Xuebijing improves intestinal microcirculation dysfunction in septic rats by regulating the VEGF-A/PI3K/Akt signaling pathway

doi:10.5847/wjem.j.1920-8642.2024.035

Abstract

Abstract:

BACKGROUND: This study aims to explore whether Xuebijing (XBJ) can improve intestinal microcirculation dysfunction in sepsis and its mechanism.
METHODS: A rat model of sepsis was established by cecal ligation and puncture (CLP). A total of 30 male SD rats were divided into four groups: sham group, CLP group, XBJ + axitinib group, and XBJ group. XBJ was intraperitoneally injected 2 h before CLP. Hemodynamic data (blood pressure and heart rate) were recorded. The intestinal microcirculation data of the rats were analyzed via microcirculation imaging. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) in the rats. Histological analysis and transmission electron microscopy were used to analyze the injury of small intestinal microvascular endothelial cells and small intestinal mucosa in rats. The expression of vascular endothelial growth factor A (VEGF-A), phosphoinositide 3-kinase (PI3K), phosphorylated PI3K (p-PI3K), protein kinase B (Akt), and phosphorylated Akt (p-Akt) in the small intestine was analyzed via Western blotting.
RESULTS: XBJ improved intestinal microcirculation dysfunction in septic rats, alleviated the injury of small intestinal microvascular endothelial cells and small intestinal mucosa, and reduced the systemic inflammatory response. Moreover, XBJ upregulated the expression of VEGF-A, p-PI3K/total PI3K, and p-Akt/total Akt in the rat small intestine.
CONCLUSION: XBJ may improve intestinal microcirculation dysfunction in septic rats possibly through the VEGF-A/PI3K/Akt signaling pathway.

Key words: Sepsis, Xuebijing, Vascular endothelial growth factor A, Microcirculation, Rat, Phosphoinositide 3-kinase, Protein kinase B

A-ling Tang, Yan Li, Li-chao Sun, Xiao-yu Liu, Nan Gao, Sheng-tao Yan, Guo-qiang Zhang. Xuebijing improves intestinal microcirculation dysfunction in septic rats by regulating the VEGF-A/PI3K/Akt signaling pathway[J]. World Journal of Emergency Medicine, 2024, 15(3): 206-213.

Figures/Tables 5

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References 31

1	Zhang WY, Chen ZH, An XX, Li H, Zhang HL, Wu SJ, et al. Analysis and validation of diagnostic biomarkers and immune cell infiltration characteristics in pediatric sepsis by integrating bioinformatics and machine learning. World J Pediatr. 2023; 19(11):1094-1103.
2	Wei JX, Jiang HL, Chen XH. Endothelial cell metabolism in sepsis. World J Emerg Med. 2023; 14(1):10-6.
3	Lelubre C, Vincent JL. Mechanisms and treatment of organ failure in sepsis. Nat Rev Nephrol. 2018; 14(7):417-27. doi: 10.1038/s41581-018-0005-7 pmid: 29691495
4	Tang AL, Shen MJ, Zhang GQ. Intestinal microcirculation dysfunction in sepsis: pathophysiology, clinical monitoring, and therapeutic interventions. World J Emerg Med. 2022; 13(5):343-8. doi: 10.5847/wjem.j.1920-8642.2022.031 pmid: 36119779
5	Heitrich M, García DM, Stoyanoff TR, Rodríguez JP, Todaro JS, Aguirre MV. Erythropoietin attenuates renal and pulmonary injury in polymicrobial induced-sepsis through EPO-R, VEGF and VEGF-R2 modulation. Biomed Pharmacother. 2016;82:606-13.
6	Thickett DR, Armstrong L, Millar AB. A role for vascular endothelial growth factor in acute and resolving lung injury. Am J Respir Crit Care Med. 2002; 166(10):1332-7.
7	Abid MR, Guo SD, Minami T, Spokes KC, Ueki K, Skurk C, et al. Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol. 2004; 24(2):294-300. doi: 10.1161/01.ATV.0000110502.10593.06 pmid: 14656735
8	Jiang BH, Liu LZ. Akt signaling in regulating angiogenesis. Curr Cancer Drug Targets. 2008; 8(1):19-26.
9	Sun Z, Zuo L, Sun T, Tang J, Ding D, Zhou L, et al. Chemical profiling and quantification of Xuebijing injection, a systematic quality control strategy using UHPLC-Q Exactive hybrid quadrupole-orbitrap high-resolution mass spectrometry. Sci Rep. 2017; 7(1):16921. doi: 10.1038/s41598-017-17170-y pmid: 29208914
10	Liu JF, Wang ZZ, Lin J, Li T, Guo XJ, Pang R, et al. Xuebijing injection in septic rats mitigates kidney injury, reduces cortical microcirculatory disorders, and suppresses activation of local inflammation. J Ethnopharmacol. 2021; 276:114199.
11	Huang ZY, Yang P. Effect of Xuebijing on intestinal microcirculation in septic rats. Proceedings of 17th Annual Congress of the Chinese Society for Emergency Medicine. 2014;109-10. (Article in Chinese)
12	Rittirsch D, Huber-Lang MS, Flierl MA, Ward PA. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc. 2009; 4(1):31-6. doi: 10.1038/nprot.2008.214 pmid: 19131954
13	Pancoto JAT, Corrêa PBF, Oliveira-Pelegrin GR, Rocha MJA. Autonomic dysfunction in experimental sepsis induced by cecal ligation and puncture. Auton Neurosci. 2008; 138(1-2):57-63.
14	Zhang QF, Gao ZJ, Zhang ZW, Zhao XG, Feng JK, Xu YF, et al. Impacts of high-voltage electrical burn on serum platelet-related factors and platelet aggregation number in rats and the interventive effect of Xuebijing. Zhonghua Shao Shang Za Zhi. 2020; 36(6):426-32. (Article in Chinese)
15	Imai S, Miyake H, Fujisawa M. Acceleration of proteinuria without significant impact on renal function and its protection by angiotensin II receptor blocker in rats treated with axitinib. Target Oncol. 2016; 11(3):309-15. doi: 10.1007/s11523-015-0393-6 pmid: 26423685
16	Zhang L, Wang YX, Cao C, Zhu YK, Huang W, Yang Y, et al. Beneficial effect of Xuebijing against Pseudomonas aeruginosa infection in Caenorhabditis elegans. Front Pharmacol. 2022; 13: 949608.
17	Thorburn T, Aali M, Kostek L, LeTourneau-Paci C, Colp P, Zhou J, et al. Anti-inflammatory effects of a novel iron chelator, DIBI, in experimental sepsis. Clin Hemorheol Microcirc. 2017; 67(3-4):241-50. doi: 10.3233/CH-179205 pmid: 28869457
18	Dumbarton TC, Maxan A, Farah N, Sharawy N, Zhou J, Nantais J, et al. Tetrahydrobiopterin improves microcirculation in experimental sepsis. Clin Hemorheol Microcirc. 2017; 67(1):15-24. doi: 10.3233/CH-160207 pmid: 28598830
19	Andersson A, Rundgren M, Kalman S, Rooyackers O, Brattstrom O, Oldner A, et al. Gut microcirculatory and mitochondrial effects of hyperdynamic endotoxaemic shock and norepinephrine treatment. Br J Anaesth. 2012; 108(2):254-61. doi: 10.1093/bja/aer379 pmid: 22157851
20	Liu ZJ, Zeng ZH, Wu CD, Liu H. Tropisetron inhibits sepsis by repressing hyper-inflammation and regulating the cardiac action potential in rat models. Biomed Pharmacother. 2019; 110:380-8. doi: S0753-3322(18)35470-2 pmid: 30529771
21	Li J, Olaleye OE, Yu X, Jia WW, Yang JL, Lu C, et al. High degree of pharmacokinetic compatibility exists between the five-herb medicine Xuebijing and antibiotics comedicated in sepsis care. Acta Pharm Sin B. 2019; 9(5):1035-49. doi: 10.1016/j.apsb.2019.06.003 pmid: 31649852
22	Yin Q, Li CS. Treatment effects of Xuebijing injection in severe septic patients with disseminated intravascular coagulation. Evid Based Complement Alternat Med. 2014; 2014:949254.
23	Liao XZ, Tao LT, Liu JH, Gu YY, Xie J, Chen YL, et al. Matrine combined with cisplatin synergistically inhibited urothelial bladder cancer cells via down-regulating VEGF/PI3K/Akt signaling pathway. Cancer Cell Int. 2017; 17:124.
24	Ruan GX, Kazlauskas A. VEGF-A engages at least three tyrosine kinases to activate PI3K/Akt. Cell Cycle. 2012; 11(11):2047-8.
25	Sljivancanin Jakovljevic T, Martic J, Jacimovic J, Nikolic N, Milasin J, Mitrović TL. Association between innate immunity gene polymorphisms and neonatal sepsis development: a systematic review and meta-analysis. World J Pediatr. 2022; 18(10):654-70. doi: 10.1007/s12519-022-00569-7 pmid: 35666457
26	Sun P, Wei S, Wei X, Wang JQ, Zhang YY, Qiao MQ, et al. Anger emotional stress influences VEGF/VEGFR2 and its induced PI3K/Akt/mTOR signaling pathway. Neural Plast. 2016; 2016:4129015.
27	Jesmin S, Zaedi S, Islam AM, Sultana SN, Iwashima Y, Wada T, et al. Time-dependent alterations of VEGF and its signaling molecules in acute lung injury in a rat model of sepsis. Inflammation. 2012; 35(2):484-500. doi: 10.1007/s10753-011-9337-1 pmid: 21528367
28	Zhou WA, Lai XX, Wang X, Yao XQ, Wang WH, Li S. Network pharmacology to explore the anti-inflammatory mechanism of Xuebijing in the treatment of sepsis. Phytomedicine. 2021; 85: 153543.
29	Zheng WJ, Yan Q, Ni YS, Zhan SF, Yang LL, Zhuang HF, et al. Examining the effector mechanisms of Xuebijing injection on COVID-19 based on network pharmacology. BioData Min. 2020; 13:17.
30	Han XY, Liu X, Zhao X, Wang XK, Sun YZ, Qu C, et al. Dapagliflozin ameliorates sepsis-induced heart injury by inhibiting cardiomyocyte apoptosis and electrical remodeling through the PI3K/Akt pathway. Eur J Pharmacol. 2023; 955: 175930.
31	Bi CF, Liu J, Hao SW, Xu ZX, Ma X, Kang XF, et al. Xuebijing injection protects against sepsis-induced myocardial injury by regulating apoptosis and autophagy via mediation of PI3K/Akt/mTOR signaling pathway in rats. Aging. 2023; 15(10):4374-90.

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