associated with evolved changes in breathing in high-altitude deer mice","volume":"225","author":"Ivy","year":"2022","journal-title":"J. Exp. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/jms.3304","article-title":"Detection of efaproxiral (RSR13) and its metabolites in equine by liquid chromatography tandem mass spectrometry","volume":"49","author":"Yi","year":"2014","journal-title":"J. Mass Spectrom."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"101205","DOI":"10.1016\/j.fbio.2021.101205","article-title":"Current trends on resveratrol bioactivities to treat periodontitis","volume":"42","author":"Quispe","year":"2021","journal-title":"Food Biosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1111\/bph.13492","article-title":"Antioxidant effects of resveratrol in the cardiovascular system","volume":"174","author":"Xia","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.canlet.2021.05.001","article-title":"Resveratrol for cancer therapy: Challenges and future perspectives","volume":"515","author":"Ren","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e1900423","DOI":"10.1002\/pmic.201900423","article-title":"Quantitative Proteomics Reveals the Effects of Resveratrol on High-Altitude Polycythemia Treatment","volume":"20","author":"Deng","year":"2020","journal-title":"Proteomics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1515\/bc.2010.100","article-title":"Resveratrol treatment induces redox stress in red blood cells: A possible role of caspase 3 in metabolism and anion transport","volume":"391","author":"Galtieri","year":"2010","journal-title":"Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1039\/C4FO00407H","article-title":"Resveratrol prevents cigarette smoke-induced keratinocytes damage","volume":"5","author":"Sticozzi","year":"2014","journal-title":"Food Funct."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1515\/hsz-2013-0257","article-title":"Molecular interactions of hemoglobin with resveratrol: Potential protective antioxidant role and metabolic adaptations of the erythrocyte","volume":"395","author":"Tellone","year":"2014","journal-title":"Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1002\/mnfr.200500022","article-title":"Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications","volume":"49","author":"Villegas","year":"2005","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Cao, B., Qin, J., Pan, B., Qazi, I.H., Ye, J., Fang, Y., and Zhou, G. (2022). Oxidative Stress and Oocyte Cryopreservation: Recent Advances in Mitigation Strategies Involving Antioxidants. Cells, 11.","DOI":"10.3390\/cells11223573"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1007\/s10895-007-0220-2","article-title":"Transport of a cancer chemopreventive polyphenol, resveratrol: Interaction with serum albumin and hemoglobin","volume":"17","author":"Lu","year":"2007","journal-title":"J Fluoresc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6406","DOI":"10.1016\/j.bmc.2008.05.002","article-title":"Design, synthesis and spectroscopic studies of resveratrol aliphatic acid ligands of human serum albumin","volume":"16","author":"Jiang","year":"2008","journal-title":"Bioorgan. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1021\/acs.molpharmaceut.8b00108","article-title":"A Triazole Disulfide Compound Increases the Affinity of Hemoglobin for Oxygen and Reduces the Sickling of Human Sickle Cells","volume":"15","author":"Nakagawa","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"953","DOI":"10.2116\/analsci.33.953","article-title":"Development of Time-course Oxygen Binding Analysis for Hemoglobin-based Oxygen Carriers","volume":"33","author":"Okamoto","year":"2017","journal-title":"Anal. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.2147\/DDDT.S157570","article-title":"Development and validation of an oxygen dissociation assay, a screening platform for discovering, and characterizing hemoglobin-oxygen affinity modifiers","volume":"12","author":"Patel","year":"2018","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1515\/hsz-2022-0188","article-title":"Novel insights into heme binding to hemoglobin","volume":"403","author":"Hopp","year":"2022","journal-title":"Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1016\/j.jmb.2012.12.018","article-title":"Hemoglobin allostery: New views on old players","volume":"425","author":"Miele","year":"2013","journal-title":"J. Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.bpc.2017.04.005","article-title":"Bohr effect of native and chemically modified hemoglobins: Quantitative analyses based on the Wyman equation","volume":"226","author":"Okonjo","year":"2017","journal-title":"Biophys. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/S0360-3016(00)01532-7","article-title":"A phase I study of RSR13, a radiation-enhancing hemoglobin modifier: Tolerance of repeated intravenous doses and correlation of pharmacokinetics with pharmacodynamics","volume":"49","author":"Kavanagh","year":"2001","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1038\/s41467-021-24069-w","article-title":"Phase Ib dose-escalation study of the hypoxia-modifier Myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors","volume":"12","author":"Schneider","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"931","DOI":"10.3389\/fphys.2019.00931","article-title":"Antisickling Drugs Targeting betaCys93 Reduce Iron Oxidation and Oxidative Changes in Sickle Cell Hemoglobin","volume":"10","author":"Kassa","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Woyke, S., Mair, N., Ortner, A., Haller, T., Ronzani, M., Rugg, C., Str\u00f6hle, M., Wintersteiger, R., and Gatterer, H. (2021). Dose- and Sex-Dependent Changes in Hemoglobin Oxygen Affinity by the Micronutrient 5-Hydroxymethylfurfural and alpha-Ketoglutaric Acid. Nutrients, 13.","DOI":"10.3390\/nu13103448"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1113\/JP279161","article-title":"Influence of high affinity haemoglobin on the response to normoxic and hypoxic exercise","volume":"598","author":"Dominelli","year":"2020","journal-title":"J. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e2023936118","DOI":"10.1073\/pnas.2023936118","article-title":"Evolved increases in hemoglobin-oxygen affinity and the Bohr effect coincided with the aquatic specialization of penguins","volume":"118","author":"Signore","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"jeb185470","DOI":"10.1242\/jeb.185470","article-title":"Allosteric mechanisms underlying the adaptive increase in hemoglobin-oxygen affinity of the bar-headed goose","volume":"221","author":"Jendroszek","year":"2018","journal-title":"J. Exp. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"101037","DOI":"10.1016\/j.mam.2021.101037","article-title":"Hemoglobin allostery and pharmacology","volume":"84","author":"Bellelli","year":"2022","journal-title":"Mol. Asp. Med."},{"key":"ref_45","first-page":"240","article-title":"GBT1118, a voxelotor analog, protects red blood cells from damage during severe hypoxia","volume":"14","author":"Tarasev","year":"2022","journal-title":"Am. J. Transl. Res."},{"key":"ref_46","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":"Yalcin","year":"2012","journal-title":"Am. J. Physiol. -Heart Circ. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1080\/10245332.2017.1396046","article-title":"Investigation of the differences between the Tibetan and Han populations in the hemoglobin-oxygen affinity of red blood cells and in the adaptation to high-altitude environments","volume":"23","author":"Li","year":"2018","journal-title":"Hematology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.lfs.2018.11.053","article-title":"Polydatin attenuates spinal cord injury in rats by inhibiting oxidative stress and microglia apoptosis via Nrf2\/HO-1 pathway","volume":"217","author":"Lv","year":"2019","journal-title":"Life Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"109227","DOI":"10.1016\/j.biopha.2019.109227","article-title":"SIRT1 activation attenuates cardiac fibrosis by endothelial-to-mesenchymal transition","volume":"118","author":"Liu","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7296092","DOI":"10.1155\/2016\/7296092","article-title":"SIRT1\/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model","volume":"2016","author":"Xu","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_51","first-page":"27","article-title":"Antigenotoxic effects of resveratrol: Assessment of in vitro and in vivo response","volume":"31","author":"Abraham","year":"2016","journal-title":"Mutagenesis"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Murdoch, D.R. (1999). High Life: A History of High Altitude Physiology and Medicine, Oxford University Press.","DOI":"10.1136\/bmj.318.7198.1631"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/nyas.12719","article-title":"Early history of high-altitude physiology","volume":"1365","author":"West","year":"2016","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.revmed.2016.06.003","article-title":"High oxygen affinity hemoglobins","volume":"38","author":"Mangin","year":"2017","journal-title":"Rev. M\u00e9d. Interne"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1089\/ham.2006.1049","article-title":"Hemoglobin P50 during A Simulated Ascent of Mt. Everest, Operation Everest II","volume":"8","author":"Wagner","year":"2007","journal-title":"High Alt. Med. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"565","DOI":"10.2108\/zsj.23.565","article-title":"Influence of Allosteric Effectors and Temperature on Oxygen Binding Properties and the Bohr Effect of Bovine Hemoglobin","volume":"23","author":"Sasagawa","year":"2006","journal-title":"Zool. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"102520","DOI":"10.1016\/j.bcmd.2020.102520","article-title":"Modulation of red blood cell oxygen affinity with a novel allosteric modifier of hemoglobin is additive to the Bohr effect","volume":"87","author":"Evans","year":"2021","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1080\/21691401.2020.1770272","article-title":"The P50 value detected by the oxygenation-dissociation analyser and blood gas analyser","volume":"48","author":"Chu","year":"2020","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6130","DOI":"10.1093\/nar\/gkz312","article-title":"Zfp217 mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to promote adipogenic differentiation","volume":"47","author":"Song","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1097\/01.HS9.0000564348.52740.18","article-title":"Central physiologic mechanisms which augment oxygen release (bohr effect and 2,3-dpg binding) are preserved in the presence of voxelotor at the therapeutic target of 30% hb modification:ps1522","volume":"3","author":"Pochron","year":"2019","journal-title":"HemaSphere"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"30816","DOI":"10.1073\/pnas.2012745117","article-title":"Dissection of the general two-step di-C-glycosylation pathway for the biosynthesis of (iso)schaftosides in higher plants","volume":"117","author":"Wang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1021\/ci900508k","article-title":"LowModeMD\u2014Implicit low-mode velocity filtering applied to conformational search of macrocycles and protein loops","volume":"50","author":"Labute","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1006\/jmbi.1996.0124","article-title":"Crystal structure of T state haemoglobin with oxygen bound at all four haems","volume":"256","author":"Paoli","year":"1996","journal-title":"J. Mol. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1021\/ci100241y","article-title":"Analyzing the topology of active sites: On the prediction of pockets and subpockets","volume":"50","author":"Volkamer","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1002\/jcc.20933","article-title":"The generalized Born\/volume integral implicit solvent model: Estimation of the free energy of hydration using London dispersion instead of atomic surface area","volume":"29","author":"Labute","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e0110021","DOI":"10.1128\/mBio.01100-21","article-title":"Clinically Relevant Mutations of Mycobacterial GatCAB Inform Regulation of Translational Fidelity","volume":"12","author":"Li","year":"2021","journal-title":"mBio"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.chom.2020.04.023","article-title":"Identification of Human Single-Domain Antibodies against SARS-CoV-2","volume":"27","author":"Wu","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"34508","DOI":"10.1074\/jbc.M203135200","article-title":"Global Allostery Model of Hemoglobin","volume":"277","author":"Yonetani","year":"2002","journal-title":"J. Biol. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/5\/2050\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:39:20Z","timestamp":1760121560000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/5\/2050"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,22]]},"references-count":68,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["molecules28052050"],"URL":"https:\/\/doi.org\/10.3390\/molecules28052050","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,22]]}}}