Research on novel inflammatory biomarkers and cerebral edema after acute ischemic stroke_West China Medical Journal

Authors：

CHEN Yitang ^1,2 , LEI Kaixin ² ,  GUO Wen ¹

1. Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding?author：

GUO Wen, Email: guowen@wchscu.cn

Keywords：

Acute ischemic stroke; cerebral edema; inflammatory biomarkers; blood-brain barrier

DOI：

10.7507/1002-0179.202604105

Video：

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Abstract Full text Figures/Tables Video References Cited by

Malignant cerebral edema following cerebral infarction carries a high mortality rate, and its development involves two sequential phases: cytotoxic edema and vasogenic edema. According to the pathological timeline of post-ischemic brain edema, this review categorizes novel inflammatory biomarkers into five classes: upstream initiating signals, key molecules of the inflammasome and pyroptosis pathways, direct effectors of blood–brain barrier disruption and cerebral edema, brain tissue-specific structural injury markers, and novel acute-phase and immunoregulatory serum markers. The aim is to summarize the underlying molecular mechanisms and clinical relevance of these markers, thereby providing a reference for early intervention in post-infarction cerebral edema.

Citation： CHEN Yitang, LEI Kaixin, GUO Wen. Research on novel inflammatory biomarkers and cerebral edema after acute ischemic stroke. West China Medical Journal, 2026, 41(5): 839-844. doi: 10.7507/1002-0179.202604105 Copy

1.	Tsivgoulis G, Katsanos AH, Sandset EC, et al. Thrombolysis for acute ischaemic stroke: current status and future perspectives. Lancet Neurol, 2023, 22(5): 418-429.
2.	Zhang J, Luo Z, Zeng Y. Predictive modeling of early neurological deterioration in patients with acute ischemic stroke. World Neurosurg, 2024, 191: 58-67.
3.	Cao Y, Chen Y, Zhang X, et al. Analysis of prognostic risk factors for ischemic stroke in China: a multicentre retrospective clinical study; a national survey in China. Curr Neurovasc Res, 2022, 19(1): 117-126.
4.	Ng FC, Yassi N, Sharma G, et al. Cerebral edema in patients with large hemispheric infarct undergoing reperfusion treatment: a HERMES meta-analysis. Stroke, 2021, 52(11): 3450-3458.
5.	Liotta EM. Management of cerebral edema, brain compression, and intracranial pressure. Continuum (Minneap Minn), 2021, 27(5): 1172-1200.
6.	Qiu YM, Zhang CL, Chen AQ, et al. Immune cells in the BBB disruption after acute ischemic stroke: targets for immune therapy?. Front Immunol, 2021, 12: 678744.
7.	Chen S, Shao L, Ma L. Cerebral edema formation after stroke: emphasis on blood-brain barrier and the lymphatic drainage system of the brain. Front Cell Neurosci, 2021, 15: 716825.
8.	Li J, Wang Z, Li J, et al. HMGB1: a new target for ischemic stroke and hemorrhagic transformation. Transl Stroke Res, 2025, 16(3): 990-1015.
9.	Zolondick AA, Gaudino G, Xue J, et al. Asbestos-induced chronic inflammation in malignant pleural mesothelioma and related therapeutic approaches-a narrative review. Precis Cancer Med, 2021, 4: 27.
10.	Zhang J, Takahashi HK, Liu K, et al. Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats. Stroke, 2011, 42(5):1420-1428.
11.	Jin L, Zhu Z, Hong L, et al. ROS-responsive 18β-glycyrrhetic acid-conjugated polymeric nanoparticles mediate neuroprotection in ischemic stroke through HMGB1 inhibition and microglia polarization regulation. Bioact Mater, 2022, 19: 38-49.
12.	Hu JX, Ma WJ, He LY, et al. Macrophage migration inhibitory factor (MIF) acetylation protects neurons from ischemic injury. Cell Death Dis, 2022, 13(5): 466.
13.	Zhao L, Zhao BH, Ruze A, et al. Distinct roles of MIF in the pathogenesis of ischemic heart disease. Cytokine Growth Factor Rev, 2024, 80: 121-137.
14.	Wang L, Zis O, Ma G, et al. Upregulation of macrophage migration inhibitory factor gene expression in stroke. Stroke, 2009, 40(3): 973-976.
15.	Sung W, Kim YS, Lee KY, et al. Aspirin modulates inflammatory biomarkers in patients with subcortical silent brain infarcts. Front Aging Neurosci, 2025, 16: 1507683.
16.	Liu YC, Tsai YH, Tang SC, et al. Cytokine MIF enhances blood-brain barrier permeability: impact for therapy in ischemic stroke. Sci Rep, 2018, 8(1): 743.
17.	Guo W, Xu M, Song X, et al. Association of serum macrophage migration inhibitory factor with 3-month poor outcome and malignant cerebral edema in patients with large hemispheric infarction. Neurocrit Care, 2024, 41(2): 558-567.
18.	Tajalli-Nezhad S, Mohammadi S, Atlasi MA, et al. Calcitriol modulate post-ischemic TLR signaling pathway in ischemic stroke patients. J Neuroimmunol, 2023, 375: 578013.
19.	Pascual M, Calvo-Rodriguez M, Nú?ez L, et al. Toll-like receptors in neuroinflammation, neurodegeneration, and alcohol-induced brain damage. IUBMB Life, 2021, 73(7): 900-915.
20.	Abdul Y, Abdelsaid M, Li W, et al. Inhibition of Toll-like receptor-4 (TLR-4) improves neurobehavioral outcomes after acute ischemic stroke in diabetic rats: possible role of vascular endothelial TLR-4. Mol Neurobiol, 2019, 56(3): 1607-1617.
21.	Han PP, Han Y, Shen XY, et al. NLRP3 inflammasome activation after ischemic stroke. Behav Brain Res, 2023, 452: 114578.
22.	Li H, Guan Y, Liang B, et al. Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome. Eur J Pharmacol, 2022, 928: 175091.
23.	Masenga SK, Kirabo A. The NLRP3 inflammasome in ischemic stroke. Front Stroke, 2024, 3: 1382379.
24.	Wang H, Zhong D, Chen H, et al. NLRP3 inflammasome activates interleukin-23/interleukin-17 axis during ischaemia-reperfusion injury in cerebral ischaemia in mice. Life Sci, 2019, 227: 101-113.
25.	Wang H, Chen H, Jin J, et al. Inhibition of the NLRP3 inflammasome reduces brain edema and regulates the distribution of aquaporin-4 after cerebral ischaemia-reperfusion. Life Sci, 2020, 251: 117638.
26.	Wang Y, Huang H, He W, et al. Association between serum NLRP3 and malignant brain edema in patients with acute ischemic stroke. BMC Neurol, 2021, 21(1): 341.
27.	Sayed A, Munir M, Nabet MS, et al. Galectin-3: a novel marker for the prediction of stroke incidence and clinical prognosis. Mediators Inflamm, 2022, 2022: 2924773.
28.	Luo Y, Cheng J, Fu Y, et al. D-allose Inhibits TLR4/PI3K/AKT signaling to attenuate neuroinflammation and neuronal apoptosis by inhibiting Gal-3 following ischemic stroke. Biol Proced Online, 2023, 25(1): 30.
29.	Cui Y, Zhang NN, Wang D, et al. Modified citrus pectin alleviates cerebral ischemia/reperfusion injury by inhibiting NLRP3 inflammasome activation via TLR4/NF-κB signaling pathway in Microglia. J Inflamm Res, 2022, 15: 3369-3385.
30.	Emmerich J, Chanpura A, Lu T, et al. Blood-based MMP-9 for the early differentiation of acute ischemic stroke: a systematic review and meta-analysis. J Stroke Cerebrovasc Dis, 2025, 34(11): 108454.
31.	Krishnamoorthy S, Singh G, Jose KJ, et al. Biomarkers in the prediction of hemorrhagic transformation in acute stroke: a systematic review and meta-analysis. Cerebrovasc Dis, 2022, 51(2): 235-247.
32.	Serena J, Blanco M, Castellanos M, et al. The prediction of malignant cerebral infarction by molecular brain barrier disruption markers. Stroke, 2005, 36(9): 1921-1926.
33.	Rodríguez JA, Sobrino T, Orbe J, et al. proMetalloproteinase-10 is associated with brain damage and clinical outcome in acute ischemic stroke. J Thromb Haemost, 2013, 11(8): 1464-1473.
34.	Millán M, Sobrino T, Arenillas JF, et al. Biological signatures of brain damage associated with high serum ferritin levels in patients with acute ischemic stroke and thrombolytic treatment. Dis Markers, 2008, 25(3): 181-188.
35.	Moldes O, Sobrino T, Millán M, et al. High serum levels of endothelin-1 predict severe cerebral edema in patients with acute ischemic stroke treated with t-PA. Stroke, 2008, 39(7): 2006-2010.
36.	Zhang H, Wang J, Zhang S, et al. Aquaporin 4 and its isoforms regulation ameliorate AQP4 Mis-localization-induced glymphatic dysfunction in ischemic stroke. J Adv Res, 2026, 80: 835-849.
37.	He Y, Yang Q, Liu H, et al. Effect of blood pressure on early neurological deterioration of acute ischemic stroke patients with intravenous rt-PA thrombolysis may be mediated through oxidative stress induced blood-brain barrier disruption and AQP4 upregulation. J Stroke Cerebrovasc Dis, 2020, 29(8): 104997.
38.	Ramiro L, Simats A, Penalba A, et al. Circulating aquaporin-4 as a biomarker of early neurological improvement in stroke patients: a pilot study. Neurosci Lett, 2020, 714: 134580.
39.	Hawash AMA, Zaytoun TM, Helmy TA, et al. S100B and brain ultrasound: novel predictors for functional outcome in acute ischemic stroke patients. Clin Neurol Neurosurg, 2023, 233: 107907.
40.	Khandare P, Saluja A, Solanki RS, et al. Serum S100B and NSE levels correlate with infarct size and bladder-bowel involvement among acute ischemic stroke patients. J Neurosci Rural Pract, 2022, 13(2): 218-225.
41.	Wunderlich MT, Wallesch CW, Goertler M. Release of neurobiochemical markers of brain damage is related to the neurovascular status on admission and the site of arterial occlusion in acute ischemic stroke. J Neurol Sci, 2004, 227(1): 49-53.
42.	Tanaka Y, Koizumi C, Marumo T, et al. Serum S100B indicates brain edema formation and predicts long-term neurological outcomes in rat transient middle cerebral artery occlusion model. Brain Res, 2007, 1137(1): 140-145.
43.	Forró T, Manu DR, B?jenaru OL, et al. GFAP as astrocyte-derived extracellular vesicle cargo in acute ischemic stroke patients-a pilot study. Int J Mol Sci, 2024, 25(11): 5726.
44.	Abdelhak A, Foschi M, Abu-Rumeileh S, et al. Blood GFAP as an emerging biomarker in brain and spinal cord disorders. Nat Rev Neurol, 2022, 18(3): 158-172.
45.	Korley FK, Jain S, Sun X, et al. Prognostic value of day-of-injury plasma GFAP and UCH-L1 concentrations for predicting functional recovery after traumatic brain injury in patients from the US TRACK-TBI cohort: an observational cohort study. Lancet Neurol, 2022, 21(9): 803-813.
46.	Lei J, Gao G, Feng J, et al. Glial fibrillary acidic protein as a biomarker in severe traumatic brain injury patients: a prospective cohort study. Crit Care, 2015, 19: 362.
47.	Peng H, Zhang L, Tang Y, et al. Exploring PTX3: a promising diagnostic marker and therapeutic target in neurology. Gene, 2025, 969: 149724.
48.	Matsubara J, Sugiyama S, Nozaki T, et al. Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction. J Am Coll Cardiol, 2011, 57(7): 861-869.
49.	Zhang A, Zhang Z, Liu R, et al. Human umbilical cord mesenchymal stem cell-derived exosomes inhibit inflammation and fibrotic scar formation after intracerebral hemorrhage. Mol Cell Biochem, 2025, 480(8): 4829-4847.
50.	Rodriguez-Grande B, Swana M, Nguyen L, et al. The acute-phase protein PTX3 is an essential mediator of glial scar formation and resolution of brain edema after ischemic injury. J Cereb Blood Flow Metab, 2014, 34(3): 480-488.
51.	Tu Y, Wang M, Wu S, et al. sST2 as a Promising cardiac biomarker after ischemic stroke with elevated systolic blood pressure. JACC Asia, 2025, 5(12): 1631-1633.
52.	Ahmadzadeh K, Dizaji SR, Balabandian M, et al. Soluble suppression of tumorigenicity-2 as a candidate prognostic marker for stroke: a systematic review. Ann Lab Med, 2023, 43(6): 585-595.
53.	Bevers MB, An J, Yoo A, et al. Brain Endothelial soluble ST2 production and cerebral edema in a rat model of ischemic stroke. Ann Neurol, 2026, 99(1): 134-147.

1. Tsivgoulis G, Katsanos AH, Sandset EC, et al. Thrombolysis for acute ischaemic stroke: current status and future perspectives. Lancet Neurol, 2023, 22(5): 418-429.
2. Zhang J, Luo Z, Zeng Y. Predictive modeling of early neurological deterioration in patients with acute ischemic stroke. World Neurosurg, 2024, 191: 58-67.
3. Cao Y, Chen Y, Zhang X, et al. Analysis of prognostic risk factors for ischemic stroke in China: a multicentre retrospective clinical study; a national survey in China. Curr Neurovasc Res, 2022, 19(1): 117-126.
4. Ng FC, Yassi N, Sharma G, et al. Cerebral edema in patients with large hemispheric infarct undergoing reperfusion treatment: a HERMES meta-analysis. Stroke, 2021, 52(11): 3450-3458.
5. Liotta EM. Management of cerebral edema, brain compression, and intracranial pressure. Continuum (Minneap Minn), 2021, 27(5): 1172-1200.
6. Qiu YM, Zhang CL, Chen AQ, et al. Immune cells in the BBB disruption after acute ischemic stroke: targets for immune therapy?. Front Immunol, 2021, 12: 678744.
7. Chen S, Shao L, Ma L. Cerebral edema formation after stroke: emphasis on blood-brain barrier and the lymphatic drainage system of the brain. Front Cell Neurosci, 2021, 15: 716825.
8. Li J, Wang Z, Li J, et al. HMGB1: a new target for ischemic stroke and hemorrhagic transformation. Transl Stroke Res, 2025, 16(3): 990-1015.
9. Zolondick AA, Gaudino G, Xue J, et al. Asbestos-induced chronic inflammation in malignant pleural mesothelioma and related therapeutic approaches-a narrative review. Precis Cancer Med, 2021, 4: 27.
10. Zhang J, Takahashi HK, Liu K, et al. Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats. Stroke, 2011, 42(5):1420-1428.
11. Jin L, Zhu Z, Hong L, et al. ROS-responsive 18β-glycyrrhetic acid-conjugated polymeric nanoparticles mediate neuroprotection in ischemic stroke through HMGB1 inhibition and microglia polarization regulation. Bioact Mater, 2022, 19: 38-49.
12. Hu JX, Ma WJ, He LY, et al. Macrophage migration inhibitory factor (MIF) acetylation protects neurons from ischemic injury. Cell Death Dis, 2022, 13(5): 466.
13. Zhao L, Zhao BH, Ruze A, et al. Distinct roles of MIF in the pathogenesis of ischemic heart disease. Cytokine Growth Factor Rev, 2024, 80: 121-137.
14. Wang L, Zis O, Ma G, et al. Upregulation of macrophage migration inhibitory factor gene expression in stroke. Stroke, 2009, 40(3): 973-976.
15. Sung W, Kim YS, Lee KY, et al. Aspirin modulates inflammatory biomarkers in patients with subcortical silent brain infarcts. Front Aging Neurosci, 2025, 16: 1507683.
16. Liu YC, Tsai YH, Tang SC, et al. Cytokine MIF enhances blood-brain barrier permeability: impact for therapy in ischemic stroke. Sci Rep, 2018, 8(1): 743.
17. Guo W, Xu M, Song X, et al. Association of serum macrophage migration inhibitory factor with 3-month poor outcome and malignant cerebral edema in patients with large hemispheric infarction. Neurocrit Care, 2024, 41(2): 558-567.
18. Tajalli-Nezhad S, Mohammadi S, Atlasi MA, et al. Calcitriol modulate post-ischemic TLR signaling pathway in ischemic stroke patients. J Neuroimmunol, 2023, 375: 578013.
19. Pascual M, Calvo-Rodriguez M, Nú?ez L, et al. Toll-like receptors in neuroinflammation, neurodegeneration, and alcohol-induced brain damage. IUBMB Life, 2021, 73(7): 900-915.
20. Abdul Y, Abdelsaid M, Li W, et al. Inhibition of Toll-like receptor-4 (TLR-4) improves neurobehavioral outcomes after acute ischemic stroke in diabetic rats: possible role of vascular endothelial TLR-4. Mol Neurobiol, 2019, 56(3): 1607-1617.
21. Han PP, Han Y, Shen XY, et al. NLRP3 inflammasome activation after ischemic stroke. Behav Brain Res, 2023, 452: 114578.
22. Li H, Guan Y, Liang B, et al. Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome. Eur J Pharmacol, 2022, 928: 175091.
23. Masenga SK, Kirabo A. The NLRP3 inflammasome in ischemic stroke. Front Stroke, 2024, 3: 1382379.
24. Wang H, Zhong D, Chen H, et al. NLRP3 inflammasome activates interleukin-23/interleukin-17 axis during ischaemia-reperfusion injury in cerebral ischaemia in mice. Life Sci, 2019, 227: 101-113.
25. Wang H, Chen H, Jin J, et al. Inhibition of the NLRP3 inflammasome reduces brain edema and regulates the distribution of aquaporin-4 after cerebral ischaemia-reperfusion. Life Sci, 2020, 251: 117638.
26. Wang Y, Huang H, He W, et al. Association between serum NLRP3 and malignant brain edema in patients with acute ischemic stroke. BMC Neurol, 2021, 21(1): 341.
27. Sayed A, Munir M, Nabet MS, et al. Galectin-3: a novel marker for the prediction of stroke incidence and clinical prognosis. Mediators Inflamm, 2022, 2022: 2924773.
28. Luo Y, Cheng J, Fu Y, et al. D-allose Inhibits TLR4/PI3K/AKT signaling to attenuate neuroinflammation and neuronal apoptosis by inhibiting Gal-3 following ischemic stroke. Biol Proced Online, 2023, 25(1): 30.
29. Cui Y, Zhang NN, Wang D, et al. Modified citrus pectin alleviates cerebral ischemia/reperfusion injury by inhibiting NLRP3 inflammasome activation via TLR4/NF-κB signaling pathway in Microglia. J Inflamm Res, 2022, 15: 3369-3385.
30. Emmerich J, Chanpura A, Lu T, et al. Blood-based MMP-9 for the early differentiation of acute ischemic stroke: a systematic review and meta-analysis. J Stroke Cerebrovasc Dis, 2025, 34(11): 108454.
31. Krishnamoorthy S, Singh G, Jose KJ, et al. Biomarkers in the prediction of hemorrhagic transformation in acute stroke: a systematic review and meta-analysis. Cerebrovasc Dis, 2022, 51(2): 235-247.
32. Serena J, Blanco M, Castellanos M, et al. The prediction of malignant cerebral infarction by molecular brain barrier disruption markers. Stroke, 2005, 36(9): 1921-1926.
33. Rodríguez JA, Sobrino T, Orbe J, et al. proMetalloproteinase-10 is associated with brain damage and clinical outcome in acute ischemic stroke. J Thromb Haemost, 2013, 11(8): 1464-1473.
34. Millán M, Sobrino T, Arenillas JF, et al. Biological signatures of brain damage associated with high serum ferritin levels in patients with acute ischemic stroke and thrombolytic treatment. Dis Markers, 2008, 25(3): 181-188.
35. Moldes O, Sobrino T, Millán M, et al. High serum levels of endothelin-1 predict severe cerebral edema in patients with acute ischemic stroke treated with t-PA. Stroke, 2008, 39(7): 2006-2010.
36. Zhang H, Wang J, Zhang S, et al. Aquaporin 4 and its isoforms regulation ameliorate AQP4 Mis-localization-induced glymphatic dysfunction in ischemic stroke. J Adv Res, 2026, 80: 835-849.
37. He Y, Yang Q, Liu H, et al. Effect of blood pressure on early neurological deterioration of acute ischemic stroke patients with intravenous rt-PA thrombolysis may be mediated through oxidative stress induced blood-brain barrier disruption and AQP4 upregulation. J Stroke Cerebrovasc Dis, 2020, 29(8): 104997.
38. Ramiro L, Simats A, Penalba A, et al. Circulating aquaporin-4 as a biomarker of early neurological improvement in stroke patients: a pilot study. Neurosci Lett, 2020, 714: 134580.
39. Hawash AMA, Zaytoun TM, Helmy TA, et al. S100B and brain ultrasound: novel predictors for functional outcome in acute ischemic stroke patients. Clin Neurol Neurosurg, 2023, 233: 107907.
40. Khandare P, Saluja A, Solanki RS, et al. Serum S100B and NSE levels correlate with infarct size and bladder-bowel involvement among acute ischemic stroke patients. J Neurosci Rural Pract, 2022, 13(2): 218-225.
41. Wunderlich MT, Wallesch CW, Goertler M. Release of neurobiochemical markers of brain damage is related to the neurovascular status on admission and the site of arterial occlusion in acute ischemic stroke. J Neurol Sci, 2004, 227(1): 49-53.
42. Tanaka Y, Koizumi C, Marumo T, et al. Serum S100B indicates brain edema formation and predicts long-term neurological outcomes in rat transient middle cerebral artery occlusion model. Brain Res, 2007, 1137(1): 140-145.
43. Forró T, Manu DR, B?jenaru OL, et al. GFAP as astrocyte-derived extracellular vesicle cargo in acute ischemic stroke patients-a pilot study. Int J Mol Sci, 2024, 25(11): 5726.
44. Abdelhak A, Foschi M, Abu-Rumeileh S, et al. Blood GFAP as an emerging biomarker in brain and spinal cord disorders. Nat Rev Neurol, 2022, 18(3): 158-172.
45. Korley FK, Jain S, Sun X, et al. Prognostic value of day-of-injury plasma GFAP and UCH-L1 concentrations for predicting functional recovery after traumatic brain injury in patients from the US TRACK-TBI cohort: an observational cohort study. Lancet Neurol, 2022, 21(9): 803-813.
46. Lei J, Gao G, Feng J, et al. Glial fibrillary acidic protein as a biomarker in severe traumatic brain injury patients: a prospective cohort study. Crit Care, 2015, 19: 362.
47. Peng H, Zhang L, Tang Y, et al. Exploring PTX3: a promising diagnostic marker and therapeutic target in neurology. Gene, 2025, 969: 149724.
48. Matsubara J, Sugiyama S, Nozaki T, et al. Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction. J Am Coll Cardiol, 2011, 57(7): 861-869.
49. Zhang A, Zhang Z, Liu R, et al. Human umbilical cord mesenchymal stem cell-derived exosomes inhibit inflammation and fibrotic scar formation after intracerebral hemorrhage. Mol Cell Biochem, 2025, 480(8): 4829-4847.
50. Rodriguez-Grande B, Swana M, Nguyen L, et al. The acute-phase protein PTX3 is an essential mediator of glial scar formation and resolution of brain edema after ischemic injury. J Cereb Blood Flow Metab, 2014, 34(3): 480-488.
51. Tu Y, Wang M, Wu S, et al. sST2 as a Promising cardiac biomarker after ischemic stroke with elevated systolic blood pressure. JACC Asia, 2025, 5(12): 1631-1633.
52. Ahmadzadeh K, Dizaji SR, Balabandian M, et al. Soluble suppression of tumorigenicity-2 as a candidate prognostic marker for stroke: a systematic review. Ann Lab Med, 2023, 43(6): 585-595.
53. Bevers MB, An J, Yoo A, et al. Brain Endothelial soluble ST2 production and cerebral edema in a rat model of ischemic stroke. Ann Neurol, 2026, 99(1): 134-147.

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