{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T14:03:18Z","timestamp":1787320998737,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T00:00:00Z","timestamp":1723680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Talent project of Shanghai Tongren Hospital","award":["TR2023rc01"],"award-info":[{"award-number":["TR2023rc01"]}]},{"name":"The Talent project of Shanghai Tongren Hospital","award":["82101621"],"award-info":[{"award-number":["82101621"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["TR2023rc01"],"award-info":[{"award-number":["TR2023rc01"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82101621"],"award-info":[{"award-number":["82101621"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neonatal hypoxic-ischemic encephalopathy (HIE) is a critical condition characterized by significant brain damage due to insufficient blood flow and oxygen delivery at birth, leading to high rates of neonatal mortality and long-term neurological deficits worldwide. 2,3-Diphosphoglyceric acid (2,3-DPG), a small molecule metabolite prevalent in erythrocytes, plays an important role in regulating oxygen delivery, but its potential neuroprotective role in hypoxic-ischemic brain damage (HIBD) has yet to be fully elucidated. Our research reveals that the administration of 2,3-DPG effectively reduces neuron damage caused by hypoxia-ischemia (HI) both in vitro and in vivo. We observed a notable decrease in HI-induced neuronal cell apoptosis, attributed to the downregulation of Bax and cleaved-caspase 3, alongside an upregulation of Bcl-2 expression. Furthermore, 2,3-DPG significantly alleviates oxidative stress and mitochondrial damage induced by oxygen-glucose deprivation\/reperfusion (OGD\/R). The administration of 2,3-DPG in rats subjected to HIBD resulted in a marked reduction in brain edema and infarct volume, achieved through the suppression of neuronal apoptosis and neuroinflammation. Using RNA-seq analysis, we validated that 2,3-DPG offers protection against neuronal apoptosis under HI conditions by modulating the p38 MAPK pathway. These insights indicated that 2,3-DPG might act as a promising novel therapeutic candidate for HIE.<\/jats:p>","DOI":"10.3390\/ijms25168877","type":"journal-article","created":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T05:47:11Z","timestamp":1723700831000},"page":"8877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["2,3-Diphosphoglyceric Acid Alleviating Hypoxic-Ischemic Brain Damage through p38 MAPK Modulation"],"prefix":"10.3390","volume":"25","author":[{"given":"Jiawei","family":"Ni","sequence":"first","affiliation":[{"name":"Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haocong","family":"Chen","sequence":"additional","affiliation":[{"name":"Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meini","family":"Le","sequence":"additional","affiliation":[{"name":"Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4873-8832","authenticated-orcid":false,"given":"Xirong","family":"Guo","sequence":"additional","affiliation":[{"name":"Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1829-7618","authenticated-orcid":false,"given":"Xiaohua","family":"Dong","sequence":"additional","affiliation":[{"name":"Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1001\/jamapediatrics.2014.3269","article-title":"Hypoxic-ischemic encephalopathy: A review for the clinician","volume":"169","author":"Weiss","year":"2015","journal-title":"JAMA Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1056\/NEJMoa1112066","article-title":"Childhood outcomes after hypothermia for neonatal encephalopathy","volume":"366","author":"Shankaran","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s13760-020-01308-3","article-title":"Pathophysiology of hypoxic-ischemic encephalopathy: A review of the past and a view on the future","volume":"120","author":"Greco","year":"2020","journal-title":"Acta Neurol. Belg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1097\/01.JPN.0000346221.48202.7e","article-title":"The chilling details: Hypoxic-ischemic encephalopathy","volume":"23","author":"Verklan","year":"2009","journal-title":"J. Perinat. Neonatal Nurs."},{"key":"ref_5","first-page":"CD003311","article-title":"Cooling for newborns with hypoxic ischaemic encephalopathy","volume":"2013","author":"Jacobs","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1007\/s00431-021-04320-8","article-title":"New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy","volume":"181","author":"Victor","year":"2022","journal-title":"Eur. J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pneurobio.2018.05.004","article-title":"Neural stem cell therapies and hypoxic-ischemic brain injury","volume":"173","author":"Huang","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Serrenho, I., Rosado, M., Dinis, A., Cardoso, C.M., Graos, M., Manadas, B., and Baltazar, G. (2021). Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review of Preclinical Studies. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063142"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1002\/ana.22419","article-title":"Neuronal cell death in neonatal hypoxia-ischemia","volume":"69","author":"Northington","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ranjan, A.K., and Gulati, A. (2023). Advances in Therapies to Treat Neonatal Hypoxic-Ischemic Encephalopathy. J. Clin. Med., 12.","DOI":"10.3390\/jcm12206653"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"114449","DOI":"10.1016\/j.expneurol.2023.114449","article-title":"LINC00938 alleviates hypoxia ischemia encephalopathy induced neonatal brain injury by regulating oxidative stress and inhibiting JNK\/p38 MAPK signaling pathway","volume":"367","author":"Zhao","year":"2023","journal-title":"Exp. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"116941","DOI":"10.1016\/j.jep.2023.116941","article-title":"The neuroprotective mechanisms of naringenin: Inhibition of apoptosis through the PI3K\/AKT pathway after hypoxic-ischemic brain damage","volume":"318","author":"Li","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.freeradbiomed.2019.07.001","article-title":"Ghrelin attenuates oxidative stress and neuronal apoptosis via GHSR-1alpha\/AMPK\/Sirt1\/PGC-1alpha\/UCP2 pathway in a rat model of neonatal HIE","volume":"141","author":"Huang","year":"2019","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1021\/acs.jmedchem.0c01786","article-title":"FDA Approved Drugs from 2015-June 2020: A Perspective","volume":"64","author":"Bhutani","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1074\/jbc.R115.693903","article-title":"Immunometabolism: Cellular Metabolism Turns Immune Regulator","volume":"291","author":"Loftus","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/s41586-021-04082-1","article-title":"B cell-derived GABA elicits IL-10(+) macrophages to limit anti-tumour immunity","volume":"599","author":"Zhang","year":"2021","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41586-022-04884-x","article-title":"The gut metabolite indole-3 propionate promotes nerve regeneration and repair","volume":"607","author":"Serger","year":"2022","journal-title":"Nature"},{"key":"ref_18","first-page":"e22305","article-title":"The metabolomic profiling identifies N,N-dimethylglycine as a facilitator of dorsal root ganglia neuron axon regeneration after injury","volume":"36","author":"Zhang","year":"2022","journal-title":"FASEB J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1249\/00005768-198406000-00011","article-title":"Effects of phosphate loading on 2,3-diphosphoglycerate and maximal oxygen uptake","volume":"16","author":"Cade","year":"1984","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/nchembio.2453","article-title":"Bisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate","volume":"13","author":"Oslund","year":"2017","journal-title":"Nat. Chem. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1182\/blood.V76.5.1028.1028","article-title":"2,3-Diphosphoglycerate and intracellular pH as interdependent determinants of the physiologic solubility of deoxyhemoglobin S","volume":"76","author":"Poillon","year":"1990","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.resp.2007.03.011","article-title":"The role of hemoglobin oxygen affinity in oxygen transport at high altitude","volume":"158","author":"Winslow","year":"2007","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1007\/BF00315364","article-title":"Hemodynamic oxygen transport and 2,3-diphosphoglycerate changes after transfusion of patients in acute respiratory failure","volume":"12","author":"Kahn","year":"1986","journal-title":"Intensive Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1161\/CIRCULATIONAHA.116.021311","article-title":"Beneficial Role of Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia","volume":"134","author":"Liu","year":"2016","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00421-015-3228-3","article-title":"Simple accurate mathematical models of blood HbO2 and HbCO2 dissociation curves at varied physiological conditions: Evaluation and comparison with other models","volume":"116","author":"Dash","year":"2016","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ploszczyca, K., Czuba, M., Chalimoniuk, M., Gajda, R., and Baranowski, M. (2021). Red Blood Cell 2,3-Diphosphoglycerate Decreases in Response to a 30 km Time Trial Under Hypoxia in Cyclists. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.670977"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1142\/S0192415X23500520","article-title":"Metabolomics Analysis of Electroacupuncture Pretreatment Induced Neuroprotection on Mice with Ischemic Stroke","volume":"51","author":"Yang","year":"2023","journal-title":"Am. J. Chin. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s13105-018-0632-2","article-title":"NMR metabolomic study of blood plasma in ischemic and ischemically preconditioned rats: An increased level of ketone bodies and decreased content of glycolytic products 24 h after global cerebral ischemia","volume":"74","author":"Baranovicova","year":"2018","journal-title":"J. Physiol. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/S0006-8993(96)00984-5","article-title":"Fructose-1,6-bisphosphate after hypoxic ischemic injury is protective to the neonatal rat brain","volume":"741","author":"Sola","year":"1996","journal-title":"Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"176539","DOI":"10.1016\/j.ejphar.2024.176539","article-title":"Metabolomics analysis revealed the neuroprotective role of 2-phosphoglyceric acid in hypoxic-ischemic brain damage through GPX4\/ACSL4 axis regulation","volume":"971","author":"Chen","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1007\/BF00592506","article-title":"On the mechanisms of the hypoxia-induced increase of 2,3-diphosphoglycerate in erythrocytes. Studies on rat erythrocytes in vivo and on human erythrocytes in vitro","volume":"326","author":"Duhm","year":"1971","journal-title":"Pflug. Arch."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1196\/annals.1342.028","article-title":"31P NMR spectroscopy and polarographic combined study of erythrocytes treated with 5-fluorouracil: Cardiotoxicity-related changes in ATP, 2,3-BPG, and O2 metabolism","volume":"1048","author":"Spasojevic","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/0014-2999(95)00531-5","article-title":"Polyol pathway, 2,3-diphosphoglycerate in erythrocytes and diabetic neuropathy in rats","volume":"294","author":"Nakamura","year":"1995","journal-title":"Eur. J. Pharmacol."},{"key":"ref_34","first-page":"517","article-title":"Benefit of magnesium-25 carrying porphyrin-fullerene nanoparticles in experimental diabetic neuropathy","volume":"5","author":"Hosseini","year":"2010","journal-title":"Int. J. Nanomed."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.mehy.2014.10.016","article-title":"High affinity hemoglobin and Parkinson\u2019s disease","volume":"83","author":"Graham","year":"2014","journal-title":"Med. Hypotheses"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e22263","DOI":"10.1096\/fj.202101654RR","article-title":"Atorvastatin inhibits neuronal apoptosis via activating cAMP\/PKA\/p-CREB\/BDNF pathway in hypoxic-ischemic neonatal rats","volume":"36","author":"Yu","year":"2022","journal-title":"FASEB J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"110772","DOI":"10.1016\/j.brainresbull.2023.110772","article-title":"The effects of protein-rich extract from Rhizoma Gastrodiae against cerebral ischemia\/reperfusion injury via regulating MAPK and PI3K\/AKT signaling pathway","volume":"203","author":"Duan","year":"2023","journal-title":"Brain Res. Bull."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Yue, J., and Lopez, J.M. (2020). Understanding MAPK Signaling Pathways in Apoptosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072346"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5998","DOI":"10.1073\/pnas.0710980105","article-title":"Dephosphorylation of 2020, 23-bisphosphoglycerate by MIPP expands the regulatory capacity of the Rapoport-Luebering glycolytic shunt","volume":"105","author":"Cho","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","first-page":"227","article-title":"The phosphoglycerate mutases","volume":"62","author":"Watson","year":"1989","journal-title":"Adv. Enzym. Relat. Areas Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1038\/s41418-017-0034-y","article-title":"Phosphoglyceric acid mutase-1 contributes to oncogenic mTOR-mediated tumor growth and confers non-small cell lung cancer patients with poor prognosis","volume":"25","author":"Sun","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"104042","DOI":"10.1016\/j.isci.2022.104042","article-title":"VPS28 regulates brain vasculature by controlling neuronal VEGF trafficking through extracellular vesicle secretion","volume":"25","author":"Dong","year":"2022","journal-title":"iScience"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/ana.410090206","article-title":"The influence of immaturity on hypoxic-ischemic brain damage in the rat","volume":"9","author":"Rice","year":"1981","journal-title":"Ann. Neurol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/16\/8877\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:36:53Z","timestamp":1760110613000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/16\/8877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,15]]},"references-count":43,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["ijms25168877"],"URL":"https:\/\/doi.org\/10.3390\/ijms25168877","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,15]]}}}