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Research Article | Open Access

Gene expression changes implicate specific peripheral immune responses to Deep and Lobar Intracerebral Hemorrhages in humans

Bodie Kneppa, Bradley P. Andera, Glen C. Jicklingb, Heather Hulla, Alan H. Yeea, Kwan Nga, Fernando Rodrigueza, Paulina Carmona-Moraa, Hajar Aminia, Xinhua Zhana, Marisa Hakoupiana, Noor Alomara, Frank R. Sharpa, Boryana Stamovaa( )
Department of Neurology, School of Medicine, University of California at Davis, Sacramento, CA, USA
Department of Medicine, Division of Neurology, University of Alberta, Edmonton, Canada
Show Author Information

Abstract

The peripheral immune system response to Intracerebral Hemorrhage (ICH) may differ with ICH in different brain locations. Thus, we investigated peripheral blood mRNA expression of Deep ICH, Lobar ICH, and vascular risk factor-matched control subjects (n = 59). Deep ICH subjects usually had hypertension. Some Lobar ICH subjects had cerebral amyloid angiopathy (CAA). Genes and gene networks in Deep ICH and Lobar ICH were compared to controls. We found 774 differentially expressed genes (DEGs) and 2 co-expressed gene modules associated with Deep ICH, and 441 DEGs and 5 modules associated with Lobar ICH. Pathway enrichment showed some common immune/inflammatory responses between locations including Autophagy, T Cell Receptor, Inflammasome, and Neuroinflammation Signaling. Th2, Interferon, GP6, and BEX2 Signaling were unique to Deep ICH. Necroptosis Signaling, Protein Ubiquitination, Amyloid Processing, and various RNA Processing terms were unique to Lobar ICH. Finding amyloid processing pathways in blood of Lobar ICH patients suggests peripheral immune cells may participate in processes leading to perivascular/vascular amyloid in CAA vessels and/or are involved in its removal. This study identifies distinct peripheral blood transcriptome architectures in Deep and Lobar ICH, emphasizes the need for considering location in ICH studies/clinical trials, and presents potential location-specific treatment targets.

Keywords

BloodIntracerebral hemorrhageAmyloidNeutrophilsT CellsRNA expressionDeep hemorrhageLobar hemorrhage

References

1

Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11(8):720–731. https://doi.org/10.1016/S1474-4422(12)70104-7.
Crossref Google Scholar
2

Xi G, Strahle J, Hua Y, Keep RF. Progress in translational research on intracerebral hemorrhage: is there an end in sight? Prog Neurobiol. 2014;115:45–63. https://doi.org/10.1016/j.pneurobio.2013.09.007.
Crossref Google Scholar
3

Caceres JA, Goldstein JN. Intracranial hemorrhage. Emerg Med Clin North Am. 2012;30(3):771–794. https://doi.org/10.1016/j.emc.2012.06.003.
Crossref Google Scholar
4

Hostettler IC, Seiffge DJ, Werring DJ. Intracerebral hemorrhage: an update on diagnosis and treatment. Expert Rev Neurother. 2019;19(7):679–694. https://doi.org/10.1080/14737175.2019.1623671.
Crossref Google Scholar
5

van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9(2):167–176. https://doi.org/10.1016/S1474-4422(09)70340-0.
Crossref Google Scholar
6

Broderick J, Connolly S, Feldmann E, et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Circulation. 2007;116(16):e391–e413. https://doi.org/10.1161/CIRCULATIONAHA.107.183689.
Crossref Google Scholar
7

Aguilar MI, Brott TG. Update in intracerebral hemorrhage. Neurohospitalist. 2011;1(3):148–159. https://doi.org/10.1177/1941875211409050.
Crossref Google Scholar
8

Flaherty ML, Haverbusch M, Sekar P, et al. Long-term mortality after intracerebral hemorrhage. Neurology. 2006;66(8):1182–1186. https://doi.org/10.1212/01.wnl.0000208400.08722.7c.
Crossref Google Scholar
9

Falcone GJ, Biffi A, Brouwers HB, et al. Predictors of hematoma volume in deep and lobar supratentorial intracerebral hemorrhage. JAMA Neurol. 2013;70(8):988. https://doi.org/10.1001/jamaneurol.2013.98.
Crossref Google Scholar
10
Patel N, Simon S. Intracerebral Hemorrhage. American Association of Neurological Surgeons. Accessed 11/2/21, https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Intracerebral-Hemorrhage.
11

Ikram MA, Wieberdink RG, Koudstaal PJ. International epidemiology of intracerebral hemorrhage. Curr Atheroscler Rep. 2012;14(4):300–306. https://doi.org/10.1007/s11883-012-0252-1.
Crossref Google Scholar
12

Massaro AR, Sacco RL, Mohr JP, et al. Clinical discriminators of lobar and deep hemorrhages: the Stroke Data Bank. Neurology. 1991;41(12):1881–5. doi:10.1212/wnl.41.12.1881.
Crossref Google Scholar
13

Martini SR, Flaherty ML, Brown WM, et al. Risk factors for intracerebral hemorrhage differ according to hemorrhage location. Neurology. 2012;79(23):2275–2282. https://doi.org/10.1212/WNL.0b013e318276896f.
Crossref Google Scholar
14

Mracsko E, Veltkamp R. Neuroinflammation after intracerebral hemorrhage. Front Cell Neurosci. 2014;8:388. https://doi.org/10.3389/fncel.2014.00388.
Crossref Google Scholar
15

Zhang J, Shi K, Li Z, et al. Organ- and cell-specific immune responses are associated with the outcomes of intracerebral hemorrhage. FASEB J. 2018;32(1):220–229, https://doi.org/10.1096/fsb2.v32.110.1096/fj.201700324r.
Crossref Google Scholar
16
Neuroimmune communication. Nat Neurosci. 2017;20(2):127. doi:10.1038/nn.4496.
Crossref
17

Linn J, Halpin A, Demaerel P, et al. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology. 2010;74(17):1346–1350. https://doi.org/10.1212/WNL.0b013e3181dad605.
Crossref Google Scholar
18
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 29 2008;9:559. doi: 10.1186/1471-2105-9-559.
Crossref
19

Langfelder P, Horvath S. Fast R functions for robust correlations and hierarchical clustering. J Stat Softw. 2012;46(11).
Crossref Google Scholar
20

Yang Y, Han L, Yuan Y, Li J, Hei N, Liang H. Gene co-expression network analysis reveals common system-level properties of prognostic genes across cancer types. Nat Commun. 2014;5:3231. https://doi.org/10.1038/ncomms4231.
Crossref Google Scholar
21

Langfelder P, Mischel PS, Horvath S, Ravasi T. When is hub gene selection better than standard meta-analysis? PLoS ONE. 2013;8(4):e61505. https://doi.org/10.1371/journal.pone.0061505.
Crossref Google Scholar
22

Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–2504. https://doi.org/10.1101/gr.1239303.
Crossref Google Scholar
23
yFiles Layout Algorithms for Cytoscape. yWorks. Accessed 11/3/21, https://www.yworks.com/products/yfiles-layout-algorithms-for-cytoscape.
24
Watkins NA, Gusnanto A, de Bono B, et al. A HaemAtlas: characterizing gene expression in differentiated human blood cells. Blood. 7 2009;113(19):e1-9. doi:10.1182/blood-2008-06-162958.
Crossref
25

Chtanova T, Newton R, Liu SM, et al. Identification of T cell-restricted genes, and signatures for different T cell responses, using a comprehensive collection of microarray datasets. J Immunol. 2005;175(12):7837–7847. https://doi.org/10.4049/jimmunol.175.12.7837.
Crossref Google Scholar
26

Kramer A, Green J, , Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2014;30(4):523–530. https://doi.org/10.1093/bioinformatics/btt703.
Crossref Google Scholar
27
Ingenuity Downstream Effects Analysis in IPA. Accessed 2/2/22, http://pages.ingenuity.com/rs/ingenuity/images/0812%20downstream_effects_analysis_whitepaper.pdf.
28
Ingenuity Upstream Regulator Analysis in IPA. Accessed 2/2/22, http://pages.ingenuity.com/rs/ingenuity/images/0812%20upstream_regulator_analysis_whitepaper.pdf.
29

Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57. https://doi.org/10.1038/nprot.2008.211.
Crossref Google Scholar
30

Huang da W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37(1):1–13. https://doi.org/10.1093/nar/gkn923.
Crossref Google Scholar
31

Zhao X, Sun G, Zhang H, et al. Polymorphonuclear neutrophil in brain parenchyma after experimental intracerebral hemorrhage. Transl Stroke Res. 2014;5(5):554–561. https://doi.org/10.1007/s12975-014-0341-2.
Crossref Google Scholar
32

Wang J, Doré S. Inflammation after Intracerebral Hemorrhage. J Cereb Blood Flow Metab. 2007;27(5):894–908. https://doi.org/10.1038/sj.jcbfm.9600403.
Crossref Google Scholar
33

Moxon-Emre I, Schlichter LC. Neutrophil depletion reduces blood-brain barrier breakdown, axon injury, and inflammation after intracerebral hemorrhage. J Neuropathol Exp Neurol. 2011;70(3):218–235. https://doi.org/10.1097/NEN.0b013e31820d94a5.
Crossref Google Scholar
34

Zhao X, Ting S-M, Liu C-H, et al. Neutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage. Nature Commun. 2017;8(1). https://doi.org/10.1038/s41467-017-00770-7.
Crossref Google Scholar
35

Panaro MA, Mitolo V. Cellular responses to FMLP challenging: a mini-review. Immunopharmacol Immunotoxicol. 1999;21(3):397–419. https://doi.org/10.3109/08923979909007117.
Crossref Google Scholar
36

Wen Xi, Xu X, Sun W, et al. G-protein-coupled formyl peptide receptors play a dual role in neutrophil chemotaxis and bacterial phagocytosis. Mol Biol Cell. 2019;30(3):346–356. https://doi.org/10.1091/mbc.E18-06-0358.
Crossref Google Scholar
37

Walsh KB, Woo D, Adeoye O. Response to letter regarding article, “monocyte count and 30-day case fatality in intracerebral hemorrhage”. Stroke. 2015;46(11):e244. https://doi.org/10.1161/STROKEAHA.115.011288.
Crossref Google Scholar
38

Walsh KB, Sekar P, Langefeld CD, et al. Monocyte count and 30-day case fatality in intracerebral hemorrhage. Stroke. 2015;46(8):2302–2304. https://doi.org/10.1161/STROKEAHA.115.009880.
Crossref Google Scholar
39

Hammond MD, Taylor RA, Mullen MT, et al. CCR2+ Ly6C(hi) inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage. J Neurosci. 2014;34(11):3901–3909. https://doi.org/10.1523/JNEUROSCI.4070-13.2014.
Crossref Google Scholar
40

Zhao M, Tuo H, Wang S, Zhao L. The roles of monocyte and monocyte-derived macrophages in common brain disorders. Biomed Res Int. 2020;2020:1–11. https://doi.org/10.1155/2020/9396021.
Crossref Google Scholar
41

Zhao X, Grotta J, Gonzales N, Aronowski J. Hematoma resolution as a therapeutic target: the role of microglia/macrophages. Stroke. 2009;40(3 Suppl):S92–S94. https://doi.org/10.1161/STROKEAHA.108.533158.
Crossref Google Scholar
42

Pan P, Xu L, Zhang H, et al. A review of hematoma components clearance mechanism after subarachnoid hemorrhage. Front Neurosci. 2020;14:685. https://doi.org/10.3389/fnins.2020.00685.
Crossref Google Scholar
43

Carmona-Mora P, Ander BP, Jickling GC, et al. Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke. J Cereb Blood Flow Metab. 2021;41(6):1398–1416. https://doi.org/10.1177/0271678X20953912.
Crossref Google Scholar
44

Durocher M, Knepp B, Yee A, et al. Molecular correlates of hemorrhage and edema volumes following human intracerebral hemorrhage implicate inflammation, autophagy, mRNA splicing, and T cell receptor signaling. Transl Stroke Res. 2021;12(5):754–777. https://doi.org/10.1007/s12975-020-00869-y.
Crossref Google Scholar
45

Tschoe C, Bushnell CD, Duncan PW, Alexander-Miller MA, Wolfe SQ. Neuroinflammation after intracerebral hemorrhage and potential therapeutic targets. J Stroke. 2020;22(1):29–46. https://doi.org/10.5853/jos.2019.02236.
Crossref Google Scholar
46

Zhou Y, Wang Y, Wang J, Anne Stetler R, Yang QW. Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation. Prog Neurobiol. 2014;115:25–44. https://doi.org/10.1016/j.pneurobio.2013.11.003.
Crossref Google Scholar
47

Johnson HL, Chen Yi, Jin F, et al. CD8 T cell-initiated blood-brain barrier disruption is independent of neutrophil support. J Immunol. 2012;189(4):1937–1945. https://doi.org/10.4049/jimmunol.1200658.
Crossref Google Scholar
48

Mao L, Li P, Zhu W, et al. Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke. Brain. 2017;140(7):1914–1931. doi:10.1093/brain/awx111.
Crossref Google Scholar
49

Li P, Gan Yu, Sun B-L, et al. Adoptive regulatory T-cell therapy protects against cerebral ischemia. Ann Neurol. 2013;74(3):458–471. https://doi.org/10.1002/ana.23815.
Crossref Google Scholar
50

Kuhns MS, Badgandi HB. Piecing together the family portrait of TCR-CD3 complexes. Immunol Rev. 2012;250(1):120–143. https://doi.org/10.1111/imr.12000.
Crossref Google Scholar
51

Hwang JR, Byeon Y, Kim D, Park SG. Recent insights of T cell receptor-mediated signaling pathways for T cell activation and development. Exp Mol Med. 2020;52(5):750–761. https://doi.org/10.1038/s12276-020-0435-8.
Crossref Google Scholar
52

Palacios EH, Weiss A. Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene. 2004;23(48):7990–8000. https://doi.org/10.1038/sj.onc.1208074.
Crossref Google Scholar
53

Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling: balancing life and death–a new approach to cancer therapy. J Clin Invest. 2005;115(10):2625–2632. https://doi.org/10.1172/JCI26322.
Crossref Google Scholar
54

Liu T, Zhang L, Joo D, Sun SC. NF-kappaB signaling in inflammation. Signal Transduct Target Ther. 2017;2. https://doi.org/10.1038/sigtrans.2017.23.
Crossref Google Scholar
55

Lee JU, Kim LK, Choi JM. Revisiting the concept of targeting NFAT to control T cell immunity and autoimmune diseases. Front Immunol. 2018;9:2747. https://doi.org/10.3389/fimmu.2018.02747.
Crossref Google Scholar
56

Bradley LM, Dalton DK, Croft M. A direct role for IFN-gamma in regulation of Th1 cell development. J Immunol. 1996;157(4):1350–1358.
Crossref Google Scholar
57

Smeltz RB, Chen J, Ehrhardt R, Shevach EM. Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression. J Immunol. 2002;168(12):6165–6172. https://doi.org/10.4049/jimmunol.168.12.6165.
Crossref Google Scholar
58

Curtsinger JM, Agarwal P, Lins DC, Mescher MF. Autocrine IFN-gamma promotes naive CD8 T cell differentiation and synergizes with IFN-alpha to stimulate strong function. J Immunol. 2012;189(2):659–668. https://doi.org/10.4049/jimmunol.1102727.
Crossref Google Scholar
59

Lighvani AA, Frucht DM, Jankovic D, et al. T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci U S A. 2001;98(26):15137–15142. https://doi.org/10.1073/pnas.261570598.
Crossref Google Scholar
60

Ohshima Y, Yang LP, Uchiyama T, et al. OX40 costimulation enhances interleukin-4 (IL-4) expression at priming and promotes the differentiation of naive human CD4(+) T cells into high IL-4-producing effectors. Blood. 1998;92(9):3338–3345.
Crossref Google Scholar
61

Choi P, Reiser H. IL-4: role in disease and regulation of production. Clin Exp Immunol. 1998;113(3):317–319. https://doi.org/10.1046/j.1365-2249.1998.00690.x.
Crossref Google Scholar
62

Schwartz SO, Stansbury F. Significance of nucleated red blood cells in peripheral blood; analysis of 1,496 cases. J Am Med Assoc. 1954;154(16):1339–1340. https://doi.org/10.1001/jama.1954.02940500019007.
Crossref Google Scholar
63

Moras M, Lefevre SD, Ostuni MA. From erythroblasts to mature red blood cells: organelle clearance in mammals. Front Physiol. 2017;8:1076. https://doi.org/10.3389/fphys.2017.01076.
Crossref Google Scholar
64

Poh L, Kang SW, Baik SH, et al. Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke. Brain Behav Immun. 2019;75:34–47. https://doi.org/10.1016/j.bbi.2018.09.001.
Crossref Google Scholar
65

Denes A, Coutts G, Lénárt N, et al. AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3. Proc Natl Acad Sci U S A. 2015;112(13):4050–4055. https://doi.org/10.1073/pnas.1419090112.
Crossref Google Scholar
66

Ma Q, Chen S, Hu Q, Feng H, Zhang JH, Tang J. NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann Neurol. 2014;75(2):209–219. https://doi.org/10.1002/ana.24070.
Crossref Google Scholar
67

Voet S, Srinivasan S, Lamkanfi M, van Loo G. Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol Med. 2019;11(6) 10.15252/emmm.201810248.
Crossref Google Scholar
68

Zhao H, Zhang X, Dai Z, et al. P2X7 Receptor suppression preserves blood-brain barrier through inhibiting RhoA activation after experimental intracerebral hemorrhage in rats. Sci Rep. 2016;6:23286. doi:10.1038/srep23286.
Crossref Google Scholar
69
Feng L, Chen Y, Ding R, et al. P2X7R blockade prevents NLRP3 inflammasome activation and brain injury in a rat model of intracerebral hemorrhage: involvement of peroxynitrite. J Neuroinflammation. 17 2015;12:190. doi:10.1186/s12974-015-0409-2.
Crossref
70

Gultekin Y, Eren E, Ozoren N. Overexpressed NLRC3 acts as an anti-inflammatory cytosolic protein. J Innate Immun. 2015;7(1):25–36. https://doi.org/10.1159/000363602.
Crossref Google Scholar
71

Awad F, Assrawi E, Louvrier C, et al. Inflammasome biology, molecular pathology and therapeutic implications. Pharmacol Ther. 2018;187:133–149. https://doi.org/10.1016/j.pharmthera.2018.02.011.
Crossref Google Scholar
72

Park BS, Lee JO. Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp Mol Med. 2013;45:e66. doi:10.1038/emm.2013.97.
Crossref Google Scholar
73

Zhang XD, Fan QY, Qiu Z, Chen S. MiR-7 alleviates secondary inflammatory response of microglia caused by cerebral hemorrhage through inhibiting TLR4 expression. Eur Rev Med Pharmacol Sci. 2018;22(17):5597–5604. https://doi.org/10.26355/eurrev_201809_15824.
Crossref Google Scholar
74

Liu Q, Johnson EM, Lam RK, et al. Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity. Nat Immunol. 2019;20(8):1023–1034. https://doi.org/10.1038/s41590-019-0421-2.
Crossref Google Scholar
75
Hakoupian M, Ferino E, Jickling GC, et al. Bacterial lipopolysaccharide is associated with stroke. Sci Rep. Mar 22 2021;11(1):6570. doi:10.1038/s41598-021-86083-8.
Crossref
76

Zhu H, Wang Z, Yu J, et al. Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage. Prog Neurobiol. 2019;178:101610. https://doi.org/10.1016/j.pneurobio.2019.03.003.
Crossref Google Scholar
77

Ducruet AF, Zacharia BE, Hickman ZL, et al. The complement cascade as a therapeutic target in intracerebral hemorrhage. Exp Neurol. 2009;219(2):398–403. https://doi.org/10.1016/j.expneurol.2009.07.018.
Crossref Google Scholar
78

Rosell A, Vilalta A, Garcia-Berrocoso T, et al. Brain perihematoma genomic profile following spontaneous human intracerebral hemorrhage. PLoS One. 2011;6(2):e16750. doi:10.1371/journal.pone.0016750.
Crossref Google Scholar
79

Hu X, Tao C, Gan Qi, Zheng J, Li H, You C. Oxidative stress in intracerebral hemorrhage: sources, mechanisms, and therapeutic targets. Oxid Med Cell Longev. 2016;2016:1–12. https://doi.org/10.1155/2016/3215391.
Crossref Google Scholar
80

Sun J, Chen J, Li T, et al. ROS production and mitochondrial dysfunction driven by PU.1-regulated NOX4-p22(phox) activation in Abeta-induced retinal pigment epithelial cell injury. Theranostics. 2020;10(25):11637–11655. https://doi.org/10.7150/thno.48064.
Crossref Google Scholar
81

Panday A, Sahoo MK, Osorio D, Batra S. NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol Immunol. 2015;12(1):5–23. https://doi.org/10.1038/cmi.2014.89.
Crossref Google Scholar
82

Kim DW, Im SH, Kim JY, Kim DE, Oh GT, Jeong SW. Decreased brain edema after collagenase-induced intracerebral hemorrhage in mice lacking the inducible nitric oxide synthase gene. Laboratory investigation. J Neurosurg. 2009;111(5):995–1000. doi:10.3171/2009.3.JNS081285.
Crossref Google Scholar
83

Wang J, Fields J, Zhao C, et al. Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic Biol Med. 2007;43(3):408–414. https://doi.org/10.1016/j.freeradbiomed.2007.04.020.
Crossref Google Scholar
84

Zhao X, Sun G, Ting S-M, et al. Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance. J Neurochem. 2015;133(1):144–152. https://doi.org/10.1111/jnc.12974.
Crossref Google Scholar
85

Zhao X, Sun G, Zhang J, et al. Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke. 2007;38(12):3280–3286. https://doi.org/10.1161/STROKEAHA.107.486506.
Crossref Google Scholar
86

Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci. 2016;73(17):3221–3247. https://doi.org/10.1007/s00018-016-2223-0.
Crossref Google Scholar
87

Chen S, Wang X, Nisar MF, Lin M, Zhong JL. Heme oxygenases: cellular multifunctional and protective molecules against UV-induced oxidative stress. Oxid Med Cell Longev. 2019;2019:1–17. https://doi.org/10.1155/2019/5416728.
Crossref Google Scholar
88

Cherubini A, Polidori MC, Bregnocchi M, et al. Antioxidant profile and early outcome in stroke patients. Stroke. 2000;31(10):2295–2300. https://doi.org/10.1161/01.str.31.10.2295.
Crossref Google Scholar
89

Polidori MC, Mecocci P, Frei B. Plasma vitamin C levels are decreased and correlated with brain damage in patients with intracranial hemorrhage or head trauma. Stroke. 2001;32(4):898–902. https://doi.org/10.1161/01.str.32.4.898.
Crossref Google Scholar
90

Penkowa M, Carrasco J, Giralt M, Moos T, Hidalgo J. CNS wound healing is severely depressed in metallothionein I- and II-deficient mice. J Neurosci. 1999;19(7):2535–2545.
Crossref Google Scholar
91

Lu A, Tang Y, Ran R, Ardizzone TL, Wagner KR, Sharp FR. Brain genomics of intracerebral hemorrhage. J Cereb Blood Flow Metab. 2006;26(2):230–252. https://doi.org/10.1038/sj.jcbfm.9600183.
Crossref Google Scholar
92

Yamashita S, Okauchi M, Hua Y, Liu W, Keep RF, Xi G. Metallothionein and brain injury after intracerebral hemorrhage. Acta Neurochir Suppl. 2008;105:37–40. doi:10.1007/978-3-211-09469-3_8.
Crossref Google Scholar
93

Hidalgo J. Metallothioneins and brain injury: What transgenic mice tell us. Environ Health Prev Med. 2004;9(3):87–94. https://doi.org/10.1007/BF02898066.
Crossref Google Scholar
94

Katsuki H. Exploring neuroprotective drug therapies for intracerebral hemorrhage. J Pharmacol Sci. 2010;114(4):366–378. https://doi.org/10.1254/jphs.10r05cr.
Crossref Google Scholar
95

Sobrino T, Arias S, Rodríguez-González R, et al. High serum levels of growth factors are associated with good outcome in intracerebral hemorrhage. J Cereb Blood Flow Metab. 2009;29(12):1968–1974. https://doi.org/10.1038/jcbfm.2009.182.
Crossref Google Scholar
96

Cheng P, Ma L, Shaligram S, et al. Effect of elevation of vascular endothelial growth factor level on exacerbation of hemorrhage in mouse brain arteriovenous malformation. J Neurosurg. 2019;132(5):1566–1573. doi:10.3171/2019.1.JNS183112.
Crossref Google Scholar
97

Liu W, Wang X, O’Connor M, Wang G, Han F. Brain-derived neurotrophic factor and its potential therapeutic role in stroke comorbidities. Neural Plast. 2020;2020:1969482. https://doi.org/10.1155/2020/1969482.
Crossref Google Scholar
98

Xu W, Gao L, Li T, Zheng J, Shao A, Zhang J. Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) protects against neuronal apoptosis via activation of Akt/MDM2/p53 signaling pathway in a rat model of intracerebral hemorrhage. Front Mol Neurosci. 2018;11:176. https://doi.org/10.3389/fnmol.2018.00176.
Crossref Google Scholar
99

He Y, Wan S, Hua Y, Keep RF, Xi G. Autophagy after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab. 2008;28(5):897–905. https://doi.org/10.1038/sj.jcbfm.9600578.
Crossref Google Scholar
100

Yao Z, Bai Q, Wang G, Zhang JH. Mechanisms of oxidative stress and therapeutic targets following intracerebral hemorrhage. Oxid Med Cell Longev. 2021;2021:1–12. https://doi.org/10.1155/2021/8815441.
Crossref Google Scholar
101

Oh JE, Lee HK. Pattern recognition receptors and autophagy. Front Immunol. 2014;5:300. doi:10.3389/fimmu.2014.00300.
Crossref Google Scholar
102

Feng Y, Gao J, Cui Y, et al. Neuroprotective effects of resatorvid against traumatic brain injury in rat: involvement of neuronal autophagy and TLR4 signaling pathway. Cell Mol Neurobiol. 2017;37(1):155–168. https://doi.org/10.1007/s10571-016-0356-1.
Crossref Google Scholar
103

Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol. 2011;27(1):107–132. https://doi.org/10.1146/annurev-cellbio-092910-154005.
Crossref Google Scholar
104

Mizushima N. The ATG conjugation systems in autophagy. Curr Opin Cell Biol. 2020;63:1–10. https://doi.org/10.1016/j.ceb.2019.12.001.
Crossref Google Scholar
105

Judith D, Jefferies HBJ, Boeing S, Frith D, Snijders AP, Tooze SA. ATG9A shapes the forming autophagosome through Arfaptin 2 and phosphatidylinositol 4-kinase IIIbeta. J Cell Biol. 2019;218(5):1634–1652. https://doi.org/10.1083/jcb.201901115.
Crossref Google Scholar
106
Q13501 (SQSTM_HUMAN). UniProt. Accessed 2/1/22, https://www.uniprot.org/uniprot/Q13501.
107

Shpilka T, Weidberg H, Pietrokovski S, Elazar Z. Atg8: an autophagy-related ubiquitin-like protein family. Genome Biol. 2011;12(7):226. doi:10.1186/gb-2011-12-7-226.
Crossref Google Scholar
108

Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V, Elazar Z. LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis. EMBO J. 2010;29(11):1792–1802. https://doi.org/10.1038/emboj.2010.74.
Crossref Google Scholar
109

Fang Y, Gao S, Wang X, et al. Programmed cell deaths and potential crosstalk with blood-brain barrier dysfunction after hemorrhagic stroke. Front Cell Neurosci. 2020;14. https://doi.org/10.3389/fncel.2020.00068.
Crossref Google Scholar
110

Bobinger T, Burkardt P, Huttner HB, Manaenko A. Programmed cell death after intracerebral hemorrhage. Curr Neuropharmacol. 2018;16(9):1267–1281. https://doi.org/10.2174/1570159X15666170602112851.
Crossref Google Scholar
111

Andreone BJ, Larhammar M, Lewcock JW. Cell death and neurodegeneration. Cold Spring Harb Perspect Biol. 2020;12(2)doi:10.1101/cshperspect.a036434.
Crossref Google Scholar
112

Bai Q, Liu J, Wang G. Ferroptosis, a regulated neuronal cell death type after intracerebral hemorrhage. Front Cell Neurosci. 2020;14:591874. https://doi.org/10.3389/fncel.2020.591874.
Crossref Google Scholar
113

Gaschler MM, Stockwell BR. Lipid peroxidation in cell death. Biochem Biophys Res Commun. 2017;482(3):419–425. https://doi.org/10.1016/j.bbrc.2016.10.086.
Crossref Google Scholar
114

Li J, Cao F, Yin HL, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020;11(2):88. doi:10.1038/s41419-020-2298-2.
Crossref Google Scholar
115

Li Q, Han X, Lan X, et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight. 2017;2(7):e90777. doi:10.1172/jci.insight.90777.
Crossref Google Scholar
116

Zhang Z, Wu Y, Yuan S, et al. Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage. Brain Res. 2018;1701:112–125. https://doi.org/10.1016/j.brainres.2018.09.012.
Crossref Google Scholar
117

Xu YR, Lei CQ. TAK1-TABs complex: a central signalosome in inflammatory responses. Front Immunol. 2020;11:608976. https://doi.org/10.3389/fimmu.2020.608976.
Crossref Google Scholar
118

Tsuchiya Y, Nakabayashi O, Nakano H. FLIP the switch: regulation of apoptosis and necroptosis by cFLIP. Int J Mol Sci. 2015;16(12):30321–30341. https://doi.org/10.3390/ijms161226232.
Crossref Google Scholar
119

Wang H, Meng H, Li X, et al. PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP. Proc Natl Acad Sci U S A. 2017;114(45):11944–11949. https://doi.org/10.1073/pnas.1715742114.
Crossref Google Scholar
120

Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010;221(1):3–12. https://doi.org/10.1002/path.2697.
Crossref Google Scholar
121

Shahbazi J, Lock R, Liu T. Tumor protein 53-induced nuclear protein 1 enhances p53 function and represses tumorigenesis. Front Genet. 2013;4:80. https://doi.org/10.3389/fgene.2013.00080.
Crossref Google Scholar
122

Li P, Ma K, Wu HY, Wu YP, Li BX. Isoflavones induce BEX2-dependent autophagy to prevent ATR-induced neurotoxicity in SH-SY5Y Cells. Cell Physiol Biochem. 2017;43(5):1866–1879. https://doi.org/10.1159/000484075.
Crossref Google Scholar
123

Chinta SJ, Andersen JK. Dopaminergic neurons. Int J Biochem Cell Biol. 2005;37(5):942–946. https://doi.org/10.1016/j.biocel.2004.09.009.
Crossref Google Scholar
124

Chabrat A, Brisson G, Doucet-Beaupre H, et al. Transcriptional repression of Plxnc1 by Lmx1a and Lmx1b directs topographic dopaminergic circuit formation. Nat Commun. 2017;8(1):933. doi:10.1038/s41467-017-01042-0.
Crossref Google Scholar
125

Rajagopalan S, Rane A, Chinta SJ, Andersen JK. Regulation of ATP13A2 via PHD2-HIF1alpha signaling is critical for cellular iron homeostasis: implications for Parkinson's disease. J Neurosci. 2016;36(4):1086–1095. https://doi.org/10.1523/JNEUROSCI.3117-15.2016.
Crossref Google Scholar
126

Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67(1):425–479. https://doi.org/10.1146/annurev.biochem.67.1.425.
Crossref Google Scholar
127

Hallengren J, Chen PC, Wilson SM. Neuronal ubiquitin homeostasis. Cell Biochem Biophys. 2013;67(1):67–73. https://doi.org/10.1007/s12013-013-9634-4.
Crossref Google Scholar
128

Myeku N, Figueiredo-Pereira ME. Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: association with sequestosome 1/p62. J Biol Chem. 2011;286(25):22426–22440. https://doi.org/10.1074/jbc.M110.149252.
Crossref Google Scholar
129

Bednash JS, Mallampalli RK. Regulation of inflammasomes by ubiquitination. Cell Mol Immunol. 2016;13(6):722–728. https://doi.org/10.1038/cmi.2016.15.
Crossref Google Scholar
130

Liu C, Liu C, Liu H, et al. Increased expression of ubiquitin-specific protease 4 participates in neuronal apoptosis after intracerebral hemorrhage in adult rats. Cell Mol Neurobiol. 2017;37(3):427–435. https://doi.org/10.1007/s10571-016-0375-y.
Crossref Google Scholar
131

Xu Z, Li X, Chen J, et al. USP11, deubiquitinating enzyme, associated with neuronal apoptosis following intracerebral hemorrhage. J Mol Neurosci. 2016;58(1):16–27. https://doi.org/10.1007/s12031-015-0644-0.
Crossref Google Scholar
132

Qu X, Wang N, Chen W, Qi M, Xue Y, Cheng W. RNF34 overexpression exacerbates neurological deficits and brain injury in a mouse model of intracerebral hemorrhage by potentiating mitochondrial dysfunction-mediated oxidative stress. Sci Rep. 2019;9(1):16296. doi:10.1038/s41598-019-52494-x.
Crossref Google Scholar
133
Durocher M, Ander BP, Jickling G, et al. Inflammatory, regulatory, and autophagy co-expression modules and hub genes underlie the peripheral immune response to human intracerebral hemorrhage. J Neuroinflammation. 5 2019;16(1):56. doi:10.1186/s12974-019-1433-4.
Crossref
134

Hessa T, Sharma A, Mariappan M, Eshleman HD, Gutierrez E, Hegde RS. Protein targeting and degradation are coupled for elimination of mislocalized proteins. Nature. 2011;475(7356):394–397. https://doi.org/10.1038/nature10181.
Crossref Google Scholar
135

Kawahara H, Minami R, Yokota N. BAG6/BAT3: emerging roles in quality control for nascent polypeptides. J Biochem. 2013;153(2):147–160. https://doi.org/10.1093/jb/mvs149.
Crossref Google Scholar
136

Calzado MA, de la Vega L, Moller A, Bowtell DD, Schmitz ML. An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nat Cell Biol. 2009;11(1):85–91. https://doi.org/10.1038/ncb1816.
Crossref Google Scholar
137
Q6IQ16 (SPOPL_HUMAN). UniProt. Accessed 2/1/22, https://www.uniprot.org/uniprot/Q6IQ16.
138

Errington WJ, Khan MQ, Bueler SA, Rubinstein JL, Chakrabartty A, Prive GG. Adaptor protein self-assembly drives the control of a cullin-RING ubiquitin ligase. Structure. 2012;20(7):1141–1153. https://doi.org/10.1016/j.str.2012.04.009.
Crossref Google Scholar
139

Caldeira MV, Salazar IL, Curcio M, Canzoniero LM, Duarte CB. Role of the ubiquitin-proteasome system in brain ischemia: friend or foe? Prog Neurobiol. 2014;112:50–69. https://doi.org/10.1016/j.pneurobio.2013.10.003.
Crossref Google Scholar
140

Hong L, Huang HC, Jiang ZF. Relationship between amyloid-beta and the ubiquitin-proteasome system in Alzheimer's disease. Neurol Res. 2014;36(3):276–282. https://doi.org/10.1179/1743132813Y.0000000288.
Crossref Google Scholar
141

Bellia F, Lanza V, Garcia-Vinuales S, et al. Ubiquitin binds the amyloid beta peptide and interferes with its clearance pathways. Chem Sci. 2019;10(9):2732–2742. https://doi.org/10.1039/c8sc03394c.
Crossref Google Scholar
142

Gregori L, Fuchs C, Figueiredo-Pereira ME, Van Nostrand WE, Goldgaber D. Amyloid beta-protein inhibits ubiquitin-dependent protein degradation in vitro. J Biol Chem. 1995;270(34):19702–19708. https://doi.org/10.1074/jbc.270.34.19702.
Crossref Google Scholar
143

Oddo S. The ubiquitin-proteasome system in Alzheimer's disease. J Cell Mol Med. 2008;12(2):363–373. https://doi.org/10.1111/j.1582-4934.2008.00276.x.
Crossref Google Scholar
144

Himeno E, Ohyagi Y, Ma L, et al. Apomorphine treatment in Alzheimer mice promoting amyloid-beta degradation. Ann Neurol. 2011;69(2):248–256. https://doi.org/10.1002/ana.22319.
Crossref Google Scholar
145

Park HM, Kim JA, Kwak MK. Protection against amyloid beta cytotoxicity by sulforaphane: role of the proteasome. Arch Pharm Res. 2009;32(1):109–115. https://doi.org/10.1007/s12272-009-1124-2.
Crossref Google Scholar
146

Kim J. Pre-clinical neuroprotective evidences and plausible mechanisms of sulforaphane in Alzheimer's Disease. Int J Mol Sci. 2021;22(6) doi:10.3390/ijms22062929.
Crossref Google Scholar
147

Ribet D, Cossart P. Ubiquitin, SUMO, and NEDD8: key targets of bacterial pathogens. Trends Cell Biol. 2018;28(11):926–940. https://doi.org/10.1016/j.tcb.2018.07.005.
Crossref Google Scholar
148
UBA3 ubiquitin like modifier activating enzyme 3. NCBI. 2/1/22. https://www.ncbi.nlm.nih.gov/gene/9039.
149

Biffi A, Greenberg SM. Cerebral amyloid angiopathy: a systematic review. J Clin Neurol. 2011;7(1):1–9. https://doi.org/10.3988/jcn.2011.7.1.1.
Crossref Google Scholar
150

Revesz T, Ghiso J, Lashley T, et al. Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol. 2003;62(9):885–898. https://doi.org/10.1093/jnen/62.9.885.
Crossref Google Scholar
151

Sobhanifar S, Schneider B, Löhr F, et al. Structural investigation of the C-terminal catalytic fragment of presenilin 1. Proc Natl Acad Sci U S A. 2010;107(21):9644–9649. https://doi.org/10.1073/pnas.1000778107.
Crossref Google Scholar
152

Takuma K, Fang F, Zhang W, et al. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009;106(47):20021–20026. https://doi.org/10.1073/pnas.0905686106.
Crossref Google Scholar
153

Deane R, Du Yan S, Submamaryan RK, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9(7):907–913. https://doi.org/10.1038/nm890.
Crossref Google Scholar
154

Minami R, Hayakawa A, Kagawa H, Yanagi Y, Yokosawa H, Kawahara H. BAG-6 is essential for selective elimination of defective proteasomal substrates. J Cell Biol. 2010;190(4):637–650. https://doi.org/10.1083/jcb.200908092.
Crossref Google Scholar
155

Yoon SS, Jo SA. Mechanisms of amyloid-beta peptide clearance: potential therapeutic targets for Alzheimer's disease. Biomol Ther (Seoul). 2012;20(3):245–255. https://doi.org/10.4062/biomolther.2012.20.3.245.
Crossref Google Scholar
156

Pujadas L, Rossi D, Andres R, et al. Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer's disease. Nat Commun. 2014;5:3443. doi:10.1038/ncomms4443.
Crossref Google Scholar
157

Scotti MM, Swanson MS. RNA mis-splicing in disease. Nat Rev Genet. 2016;17(1):19–32. https://doi.org/10.1038/nrg.2015.3.
Crossref Google Scholar
158

Dykstra-Aiello C, Jickling GC, Ander BP, et al. Intracerebral hemorrhage and ischemic stroke of different etiologies have distinct alternatively spliced mRNA profiles in the blood: a pilot RNA-seq study. Transl Stroke Res. 2015;6(4):284–289. https://doi.org/10.1007/s12975-015-0407-9.
Crossref Google Scholar
159

Stamova B, Ander BP, Jickling G, et al. The intracerebral hemorrhage blood transcriptome in humans differs from the ischemic stroke and vascular risk factor control blood transcriptomes. J Cereb Blood Flow Metab. 2019;39(9):1818–1835. https://doi.org/10.1177/0271678X18769513.
Crossref Google Scholar
160

Burchell SR, Tang J, Zhang JH. Hematoma expansion following intracerebral hemorrhage: mechanisms targeting the coagulation cascade and platelet activation. Curr Drug Targets. 2017;18(12):1329–1344. https://doi.org/10.2174/1389450118666170329152305.
Crossref Google Scholar
161

Emiru T, Bershad EM, Zantek ND, et al. Intracerebral hemorrhage: a review of coagulation function. Clin Appl Thromb Hemost. 2013;19(6):652–662. https://doi.org/10.1177/1076029612454938.
Crossref Google Scholar
162

Quinones-Hinojosa A, Gulati M, Singh V, Lawton MT. Spontaneous intracerebral hemorrhage due to coagulation disorders. Neurosurg Focus. 2003;15(4):E3. doi:10.3171/foc.2003.15.4.3.
Crossref Google Scholar
163

Saad J, Asuka E, Schoenberger L. Physiology. Platelet activation. StatPearls;2022.
164

Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013;98(1):10–23. https://doi.org/10.1007/s12185-013-1382-0.
Crossref Google Scholar
165

Jung SM, Moroi M. Platelet glycoprotein Ⅵ. Adv Exp Med Biol. 2008;640:53–63. https://doi.org/10.1007/978-0-387-09789-3_5.
Crossref Google Scholar
166

Rocanin-Arjo A, Cohen W, Carcaillon L, et al. A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential. Blood. 2014;123(5):777–85. doi:10.1182/blood-2013-10-529628.
Crossref Google Scholar
167

Krynetskiy E, McDonnell P. Building individualized medicine: prevention of adverse reactions to warfarin therapy. J Pharmacol Exp Ther. 2007;322(2):427–434. https://doi.org/10.1124/jpet.106.117952.
Crossref Google Scholar
168

Lam W, Moosavi L. Physiology, Factor V. StatPearls; 2022.
169

Malkhassian D, Sabir S, Sharma S. Physiology, Factor ⅫⅠ. StatPearls; 2022.
170

Stamova B, Jickling GC, Ander BP, et al. Gene expression in peripheral immune cells following cardioembolic stroke is sexually dimorphic. PLoS ONE. 2014;9(7):e102550. https://doi.org/10.1371/journal.pone.0102550.
Crossref Google Scholar
171

Tian Y, Stamova B, Jickling GC, et al. Effects of gender on gene expression in the blood of ischemic stroke patients. J Cereb Blood Flow Metab. 2012;32(5):780–791. https://doi.org/10.1038/jcbfm.2011.179.
Crossref Google Scholar
172

Dykstra-Aiello C, Jickling GC, Ander BP, et al. Altered expression of long noncoding RNAs in blood after ischemic stroke and proximity to putative stroke risk loci. Stroke. 2016;47(12):2896–2903. https://doi.org/10.1161/STROKEAHA.116.013869.
Crossref Google Scholar
173

Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626–638. https://doi.org/10.1038/nri.2016.90.
Crossref Google Scholar
174

Qureshi IA, Mehler MF. Emerging role of epigenetics in stroke: part 1: DNA methylation and chromatin modifications. Arch Neurol. 2010;67(11):1316–1322. https://doi.org/10.1001/archneurol.2010.275.
Crossref Google Scholar
175

Ganti L, Jain A, Yerragondu N, et al. Female gender remains an independent risk factor for poor outcome after acute nontraumatic intracerebral hemorrhage. Neurol Res Int. 2013;2013:1–7. https://doi.org/10.1155/2013/219097.
Crossref Google Scholar
176

Umeano O, Phillips-Bute B, Hailey CE, et al. Gender and age interact to affect early outcome after intracerebral hemorrhage. PLoS ONE. 2013;8(11):e81664. https://doi.org/10.1371/journal.pone.0081664.
Crossref Google Scholar
177

James ML, Cox M, Xian Y, et al. Sex and age interactions and differences in outcomes after intracerebral hemorrhage. J Womens Health (Larchmt). 2017;26(4):380–388. https://doi.org/10.1089/jwh.2016.5849.
Crossref Google Scholar
Brain Hemorrhages
Volume 3 Issue 4,
December 2022
Pages 155-176
DOI: 10.1016/j.hest.2022.04.003
Cite this article:
Knepp B, Ander BP, Jickling GC, et al. Gene expression changes implicate specific peripheral immune responses to Deep and Lobar Intracerebral Hemorrhages in humans. Brain Hemorrhages, 2022, 3(4): 155-176. https://doi.org/10.1016/j.hest.2022.04.003

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Received: 28 March 2022
Revised: 15 April 2022
Accepted: 16 April 2022
Published: 22 April 2022
© 2022 International Hemorrhagic Stroke Association.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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