{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:09:50Z","timestamp":1784819390447,"version":"3.55.0"},"reference-count":92,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Major Scientific Research Instrument Development Program","award":["82427808"],"award-info":[{"award-number":["82427808"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Ischemia\u2013reperfusion is a rapidly evolving cascade that involves a variety of metabolic shifts whose precise timing and sequential order are still poorly understood. Clarifying these dynamics is critical for understanding the core injury trajectory of stroke and for refining time-delimited therapeutic interventions. More broadly, continuous in situ monitoring of the middle-cerebral-artery occlusion process at the system level has not yet been achieved. Here, we report the first single-subject high-resolution spatiotemporal resolution metabolic maps of the ultra-early phase of ischemic stroke in a rodent model. Matrix-assisted laser desorption\/ionization mass spectrometry (MALDI-MS) imaging mapped a metabolic abnormality area in the ischemic hemisphere that propagates from the striatum to the cortex. Microdialysis probes were then stereotaxically implanted within this metabolic abnormality area, capturing 10,429 metabolites that resolved into 16 temporally distinct trajectories aligned with probe insertion, ischemic injury, and reperfusion injury. Analysis of specific metabolic pathways mainly revealed that the delayed clearance of metabolic waste (urea and tryptamine) during early reperfusion, the transient attenuation of the citrate-to-oxaloacetate buffering gradient within the TCA cycle, and the accumulation of extracellular branched-chain amino acids all play crucial roles in shaping the injury trajectory. Simultaneously, the depletion of cellular repair mechanisms (pyrimidine synthesis) in the early phase of reperfusion also warrants our attention. These findings provide novel insights into the molecular basis and mechanisms of ischemia\u2013reperfusion and offer a comprehensive resource for further investigation.<\/jats:p>","DOI":"10.3390\/biom15111558","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T09:02:03Z","timestamp":1762419723000},"page":"1558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["High-Resolution Spatiotemporal Mapping of Cerebral Metabolism During Middle-Cerebral-Artery Occlusion\/Reperfusion Progression: Preliminary Insights"],"prefix":"10.3390","volume":"15","author":[{"given":"Zhongcheng","family":"Yuan","sequence":"first","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minhao","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingze","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guancheng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyuan","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitong","family":"Ding","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoan","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5324-4082","authenticated-orcid":false,"given":"Ming","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1161\/STROKEAHA.122.040073","article-title":"Projected Global Trends in Ischemic Stroke Incidence, Deaths and Disa-bility-Adjusted Life Years from 2020 to 2030","volume":"54","author":"Pu","year":"2023","journal-title":"Stroke"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1016\/S0140-6736(20)31404-5","article-title":"Five Insights from the Global Burden of Disease Study 2019","volume":"396","author":"Murray","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41582-023-00921-z","article-title":"Addressing Disparities in the Global Epidemiology of Stroke","volume":"20","author":"Prust","year":"2024","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/ana.410370214","article-title":"Acute Human Stroke Studied by Whole Brain Echo Planar Diffusion-Weighted Magnetic Resonance Imaging","volume":"37","author":"Warach","year":"1995","journal-title":"Ann. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/j.1747-4949.2009.00256.x","article-title":"Systematic Review of Process Indicators: Including Early Rehabilitation In-terventions Used to Measure Quality of Acute Stroke Care","volume":"4","author":"Purvis","year":"2009","journal-title":"Int. J. Stroke: Off. J. Int. Stroke Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s11883-017-0686-6","article-title":"Early Rehabilitation after Stroke: A Narrative Review","volume":"19","author":"Coleman","year":"2017","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6808184","DOI":"10.1155\/mi\/6808184","article-title":"Temporal Effects of Disease Signature Genes and Core Mechanisms in the Hyperacute Phase of Acute Ischemic Stroke: A Bioinformatics Analysis and Experimental Validation","volume":"2025","author":"Ding","year":"2025","journal-title":"Mediat. Inflamm."},{"key":"ref_8","first-page":"3445","article-title":"Animal Models of Ischemic Stroke and Their Application in Clinical Research","volume":"9","author":"Fluri","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.neuropharm.2017.09.022","article-title":"Animal Models of Ischaemic Stroke and Characterisation of the Ischaemic Penumbra","volume":"134","author":"McCabe","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e14749","DOI":"10.1016\/j.heliyon.2023.e14749","article-title":"Intracranial Hemorrhage Management in the Multi-Omics Era","volume":"9","author":"Feng","year":"2023","journal-title":"Heliyon"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1517\/14728214.2013.790363","article-title":"Emerging Neuroprotective Drugs for the Treatment of Acute Ischaemic Stroke","volume":"18","author":"Schmidt","year":"2013","journal-title":"Expert Opin. Emerg. Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Huang, J., Chen, L., Yao, Z., Sun, X., Tong, X., and Dong, S. (2023). The Role of Mitochondrial Dynamics in Cerebral Ischemia-Reperfusion Injury. Biomed. Pharmacother., 162.","DOI":"10.1016\/j.biopha.2023.114671"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Shen, L., Gan, Q., Yang, Y., Reis, C., Zhang, Z., Xu, S., Zhang, T., and Sun, C. (2021). Mitophagy in Cerebral Ischemia and Ische-mia\/Reperfusion Injury. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.687246"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"104877","DOI":"10.1016\/j.phrs.2020.104877","article-title":"Therapeutic Targets of Oxidative\/Nitrosative Stress and Neuroinflammation in Ischemic Stroke: Applications for Natural Product Efficacy with Omics and Systemic Biology","volume":"158","author":"Chen","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/s41419-021-03725-5","article-title":"Mitochondrial Ferritin Attenuates Cerebral Ischaemia\/Reperfusion Injury by Inhibiting Ferroptosis","volume":"12","author":"Wang","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.neuron.2014.06.034","article-title":"DNA Damage and Its Links to Neurodegeneration","volume":"83","author":"Madabhushi","year":"2014","journal-title":"Neuron"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuron.2014.12.007","article-title":"The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson\u2019s Disease","volume":"85","author":"Pickrell","year":"2015","journal-title":"Neuron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2583","DOI":"10.1007\/s11064-015-1581-6","article-title":"The Glymphatic System: A Beginner\u2019s Guide","volume":"40","author":"Jessen","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/nrn3689","article-title":"Disturbance of Endoplasmic Reticulum Proteostasis in Neurodegenerative Diseases","volume":"15","author":"Hetz","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1038\/nm.3232","article-title":"The Role of Autophagy in Neurodegenerative Disease","volume":"19","author":"Ra","year":"2013","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1161\/STROKEAHA.123.042308","article-title":"Imaging Advances in Stroke: Use of Advanced Neurovascular Imaging or Disruptive Innovation with Artificial Intelligence?","volume":"54","author":"Liebeskind","year":"2023","journal-title":"Stroke"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eadt7705","DOI":"10.1126\/science.adt7705","article-title":"In Vivo Multiplex Imaging of Dynamic Neurochemical Networks with Designed Far-Red Dopamine Sensors","volume":"388","author":"Zheng","year":"2025","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/s41586-024-07684-7","article-title":"Glutamate Acts on Acid-Sensing Ion Channels to Worsen Ischaemic Brain Injury","volume":"631","author":"Lai","year":"2024","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Mottahedin, A., Prag, H.A., Dannhorn, A., Mair, R., Schmidt, C., Yang, M., Sorby-Adams, A., Lee, J.J., Burger, N., and Ku-laveerasingam, D. (2023). Targeting Succinate Metabolism to Decrease Brain Injury upon Mechanical Thrombectomy Treatment of Ischemic Stroke. Redox Biol., 59.","DOI":"10.1016\/j.redox.2023.102600"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3418","DOI":"10.3324\/haematol.2023.283288","article-title":"Metabolic Signatures of Cardiorenal Dysfunction in Plasma from Sickle Cell Patients as a Function of Therapeutic Transfusion and Hydroxyurea Treatment","volume":"108","author":"Nouraie","year":"2023","journal-title":"Haematologica"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"127211","DOI":"10.1016\/j.talanta.2024.127211","article-title":"Metabolomic Study for the Identification of Symptomatic Carotid Plaque Biomarkers","volume":"284","author":"Plana","year":"2025","journal-title":"Talanta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1186\/s12974-024-03218-0","article-title":"Comprehensive Analysis of the Cerebrospinal Fluid and Serum Metabolome in Neurological Diseases","volume":"21","author":"Otto","year":"2024","journal-title":"J. Neuroinflammation"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Naik, A., Adeleye, O., Koester, S.W., Winkler, E.A., Hartke, J.N., Karahalios, K., Mihaljevic, S., Rani, A., Raikwar, S., and Rulney, J.D. (2023). Cerebrospinal Fluid Biomarkers for Diagnosis and the Prognostication of Acute Ischemic Stroke: A Systematic Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310902"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/s41392-023-01552-y","article-title":"A Metabolome Atlas of Mouse Brain on the Global Metabolic Signature Dynamics Following Short-Term Fasting","volume":"8","author":"Shao","year":"2023","journal-title":"Signal Transduct. Targeted Ther."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Baranovicova, E., Kalenska, D., Kaplan, P., Kovalska, M., Tatarkova, Z., and Lehotsky, J. (2023). Blood and Brain Metabolites after Cerebral Ischemia. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242417302"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Li, K., Wang, S., Tang, W., Chen, Y., and Li, B. (2025). MALDI MSI-Based Spatial Amine Metabolomics Revealing the Protective Effect of Combination Therapy against Cerebral Ischemia\/Reperfusion-Induced Brain Injury in Rats. J. Pharm. Biomed. Anal., 257.","DOI":"10.1016\/j.jpba.2025.116715"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1007\/s11011-024-01451-3","article-title":"Untargeted Metabolomics Unveils Critical Metabolic Signatures in Novel Phenotypes of Acute Ischemic Stroke","volume":"40","author":"Jiang","year":"2025","journal-title":"Metab. Brain Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"125060","DOI":"10.1016\/j.talanta.2023.125060","article-title":"Illustrate the Distribution and Metabolic Regulatory Effects of Pterostilbene in Cerebral Ischemia-Reperfusion Rat Brain by Mass Spectrometry Imaging and Spatial Metabolomics","volume":"266","author":"Ban","year":"2024","journal-title":"Talanta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1161\/STROKEAHA.114.005604","article-title":"Biomarker Panels in Ischemic Stroke","volume":"46","author":"Jickling","year":"2015","journal-title":"Stroke"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Tian, F., Liu, R., Fan, C., Sun, Y., Huang, X., Nie, Z., Zhao, X., and Pu, X. (2020). Effects of Thymoquinone on Small-Molecule Metabolites in a Rat Model of Cerebral Ischemia Reperfusion Injury Assessed Using MALDI-MSI. Metabolites, 10.","DOI":"10.3390\/metabo10010027"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10114","DOI":"10.1021\/ac5034566","article-title":"1,5-Diaminonaphthalene Hydrochloride Assisted Laser Desorption\/Ionization Mass Spectrometry Imaging of Small Molecules in Tissues Following Focal Cerebral Ischemia","volume":"86","author":"Liu","year":"2014","journal-title":"Anal. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Liu, R.-Z., Fan, C.-X., Zhang, Z.-L., Zhao, X., Sun, Y., Liu, H.-H., Nie, Z.-X., and Pu, X.-P. (2017). Effects of Dl-3-n-Butylphthalide on Cerebral Ischemia Infarction in Rat Model by Mass Spectrometry Imaging. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18112451"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6415","DOI":"10.1007\/s12035-021-02535-2","article-title":"Application of Metabolomics to the Discovery of Biomarkers for Ischemic Stroke in the Murine Model: A Comparison with the Clinical Results","volume":"58","author":"Jia","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1007\/s11306-019-1615-1","article-title":"Metabolomics Facilitates the Discovery of Metabolic Biomarkers and Pathways for Ischemic Stroke: A Systematic Review","volume":"15","author":"Ke","year":"2019","journal-title":"Metabolomics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5544","DOI":"10.1038\/s41467-025-60501-1","article-title":"Unraveling the Regulatory Network of Barley Grain Metabolism through the Integrative Analysis of Multiomics and mQTL","volume":"16","author":"Song","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"131214","DOI":"10.1016\/j.jhazmat.2023.131214","article-title":"Integrated Transcriptomics and Metabolomics Reveal Key Metabolic Pathway Responses in Pistia Stratiotes Under Cd Stress","volume":"452","author":"Wei","year":"2023","journal-title":"J. Hazard. Mater."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6692","DOI":"10.1038\/s41467-025-62032-1","article-title":"A Longitudinal Cohort Study Uncovers Plasma Protein Biomarkers Predating Clinical Onset and Treatment Response of Rheumatoid Arthritis","volume":"16","author":"He","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"10901","DOI":"10.1007\/s12035-024-04189-2","article-title":"Of Potential Noncoding RNAs Related to Spinal Cord Injury Based on Competing Endogenous RNAs","volume":"61","author":"Huang","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"120685","DOI":"10.1016\/j.indcrop.2025.120685","article-title":"Multi-Omic Analysis Highlights New Candidate Genes Involved in Triterpenoid and Sesquiterpenoid Biosynthesis in Codonopsis Pilosula (Franch.)","volume":"226","author":"Li","year":"2025","journal-title":"Nannf. Ind. Crops Prod."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Gao, S., Shan, D., and Tang, Y. (2024). Identification Biomarkers in Disease Progression of Obstructive Sleep Apnea from Children Serum Based on WGCNA and Mfuzz. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1452507"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5117","DOI":"10.1007\/s12035-023-03399-4","article-title":"Neuroinflammatory Biomarkers in the Brain, Cerebrospinal Fluid, and Blood after Ischemic Stroke","volume":"60","author":"Gao","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1007\/s12035-014-8952-x","article-title":"Hemorrhagic Transformation after Tissue Plasminogen Activator Reperfusion Therapy for Ischemic Stroke: Mechanisms, Models, and Biomarkers","volume":"52","author":"Wang","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"33433","DOI":"10.1021\/acsomega.0c05388","article-title":"UPLC-Q-TOF\/MS-Based Serum Metabolomics Reveals the Anti-Ischemic Stroke Mechanism of Nuciferine in MCAO Rats","volume":"5","author":"Wu","year":"2020","journal-title":"ACS Omega"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s00221-021-06054-3","article-title":"Investigation of Brain Damage Mechanism in Middle Cerebral Artery Occlusion\/Reperfusion Rats Based on i-TRAQ Quantitative Proteomics","volume":"239","author":"Ma","year":"2021","journal-title":"Exp. Brain Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"eaax7171","DOI":"10.1126\/science.aax7171","article-title":"Cerebrospinal Fluid Influx Drives Acute Ischemic Tissue Swelling","volume":"367","author":"Mestre","year":"2020","journal-title":"Science"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Huang, D., Yang, Y., Song, W., Jiang, C., Zhang, Y., Zhang, A., Lin, Z., and Ke, X. (2023). Untargeted Metabonomic Analysis of a Cerebral Stroke Model in Rats: A Study Based on UPLC\u2013MS\/MS. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1084813"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Rashad, S., Saigusa, D., Yamazaki, T., Matsumoto, Y., Tomioka, Y., Saito, R., Uruno, A., Niizuma, K., Yamamoto, M., and Tominaga, T. (2020). Metabolic Basis of Neuronal Vulnerability to Ischemia; an in Vivo Untargeted Metabolomics Approach. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-63483-w"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"107211","DOI":"10.1016\/j.jstrokecerebrovasdis.2023.107211","article-title":"Difference in Acute and Chronic Stage Ischemic Stroke Metabolic Markers with Controls","volume":"32","author":"Sidorov","year":"2023","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_54","first-page":"159","article-title":"Pekmeability Changes in the Blood-Brain Barrier: Causes and Consequences. CRC Crit","volume":"3","author":"Pardridge","year":"1975","journal-title":"Rev. Toxicol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1007\/s40620-024-01929-4","article-title":"Uremic Toxins and the Brain in Chronic Kidney Disease","volume":"37","author":"Bossola","year":"2024","journal-title":"J. Nephrol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1007\/s11011-020-00547-w","article-title":"Toxicity of Ayahuasca after 28 Days Daily Exposure and Effects on Monoamines and Brain-Derived Neurotrophic Factor (BDNF) in Brain of Wistar Rats","volume":"35","author":"Alves","year":"2020","journal-title":"Metab. Brain Dis."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Khan, M., Ullah, A., Halim, S.A., Waqas, M., Mushtaque, A., Mulk, S., Khan, F., Gao, L., Khalid, A., and Nizamani, A. (2025). Exploring Tryptamine Derivatives as Potential Agents for Diabetes and Cancer Treatment: In-Vitro Kinetics, Molecular Docking, and Cell Toxicity Based Investigations. J. Biomol. Struct. Dyn., 1\u201324.","DOI":"10.1080\/07391102.2025.2513013"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s11910-018-0885-8","article-title":"Fluid Management in Acute Brain Injury","volume":"18","author":"Rossi","year":"2018","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"254","DOI":"10.20473\/fmi.v56i4.23406","article-title":"Monitoring Serum Creatinine, Blood Urea Nitrogen in Patients Brain Injury with Mannitol Therapy","volume":"56","author":"Sari","year":"2020","journal-title":"Folia Med. Indones."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/j.cmet.2019.03.014","article-title":"Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver","volume":"29","author":"Cappel","year":"2019","journal-title":"Cell Metab."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.phrs.2018.05.014","article-title":"Physiological and Pathological Roles of Branched-Chain Amino Acids in the Regulation of Protein and Energy Metabolism and Neurological Functions","volume":"133","author":"Shimomura","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12986-018-0271-1","article-title":"Branched-Chain Amino Acids in Health and Disease: Metabolism, Alterations in Blood Plasma, and as Supplements","volume":"15","year":"2018","journal-title":"Nutr. Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s11011-024-01511-8","article-title":"Glutamate\/GABA\/Glutamine Ratios in Intact and Ischemia Reperfusion Challenged Rat Brain Subregions, the Effect of Ischemic Preconditioning","volume":"40","author":"Baranovicova","year":"2025","journal-title":"Metab. Brain Dis."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Li, W., Liu, X., Li, H., Zeng, J., Chen, Y., and Xu, B. (2024). Metabolomic and Transcriptomic Insights into the Mechanisms of Renal Ische-mia-Reperfusion Injury Progression. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-81600-x"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/nrm2249","article-title":"AMP-Activated\/SNF1 Protein Kinases: Conserved Guardians of Cellular Energy","volume":"8","author":"Hardie","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s10565-022-09716-2","article-title":"Mitochondrial Quality Control in Cardiac Ischemia\/Reperfusion Injury: New Insights into Mechanisms and Implications","volume":"39","author":"Bai","year":"2023","journal-title":"Cell Biol. Toxicol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/j.healun.2022.05.013","article-title":"Cell Death and Ischemia-Reperfusion Injury in Lung Transplantation","volume":"41","author":"Capuzzimati","year":"2022","journal-title":"J. Heart Lung Transplant."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1002\/iub.1756","article-title":"The Glutathione Cycle: Glutathione Metabolism beyond the \u03b3-Glutamyl Cycle","volume":"70","author":"Bachhawat","year":"2018","journal-title":"IUBMB Life"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/S0891-5849(99)00176-8","article-title":"Biologic and Pharmacologic Regulation of Mammalian Glutathione Synthesis","volume":"27","author":"Griffith","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1515\/hsz-2022-0236","article-title":"NMDA Receptors\u2014Regulatory Function and Pathophysiological Significance for Pancreatic Beta Cells","volume":"404","author":"Hurtado","year":"2023","journal-title":"Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0163-7258(98)00042-4","article-title":"The Role of Excitotoxicity in Neurodegenerative Disease: Implications for Therapy","volume":"81","author":"Doble","year":"1999","journal-title":"Pharmacol. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1089\/ars.2017.7216","article-title":"NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism","volume":"28","author":"Xiao","year":"2018","journal-title":"An-tioxid. Redox Signal."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"L155","DOI":"10.1093\/eurheartj\/suaa157","article-title":"Time Is Brain: Timing of Revascularization of Brain Arteries in Stroke","volume":"22","author":"Risitano","year":"2020","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Piccardi, B., Biagini, S., Iovene, V., and Palumbo, V. (2019). Blood Biomarkers of Parenchymal Damage in Ischemic Stroke Patients Treated with Revascularization Therapies. Biomark. Insights, 14.","DOI":"10.1177\/1177271919888225"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1023\/A:1022482604276","article-title":"Blood-Brain Barrier Carrier-Mediated Transport and Brain Metabolism of Amino Acids","volume":"23","author":"Pardridge","year":"1998","journal-title":"Neurochem. Res."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Shebl, N., and Salama, M. (2024). From Metabolomics to Proteomics: Understanding the Role of Dopa Decarboxylase in Parkinson\u2019s Disease. Scientific Commentary on: \u201cComprehensive Proteomics of CSF, Plasma, and Urine Identify DDC and Other Biomarkers of Early Parkinson\u2019s Disease.\u201d. Acta Neuropathol., 147.","DOI":"10.1007\/s00401-024-02739-5"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Mohapatra, S.R., Sadik, A., Sharma, S., Poschet, G., Gegner, H.M., Lanz, T.V., Lucarelli, P., Klingm\u00fcller, U., Platten, M., and Heiland, I. (2021). Hypoxia Routes Tryptophan Homeostasis towards Increased Tryptamine Production. Front. Immunol.","DOI":"10.3389\/fimmu.2021.590532"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1021\/tx100045h","article-title":"De-velopment of a Selective Modulator of Aryl Hydrocarbon (Ah) Receptor Activity That Exhibits Anti-Inflammatory Properties","volume":"23","author":"Murray","year":"2010","journal-title":"Chem. Res. Toxicol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Bock, K.W. (2020). Aryl Hydrocarbon Receptor (AHR) Functions: Balancing Opposing Processes Including Inflammatory Reactions. Biochem. Pharmacol., 178.","DOI":"10.1016\/j.bcp.2020.114093"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Kumar, P., and Deb, P.K. (2020). Pharmacology of Melatonin and Its Receptors. Frontiers in Pharmacology of Neurotransmitters, Springer.","DOI":"10.1007\/978-981-15-3556-7"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Boutin, J.A., Kennaway, D.J., and Jockers, R. (2023). Melatonin: Facts, Extrapolations and Clinical Trials. Biomolecules, 13.","DOI":"10.3390\/biom13060943"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1089\/thy.2020.0649","article-title":"Brain Gene Expression in Systemic Hypothyroidism and Mouse Models of MCT8 Deficiency: The Mct8-Oatp1c1-Dio2 Triad. Thyroid: Off","volume":"31","author":"Morte","year":"2021","journal-title":"J. Am. Thyroid Assoc."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1089\/thy.2007.0250","article-title":"Thyroid Hormone Effects on Mitochondrial Energetics. Thyroid: Off","volume":"18","author":"Harper","year":"2008","journal-title":"J. Am. Thyroid Assoc."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1080\/15548627.2015.1061849","article-title":"Thyroid Hormone Induction of Mitochondrial Activity Is Coupled to Mitophagy via ROS-AMPK-ULK1 Signaling","volume":"11","author":"Sinha","year":"2015","journal-title":"Autophagy"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1097\/TP.0b013e31819e3cdc","article-title":"Uridine-5\u2032-Triphosphate Protects against Hepatic- Ischemic\/Reperfusion Injury in Mice","volume":"87","author":"Pappo","year":"2009","journal-title":"Transplantation"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"17935","DOI":"10.1074\/jbc.RA119.012056","article-title":"Exploitation of Dihydroorotate Dehydrogenase (DHODH) and P53 Activation as Therapeutic Targets: A Case Study in Polypharmacology","volume":"295","author":"Ladds","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1161\/STROKEAHA.119.027611","article-title":"Machine Learning Approach to Identify Stroke within 4.5 Hours","volume":"51","author":"Lee","year":"2020","journal-title":"Stroke"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Zhang, X., Wang, X., Wang, S., Zhang, Y., Wang, Z., Yang, Q., Wang, S., Cao, R., Yu, B., and Zheng, Y. (2023). Machine Learning Algorithms Assisted Identification of Post-Stroke Depression Associated Biological Features. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1146620"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Zhu, D., Li, T., Wang, X., Zhao, L., Yang, X., Dang, M., Li, Y., Wu, Y., and Lu, Z. (2022). Detection of Acute Ischemic Stroke and Backtracking Stroke Onset Time via Machine Learning Analysis of Metabolomics. Biomed. Pharmacother., 155.","DOI":"10.1016\/j.biopha.2022.113641"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2632","DOI":"10.1161\/STROKEAHA.117.017112","article-title":"Translational Stroke Research","volume":"48","author":"Bosetti","year":"2017","journal-title":"Stroke"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/s41392-022-01064-1","article-title":"Signaling Pathways Involved in Ischemic Stroke: Molecular Mechanisms and Therapeutic Interventions","volume":"7","author":"Qin","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1016\/j.cmet.2024.05.016","article-title":"Astrocytic LRP1 Enables Mitochondria Transfer to Neurons and Mitigates Brain Ischemic Stroke by Suppressing ARF1 Lactylation","volume":"36","author":"Zhou","year":"2024","journal-title":"Cell Metab."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1558\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T09:38:29Z","timestamp":1762421909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,6]]},"references-count":92,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["biom15111558"],"URL":"https:\/\/doi.org\/10.3390\/biom15111558","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,6]]}}}