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Journal of Traditional Chinese Medicine >

2022 , Vol. 42 >Issue 4: 622 - 632

DOI: https://doi.org/10.19852/j.cnki.jtcm.20220617.002

Research Articles

Identification of novel biomarkers and therapeutic target candidates for stasis-heat symptom pattern of acute intracerebral hemorrhage by quantitative plasma proteomics

  • Lexin WEI ,
  • Weiyi LI ,
  • Ting TIAN ,
  • Ning ZHANG ,
  • Shijing YANG ,
  • Dongqing YANG ,
  • Guochun LI ,
  • Fang YE
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  • 1 Department of Public Health, School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
    2 Emergency Department, Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing 210001, China
    3 the Key Laboratory Department of Stasis-heat Pathogenesis of Traditional Chinese Medicine, the First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210001, China
Prof. YE Fang, the Key Research Department of Stasis-heat Pathogenesis of Traditional Chinese Medicine, the First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China. 260958@njucm.edu.cn, Telephone: +86-25-85511926
Prof. LI Guochun, Department of Public Health, School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China. dr.guochun_li@njucm.edu.cn;

Received date: 2021-04-22

  Accepted date: 2021-07-18

  Online published: 2022-07-12

Supported by

Construction and Application of Decision Support System of TCM Master Zhou Zhongying's Experience Learning in Distinguishing and Treating Major Diseases based on the Intelligent Technology(BE2019723);Dynamic Measurement and Study of Biomarker on Pathogenic Unit of Stasis-Heat in Acute Intracerebral Hemorrhage(813735)

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Abstract

OBJECTIVE: To explore the novel biomarkers and therapeutic target candidates related to the stasis-heat syndrome of acute intracerebral hemorrhage (AICH). METHODS: Applying an isobaric tagging for relative and absolute quantitation-(iTRAQ-) based quantitative proteomic approach, plasma samples from AICH patients with stasis-heat, and AICH patients with non-stasis-heat and healthy control subjects were collected and analyzed to distinguish differentially expressed proteins (DEPs) correlated to AICH with stasis-heat in this block design. The standard Western blot was applied to verify DEPs. Additionally, DEPs were analyzed via bioinformatic platforms and further approved via Ingenuity Pathway Analysis (IPA). RESULTS: A total of 26 DEPs were found among AICH with the stasis-heat, AICH with non-stasis-heat, and healthy control group. The seven DEPs compared with the non-stasis-heat group are closely related to the pathogenesis of stasis heat. These proteins showed three different protein expression patterns. The alpha-1-b glycoprotein (A1BG) and copper-protein (CP) were up-regulated in the stasis-heat group, but down-regulated in the non-stasis-heat group. Compared with the non-stasis-heat group, the expression abundance of actinin, alpha 1 (ACTN1), carbonic anhydrase I (CA1), peroxiredoxin 2 (PRDX2), and vinculin (VCL) is higher in the stasis-heat group, while the CD44 is the opposite. These differences reflect that stasis-heat syndrome has more severe inflammatory immune response, coagulation disorders and damage. Bioinformatics analysis revealed that a wide variety of cellular and metabolic processes and some signaling pathways were involved in the pathophysiology of AICH with stasis-heat. AICH with stasis-heat syndrome showed more severe inflammatory reactions, tissue damage, and coagulation disorders than non-stasis heat syndrome. CONCLUSIONS: There are differences in the protein expression patterns between the stasis-heat syndrome and non-stasis-heat syndrome. These differences reflect that stasis-heat syndrome has more severe damage. CD44, CP, ACTN1, CA1, VCL, PRDX2, and A1BG could be the potential biomarkers and therapeutic target candidates of the stasis-heat subtype. This study provides a reasonable explaination for Liangxue Tongyu decoction through anti-inflammatory and brain protection treatment.

Key words： cerebral hemorrhage; stasis-heat syndrome; biomarkers; therapeutic target; quantitative plasma proteomics

Cite this article

Lexin WEI , Weiyi LI , Ting TIAN , Ning ZHANG , Shijing YANG , Dongqing YANG , Guochun LI , Fang YE . Identification of novel biomarkers and therapeutic target candidates for stasis-heat symptom pattern of acute intracerebral hemorrhage by quantitative plasma proteomics[J]. Journal of Traditional Chinese Medicine, 2022 , 42(4) : 622 -632 . DOI: 10.19852/j.cnki.jtcm.20220617.002

References

1 Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in china and its provinces, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet 2019; 394: 1145-58.
2 Wang Y, Li Z, Gu H, et al. Report on stroke prevention and tre-atment in China. Zhong Guo Zu Zhong Za Zhi 2020; 15: 1037-43.
3 Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med 2019; 380: 1795-803.
4 O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1026 experimental treatments in acute stroke. Ann Neurol 2006; 59: 467-77.
5 Liu D, Liang J, Kang X, Ma S, Ding M. Molecule prescription: New generative point of science of medicine. Zi Ran Za Zhi 2006; 2006: 337-40.
6 Casas AI, Hassan AA, Larsen SJ, et al. From single drug targets to synergistic network pharmacology in ischemic stroke. Proc Natl Acad Sci USA 2019; 116: 7129-36.
7 Jiang C, Yang X, Dong J, Li G. Systematic review and Meta-analysis of randomized controlled trials of liangxue tongyu formula on patients with acute intracerebral hemorrhage. Front Pharmacol 2020; 11: 437.
8 Li X, Huang X, Tang Y, et al. Assessing the pharmacological and therapeutic efficacy of traditional chinese medicine liangxue tongyu prescription for intracerebral hemorrhagic stroke in neurological disease models. Front Pharmacol 2018; 9: 1169.
9 Guo Q, Yang S, Yang D, et al. Differential mrna expression combined with network pharmacology reveals network effects of liangxue tongyu prescription for acute intracerebral hemorrhagic rats. J Ethnopharmacol 2020; 246: 112231.
10 Chen Y, Dong J, Yang D, et al. Synergistic network pharmacology for traditional chinese medicine liangxue tongyu formula in acute intracerebral hemorrhagic stroke. Neural Plast 2021; 2021: 8874296.
11 Huang X, Li GC, Yin L, Zhang ZH, Liang YX, Chen HB. The effective parts of Liangxue Tongyu prescription on cooling-blood and activating-blood and analysis of chemical constituents by hplc-ms and gc-ms. Yao Xue Xue Bao 2015; 50: 86-93.
12 Guo W, Zhang L, Wu M, et al. Liangxue Tongyu Fang for treating acuter-phase cerebral hemorrhage in 168 cases. Beijing Zhong Yi Yao Da Xue Xue Bao. 2012; 35: 603-6+19.
13 Tian T, Li G, Guo W. Research of biomarkers in the Yu-Re pathogenic unit of acute cerebral hemorrhage. Shi Zhen Guo Yi Guo Yao 2016; 27: 183-6.
14 Tian T, Guo W, Li G. Research on clinical manifestation of heat stagnation pathogenesis in acute cerebral hemorrhage. Zhong Yi Za Zhi 2016; 57: 838-42.
15 Xu X, Chen X, Zhang J, Xu B. Study on the accuracy and reliability of the abc/2 formula for volume assessment of intracerebral he- matoma. Zhong Guo Shen Jing Jing Shen Ji Bing Za Zhi 2015; 41: 87-91.
16 Li G, Zhou X, Wang J, et al. Research on measuring scale for pathogen unit of hemorrhagic stroke due to heat-stasis. Nanjing Zhong Yi Yao Da Xue Xue Bao 2015; 31: 428-32.
17 Li GC, Zhang L, Yu M, et al. Identification of novel biomarker and therapeutic target candidates for acute intracerebral hemorrhage by quantitative plasma proteomics. Clin Proteomics 2017; 14: 14.
18 Mi H, Muruganujan A, Thomas PD. Panther in 2013: Modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees. Nucleic Acids Res 2013; 41: 377-86.
19 Zhou Z. Research on the syndrome and treatment of intracerebral hemorrhage (haemostasis and heat syndrome). Zhong Yi Yao Xue Kan 2002; 2002: 709-11+23.
20 Zhou Z. Theory of stasis-heat. Nanjing Zhong Yi Yao Da Xue Xue Bao 2006; 2006: 273-6+331.
21 Jiang B, Tian L, Xu L. Effects of Liangxue Tongyu on hematological system and brain injury after cerebral ischemia in rats. Zhong Guo Lao Nian Xue Za Zhi 2015; 35: 134-6.
22 He C, Huang J, Wang W, et al. Effects of Liangxue Tongyu formula on brain edema and expressions of matrix metalloprooteinase-9 and tissue inhibitor of metalloproteinase-1 in rats with intracerebral hemorrhage. Zhong Xi Yi Jie He Xue Bao 2010; 8: 347-51.
23 Schwarz S, Hafner K, Aschoff A, Schwab S. Incidence and prognostic significance of fever following intracerebral hemorrhage. Neurology 2000; 54: 354-61.
24 Rosell A, Cuadrado E, Ortega-Aznar A, Hernandez-Guillamon M, Lo EH, Montaner J. Mmp-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type iv collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 2008; 39: 1121-6.
25 Cao G, Savani RC, Fehrenbach M, et al. Involvement of endothelial cd44 during in vivo angiogenesis. Am J Pathol 2006; 169: 325-36.
26 Winder SJ, Ayscough KR. Actin-binding proteins. J Cell Sci 2005; 118: 651-4.
27 Bois PR, O'Hara BP, Nietlispach D, Kirkpatrick J, Izard T. The vinculin binding sites of talin and alpha-actinin are sufficient to activate vinculin. J Biol Chem 2006; 281: 7228-36.
28 Shah DI, Singh M. Involvement of rho-kinase in experimental vascular endothelial dysfunction. Mol Cell Biochem 2006; 283: 191-9.
29 Liu X, Lu D, Bowser R, Liu J. Expression of carbonic anhydrase i in motor neurons and alterations in als. Int J Mol Sci 2016; 17: 1820.
30 Yang G, Hu R, Zhang C, et al. A combination of serum iron, ferritin and transferrin predicts outcome in patients with intracerebral hemorrhage. Sci Rep 2016; 6: 21970.
31 Liu H, Hua Y, Keep RF, Xi G. Brain ceruloplasmin expression after experimental intracerebral hemorrhage and protection against iron-induced brain injury. Transl Stroke Res 2019; 10: 112-9.
32 Tian M, Cui YZ, Song GH, et al. Proteomic analysis identifies MMP-9, DJ-1 and A1BG as overexpressed proteins in pancreatic juice from pancreatic ductal adenocarcinoma patients. BMC Cancer 2008; 8: 241.
33 Bai S, Liu S, Guo X, et al. Proteome analysis of biomarkers in the cerebrospinal fluid of neuromyelitis optica patients. Mol Vis 2009; 15: 1638-48.
34 Sevilla L, Zaldumbide A, Pognonec P, Boulukos KE. Transcriptional regulation of the Bcl-X gene encoding the anti-apoptotic Bcl-XL protein by ets, rel/nfkappab, stat and ap1 transcription factor families. Histol Histopathol 2001; 16: 595-601.
35 Xi S, Gooding WE, Grandis JR. In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy. Oncogene 2005; 24: 970-9.
36 Liu J, Su G, Gao J, Tian Y, Liu X, Zhang Z. Effects of peroxiredoxin 2 in neurological disorders: a review of its molecular mechanisms. Neurochem Res 2020; 45: 720-30.
37 Frantz S, Kobzik L, Kim YD, et al. Toll4 (tlr4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest 1999; 104: 271-80.
38 Zhao F, Huang Y, Li G. Influence of Liangxue Tongyu Fang on proliferation, secretion and related signaling pathway proteins expression in vec. Nanjing Zhong Yi Yao Da Xue Xue Bao 2018; 34: 510-2.
39 Norata GD, Ongari M, Uboldi P, Pellegatta F, Catapano AL. Liver x receptor and retinoic x receptor agonists modulate the expression of genes involved in lipid metabolism in human endothelial cells. Int J Mol Med 2005; 16: 717-22.
40 Gruys E, Toussaint MJ, Niewold TA, Koopmans SJ. Acute phase reaction and acute phase proteins. J Zhejiang Univ Sci B 2005; 6: 1045-56.
41 Hajjar DP, Pomerantz KB. Signal transduction in atherosclerosis: Integration of cytokines and the eicosanoid network. FASEB J 1992; 6: 2933-41.
42 Schmidt A, Hall MN. Signaling to the actin cytoskeleton. Annu Rev Cell Dev Biol 1998; 14: 305-38.
43 Carpenter CL. Actin cytoskeleton and cell signaling. Crit Care Med 2000; 4 Suppl(28):N94-9.
44 Suzuki M, Ogawa A, Sakurai Y, et al. Thrombin activity in cerebrospinal fluid after subarachnoid hemorrhage. Stroke 1992; 23: 1181-2.
45 Sorimachi H, Ono Y. Regulation and physiological roles of the calpain system in muscular disorders. Cardiovasc Res 2012; 96: 11-22.
46 Nishimura T, Takeichi M. Remodeling of the adherens junctions during morphogenesis. Curr Top Dev Biol 2009; 89: 33-54.
47 Lopez-Colome AM, Lee-Rivera I, Benavides-Hidalgo R, Lopez E. Paxillin: a crossroad in pathological cell migration. J Hematol Oncol 2017; 10: 50.
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