A combination of <em>Sophora flavescens</em> alkaloids and <em>Panax quinquefolium</em> saponins attenuates coxsackievirus B3‑induced acute myocarditis in mice via NF‑κB signaling

Liu,Menghui; Fan,Meiling; Xu,Huibo; Liu,Bo; Wang,Xin; Wen,Fuchun; Ji,Fenglan; Ding,Tao

doi:10.3892/etm.2023.11991

A combination of Sophora flavescens alkaloids and Panax quinquefolium saponins attenuates coxsackievirus B3‑induced acute myocarditis in mice via NF‑κB signaling

Authors:
- Menghui Liu
- Meiling Fan
- Huibo Xu
- Bo Liu
- Xin Wang
- Fuchun Wen
- Fenglan Ji
- Tao Ding
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Affiliations: Department of Pediatrics, Jilin Academy of Traditional Chinese Medicine, Changchun, Jilin 130012, P.R. China, Department of Cardiology, The First Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin 130012, P.R. China, Pharmacodynamic and Toxicological Evaluation Center, Jilin Academy of Traditional Chinese Medicine, Changchun, Jilin 130012, P.R. China
Published online on: May 4, 2023 https://doi.org/10.3892/etm.2023.11991
Article Number: 292
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Timely treatment of viral myocarditis (VMC), a form of cardiac inflammation caused by viral infections, can reduce the occurrence of dilated cardiomyopathy and sudden death. Our previous study demonstrated the anti‑inflammatory and anti‑fibrotic effects of KX, a combination of Sophora flavescens alkaloids and Panax quinquefolium saponins, on an autoimmune myocarditis model in vivo. The present study explored the effects of KX on coxsackievirus B3 (CVB3)‑induced acute VMC in mice. Mice were randomly divided into four groups: Control, VMC, KX‑high (275 mg/kg) and KX‑low (138 mg/kg). Mice in the VMC, KX‑high and KX‑low groups received injections of CVB3 to establish the VMC model, and those in the KX‑high and KX‑low groups also received KX by gavage (10 ml/kg) 2 h after virus injection until euthanasia was performed on day 7 or 21. Mice in the control group received an equal KX volume of purified water. The levels of lactate dehydrogenase (LDH), creatine kinase‑myocardial band (CK‑MB), cardiac troponin I (cTn‑I), IL‑1β, IL‑6, TNF‑α and high‑sensitive C‑reactive protein (hs‑CRP) in mouse serum was measured using ELISA. Myocardial tissue structure and degree of injury were observed using hematoxylin and eosin staining. Western blotting and reverse transcription‑quantitative PCR were performed to detect the expression levels of NF‑κB pathway‑related mRNA and protein in myocardial tissue. The results showed that the inflammation and myocardial damage levels of the mice in the VMC group were higher at 7 days than those at 21 days. At both 7 and 21 days, KX decreased the serum CK‑MB, LDH, cTn‑I, IL‑6, TNF‑α and hs‑CRP levels, and inhibited NF‑κB pathway‑related mRNA and protein expression in the myocardium of mice. These findings indicated that KX may reduce the inflammatory response and attenuate the pathological damage in the acute and subacute phases of CVB3‑induced VMC through the NF‑κB pathway.

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1	Putschoegl A and Auerbach S: Diagnosis, evaluation, and treatment of myocarditis in children. Pediatr Clin North Am. 67:855–874. 2020.PubMed/NCBI View Article : Google Scholar
2	Doolan A, Langlois N and Semsarian C: Causes of sudden cardiac death in young Australians. Med J Aust. 180:110–112. 2004.PubMed/NCBI View Article : Google Scholar
3	Fairley CK, Ryan M, Wall PG and Weinberg J: The organisms reported to cause infective myocarditis and pericarditis in England and Wales. J Infect. 32:223–225. 1996.PubMed/NCBI View Article : Google Scholar
4	Woodruff JF: Viral myocarditis. A review. Am J Pathol. 101:425–484. 1980.PubMed/NCBI
5	He Y, Chipman PR, Howitt J, Bator CM, Whitt MA, Baker TS, Kuhn RJ, Anderson CW, Freimuth P and Rossmann MG: Interaction of coxsackievirus B3 with the full length coxsackievirus-adenovirus receptor. Nat Struct Biol. 8:874–878. 2001.PubMed/NCBI View Article : Google Scholar
6	Pollack A, Kontorovich AR, Fuster V and Dec GW: Viral myocarditis-diagnosis, treatment options, and current controversies. Nat Rev Cardiol. 12:670–680. 2015.PubMed/NCBI View Article : Google Scholar
7	Brucato A, Imazio M, Gattorno M, Lazaros G, Maestroni S, Carraro M, Finetti M, Cumetti D, Carobbio A, Ruperto N, et al: Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: The AIRTRIP randomized clinical trial. JAMA. 316:1906–1912. 2016.PubMed/NCBI View Article : Google Scholar
8	Scott IC, Hajela V, Hawkins PN and Lachmann HJ: A case series and systematic literature review of anakinra and immunosuppression in idiopathic recurrent pericarditis. J Cardiol Cases. 4:e93–e97. 2011.PubMed/NCBI View Article : Google Scholar
9	Tschöpe C, Ammirati E, Bozkurt B, Caforio ALP, Cooper LT, Felix SB, Hare JM, Heidecker B, Heymans S, Hübner N, et al: Myocarditis and inflammatory cardiomyopathy: Current evidence and future directions. Nat Rev Cardiol. 18:169–193. 2021.PubMed/NCBI View Article : Google Scholar
10	Li FS and Weng JK: Demystifying traditional herbal medicine with modern approach. Nat Plants. 3(17109)2017.PubMed/NCBI View Article : Google Scholar
11	Niu Y, Dong Q and Li R: Matrine regulates Th1/Th2 cytokine responses in rheumatoid arthritis by attenuating the NF-κB signaling. Cell Biol Int. 41:611–621. 2017.PubMed/NCBI View Article : Google Scholar
12	Zheng X, Wang S, Zou X, Jing Y, Yang R, Li S and Wang F: Ginsenoside Rb1 improves cardiac function and remodeling in heart failure. Exp Anim. 66:217–228. 2017.PubMed/NCBI View Article : Google Scholar
13	Wang QW, Yu XF, Xu HL, Zhao XZ and Sui DY: Ginsenoside re improves isoproterenol-induced myocardial fibrosis and heart failure in rats. Evid Based Complement Alternat Med. 2019(3714508)2019.PubMed/NCBI View Article : Google Scholar
14	Liu M, Lin Y, Xu H, Li L and Ding T: Combination of Sophora flavescens alkaloids and Panax quinquefolium saponins modulates different stages of experimental autoimmune myocarditis via the NF-κB and TGF-β1 pathways. Exp Ther Med. 24(570)2022.PubMed/NCBI View Article : Google Scholar
15	Aretz HT: Myocarditis: The dallas criteria. Hum Pathol. 18:619–624. 1987.PubMed/NCBI View Article : Google Scholar
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
17	Sinagra G, Anzini M, Pereira NL, Bussani R, Finocchiaro G, Bartunek J and Merlo M: Myocarditis in clinical practice. Mayo Clin Proc. 91:1256–1266. 2016.PubMed/NCBI View Article : Google Scholar
18	Liu M, Lin Y, Xu H, Wang X, Liu B, Fan M, Ding T and Li L: Mechanism of the combination of KuShen and XiYangShen on myocarditis based on network pharmacology and animal experiments. Pharmacol Res-Mod Chin Med. 4(100141)2022.
19	Błyszczuk P: Myocarditis in humans and in experimental animal models. Front Cardiovasc Med. 6(64)2019.PubMed/NCBI View Article : Google Scholar
20	Lasrado N and Reddy J: An overview of the immune mechanisms of viral myocarditis. Rev Med Virol. 30:1–14. 2020.PubMed/NCBI View Article : Google Scholar
21	Kandolf R, Ameis D, Kirschner P, Canu A and Hofschneider PH: In situ detection of enteroviral genomes in myocardial cells by nucleic acid hybridization: An approach to the diagnosis of viral heart disease. Proc Natl Acad Sci USA. 84:6272–6276. 1987.PubMed/NCBI View Article : Google Scholar
22	Badorff C, Lee GH, Lamphear BJ, Martone ME, Campbell KP, Rhoads RE and Knowlton KU: Enteroviral protease 2A cleaves dystrophin: Evidence of cytoskeletal disruption in an acquired cardiomyopathy. Nat Med. 5:320–326. 1999.PubMed/NCBI View Article : Google Scholar
23	Huber SA, Sartini D and Exley M: Vgamma4(+) T cells promote autoimmune CD8(+) cytolytic T-lymphocyte activation in coxsackievirus B3-induced myocarditis in mice: Role for CD4(+) Th1 cells. J Virol. 76:10785–10790. 2002.PubMed/NCBI View Article : Google Scholar
24	Izumi T, Takehana H, Matsuda C, Yokoyama H, Kohno K, Suzuki K and Inomata T: Experimental autoimmune myocarditis and its pathomechanism. Herz. 25:274–278. 2000.PubMed/NCBI View Article : Google Scholar
25	Esfandiarei M and McManus BM: Molecular biology and pathogenesis of viral myocarditis. Annu Rev Pathol. 3:127–155. 2008.PubMed/NCBI View Article : Google Scholar
26	Liu T, Zhang M, Niu H, Liu J, Ruilian M, Wang Y, Xiao Y, Xiao Z, Sun J, Dong Y and Liu X: Astragalus polysaccharide from Astragalus Melittin ameliorates inflammation via suppressing the activation of TLR-4/NF-κB p65 signal pathway and protects mice from CVB3-induced virus myocarditis. Int J Biol Macromol. 126:179–186. 2019.PubMed/NCBI View Article : Google Scholar
27	Gu X, Li Y, Chen K, Wang X, Wang Z, Lian H, Lin Y, Rong X, Chu M, Lin J and Guo X: Exosomes derived from umbilical cord mesenchymal stem cells alleviate viral myocarditis through activating AMPK/mTOR-mediated autophagy flux pathway. J Cell Mol Med. 24:7515–7530. 2020.PubMed/NCBI View Article : Google Scholar
28	Kubota T, Bounoutas GS, Miyagishima M, Kadokami T, Sanders VJ, Bruton C, Robbins PD, McTiernan CF and Feldman AM: Soluble tumor necrosis factor receptor abrogates myocardial inflammation but not hypertrophy in cytokine-induced cardiomyopathy. Circulation. 101:2518–2525. 2000.PubMed/NCBI View Article : Google Scholar
29	Kraft L, Erdenesukh T, Sauter M, Tschöpe C and Klingel K: Blocking the IL-1β signalling pathway prevents chronic viral myocarditis and cardiac remodeling. Basic Res Cardiol. 114(11)2019.PubMed/NCBI View Article : Google Scholar
30	Yue-Chun L, Gu XH, Li-Sha G, Zhou DP, Xing C, Guo XL, Pan LL, Song SY, Yu LL, Chen GY, et al: Vagus nerve plays a pivotal role in CD4+ T cell differentiation during CVB3-induced murine acute myocarditis. Virulence. 12:360–376. 2021.PubMed/NCBI View Article : Google Scholar
31	Sen R and Baltimore D: Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 46:705–716. 1986.PubMed/NCBI View Article : Google Scholar
32	Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS, Lee KY, Bussey C, Steckel M, Tanaka N, et al: TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev. 19:2668–2681. 2005.PubMed/NCBI View Article : Google Scholar
33	Cheng Z, Taylor B, Ourthiague DR and Hoffmann A: Distinct single-cell signaling characteristics are conferred by the MyD88 and TRIF pathways during TLR4 activation. Sci Signal. 8(ra69)2015.PubMed/NCBI View Article : Google Scholar
34	Xue YL, Zhang SX, Zheng CF, Li YF, Zhang LH, Hao YF, Wang S and Li XW: Silencing of STAT4 protects against autoimmune myocarditis by regulating Th1/Th2 immune response via inactivation of the NF-κB pathway in rats. Inflammation. 42:1179–1189. 2019.PubMed/NCBI View Article : Google Scholar
35	Pan A, Tan Y, Wang Z and Xu G: STAT4 silencing underlies a novel inhibitory role of microRNA-141-3p in inflammation response of mice with experimental autoimmune myocarditis. Am J Physiol Heart Circ Physiol. 317:H531–H540. 2019.PubMed/NCBI View Article : Google Scholar
36	Zhu Z, Xueying L, Chunlin L, Wen X, Rongrong Z, Jing H, Meilan J, Yuwei X and Zili W: Effect of berberine on LPS-induced expression of NF-κB/MAPK signalling pathway and related inflammatory cytokines in porcine intestinal epithelial cells. Innate Immun. 26:627–634. 2020.PubMed/NCBI View Article : Google Scholar
37	Hu J, Luo J, Zhang M, Wu J, Zhang Y, Kong H, Qu H, Cheng G and Zhao Y: Protective effects of radix sophorae flavescentis carbonisata-based carbon dots against ethanol-induced acute gastric ulcer in rats: Anti-inflammatory and antioxidant activities. Int J Nanomedicine. 16:2461–2475. 2021.PubMed/NCBI View Article : Google Scholar
38	Liu ZL, Liu ZJ, Liu JP, Yang M and Kwong J: Herbal medicines for viral myocarditis. Cochrane Database Syst Rev. (CD003711)2010.PubMed/NCBI View Article : Google Scholar
39	Matsumori A, Wang H, Abelmann WH and Crumpacker CS: Treatment of viral myocarditis with ribavirin in an animal preparation. Circulation. 71:834–839. 1985.PubMed/NCBI View Article : Google Scholar