Resveratrol‑loaded nanoparticles inhibit enterovirus 71 replication through the oxidative stress‑mediated ERS/autophagy pathway

  • Authors:
    • Na Du
    • Xiao‑Hua Li
    • Wan‑Guo Bao
    • Bin Wang
    • Guang Xu
    • Feng Wang
  • View Affiliations

  • Published online on: May 28, 2019     https://doi.org/10.3892/ijmm.2019.4211
  • Pages: 737-749
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Abstract

A number of studies have demonstrated that resveratrol (RES) has a variety of biological functions, including cardiovascular protective effects, treatment of mutations, and anti‑inflammatory, anti‑tumor and antiviral effects. In the present study, RES‑loaded nanoparticles (RES‑NPs) were used to protect rhabdosarcoma (RD) cells from enterovirus 71 (EV71) infection, and the relevant mechanisms were also explored. An amphiphilic copolymer, monomethoxy poly (ethylene glycol)‑b‑poly (D,L‑lactide), was used as vehicle material, and RES‑NPs with necessitated drug‑loading content and suitable sizes were prepared under optimized conditions. RES‑NPs exhibited the ability to inhibit the increase of intracellular oxidative stress. The prospective mechanism for the function of RES‑NPs suggested was that RES‑NPs may inhibit the oxidative stress‑mediated PERK/eIF2α/ATF4 signaling pathway, downregulate the autophagy pathway and resist EV71‑induced RD cells injury. Furthermore, RES‑NPs treatment markedly inhibited the secretion of inflammatory factors, including interleukin (IL)‑6, IL‑8 and tumor necrosis factor‑α elicited by EV71 infection. Concomitantly, inhibitors of oxidative stress, endoplasmic reticulum stress (ERS) or autophagy were demonstrated to negate the anti‑inflammatory and antiviral effects of RES‑NPs on EV71‑infected RD cells. These results demonstrated that RES‑NPs attenuated EV71‑induced viral replication and inflammatory effects by inhibiting the oxidative stress‑mediated ERS/autophagy signaling pathway. In view of their safety and efficiency, these RES‑NPs have potential applications in protecting RD cells from EV71 injury.

References

1 

Lin JY and Shih SR: Cell and tissue tropism of enterovirus 71 and other enteroviruses infections. J Biomed Sci. 21:182014. View Article : Google Scholar : PubMed/NCBI

2 

Zhou ZM, Xu Y, Hu CS, Pan QJ and Wei JJ: Epidemiological features of hand, foot and mouth disease during the period of 2008-14 in Wenzhou, China. J Trop Pediatr. 63:182–188. 2017.

3 

Garmaroudi FS, Marchant D, Hendry R, Luo H, Yang D, Ye X, Shi J and McManus BM: Coxsackievirus B3 replication and pathogenesis. Future Microbiol. 10:629–653. 2015. View Article : Google Scholar : PubMed/NCBI

4 

Huang YT, Liao JT, Yen LC, Chang YK, Lin YL and Liao CL: Japanese encephalitis virus replicon-based vaccine expressing enterovirus-71 epitope confers dual protection from lethal challenges. J Biomed Sci. 22:742015. View Article : Google Scholar : PubMed/NCBI

5 

Gaaloul I, Riabi S, Harrath R, Hunter T, Hamda KB, Ghzala AB, Huber S and Aouni M: Coxsackievirus B detection in cases of myocarditis, myopericarditis, pericarditis and dilated cardiomy-opathy in hospitalized patients. Mol Med Rep. 10:2811–2818. 2014. View Article : Google Scholar : PubMed/NCBI

6 

Lee KY: Enterovirus 71 infection and neurological complications. Korean J Pediatr. 59:395–401. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Wang Y, Zou G, Xia A, Wang X, Cai J, Gao Q, Yuan S, He G, Zhang S, Zeng M and Altmeyer R: Enterovirus 71 infection in children with hand, foot, and mouth disease in Shanghai, China: Epidemiology, clinical feature and diagnosis. Virol J. 12:832015. View Article : Google Scholar : PubMed/NCBI

8 

Esposito S and Principi N: Hand, foot and mouth disease: Current knowledge on clinical manifestations, epidemiology, aetiology and prevention. Eur J Clin Microbiol Infect Dis. 37:391–398. 2018. View Article : Google Scholar : PubMed/NCBI

9 

Yang ZY, Chen XQ, Sun D and Wei D: Mortality in children with severe hand, foot and mouth disease in Guangxi, China. Indian Pediatr. 55:137–139. 2018. View Article : Google Scholar

10 

Huang X, Zhang X, Wang F, Wei H, Ma H, Sui M, Lu J, Wang H, Dumler JS, Sheng G and Xu B: Clinical efficacy of therapy with recombinant human interferon α1b in hand, foot, and mouth disease with enterovirus 71 infection. PLoS One. 11:e01489072016. View Article : Google Scholar

11 

Zhu Z, Ye X, Ku Z, Liu Q, Shen C, Luo H, Luan H, Zhang C, Tian S, Lim C, et al: Transcutaneous immunization via rapidly dissolvable microneedles protects against hand-foot-and-mouth disease caused by enterovirus 71. J Control Release. 243:291–302. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Jiewei T, Lei W, Xiufeng L, Heming Z, Xiaoguang L, Haiyan F and Yongqiang T: Microbial transformation of resveratrol by endophyte Streptomyces sp A12 isolated from Polygonum cuspidatum. Nat Prod Res. 32:2343–2346. 2018. View Article : Google Scholar

13 

Zhao G, Jiang K, Wu H, Qiu C, Deng G and Peng X: Polydatin reduces staphylococcus aureus lipoteichoic acid-induced injury by attenuating reactive oxygen species generation and TLR2-NFκB signaling. J Cell Mol Med. 21:2796–2808. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Heo JR, Kim SM, Hwang KA, Kang JH and Choi KC: Resveratrol induced reactive oxygen species and endoplasmic reticulum stress-mediated apoptosis, and cell cycle arrest in the A375SM malignant melanoma cell line. Int J Mol Med. 42:1427–1435. 2018.PubMed/NCBI

15 

Huang YT, Chen YY, Lai YH, Cheng CC, Lin TC, Su YS, Liu CH and Lai PC: Resveratrol alleviates the cytotoxicity induced by the radiocontrast agent, ioxitalamate, by reducing the production of reactive oxygen species in HK-2 human renal proximal tubule epithelial cells in vitro. Int J Mol Med. 37:83–91. 2016. View Article : Google Scholar :

16 

Li K, Li Y, Mi J, Mao L, Han X and Zhao J: Resveratrol protects against sodium nitroprusside induced nucleus pulposus cell apoptosis by scavenging ROS. Int J Mol Med. 41:2485–2492. 2018.PubMed/NCBI

17 

Zhang L, Li Y, Gu Z, Wang Y, Shi M, Ji Y, Sun J, Xu X, Zhang L, Jiang J and Shi W: Resveratrol inhibits enterovirus 71 replication and pro-inflammatory cytokine secretion in rhabdosarcoma cells through blocking IKKs/NF-κB signaling pathway. PLoS One. 10:e01168792015. View Article : Google Scholar

18 

Zhao X, Xu J, Song X, Jia R, Yin Z, Cheng A, Jia R, Zou Y, Li L, Yin L, et al: Antiviral effect of resveratrol in ducklings infected with virulent duck enteritis virus. Antiviral Res. 130:93–100. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Li K, Liu Y, Zhang S, Xu Y, Jiang J, Yin F, Hu Y, Han B, Ge S, Zhang L and Wang Y: Folate receptor-targeted ultrasonic PFOB nanoparticles: Synthesis, characterization and application in tumor-targeted imaging. Int J Mol Med. 39:1505–1515. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Jiang X, Zhong Y, Zheng L and Zhao J: Nano-hydroxyapatite/collagen film as a favorable substrate to maintain the phenotype and promote the growth of chondrocytes cultured in vitro. Int J Mol Med. 41:2150–2158. 2018.PubMed/NCBI

21 

Wu L, Chen M, Mao H, Wang N, Zhang B, Zhao X, Qian J and Xing C: Albumin-based nanoparticles as methylprednisolone carriers for targeted delivery towards the neonatal Fc receptor in glomerular podocytes. Int J Mol Med. 39:851–860. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Xu C, Peng Y, Zhang Q, Xu XP, Kong XM and Shi WF: USP4 positively regulates RLR-induced NF-κB activation by targeting TRAF6 for K48-linked deubiquitination and inhibits enterovirus 71 replication. Sci Rep. 8:134182018. View Article : Google Scholar

23 

Hamilton MA, Russo RC and Thurston RV: Trimmed Spearman-Karber method for estimating median lethal concentrations in toxicity bioassays. Environ Sci Technol. 11:714–719. 1977. View Article : Google Scholar

24 

Reed LJ and Muench H: A simple method of estimating fifty percent endpoints. Am J Epidemiol. 27:493–497. 1938. View Article : Google Scholar

25 

Li J, Zhou Y, Zhang W, Bao C and Xie Z: Relief of oxidative stress and cardiomyocyte apoptosis by using curcumin nanoparticles. Collolds Surf B Biointerfaces. 153:174–182. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Song S, Tan J, Miao Y and Zhang Q: Crosstalk of ER stress-mediated autophagy and ER-phagy: Involvement of UPR and the core autophagy machinery. J Cell Physiol. 233:3867–3874. 2018. View Article : Google Scholar

27 

Fraser JE, Wang C, Chan KW, Vasudevan SG and Jans DA: Novel dengue virus inhibitor 4-HPR activates ATF4 independent of protein kinase R-like endoplasmic reticulum kinase and elevates levels of eIF2α phosphorylation in virus infected cells. Antiviral Res. 130:1–6. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Thomas M, Davis T, Loos B, Sishi B, Huisamen B, Strijdom H and Engelbrecht AM: Autophagy is essential for the maintenance of amino acids and ATP levels during acute amino acid starvation in MDAMB231 cells. Cell Biochem Funct. 36:65–79. 2018. View Article : Google Scholar : PubMed/NCBI

29 

Lekli I, Haines DD, Balla G and Tosaki A: Autophagy: An adaptive physiological countermeasure to cellular senescence and ischaemia/reperfusion-associated cardiac arrhythmias. J Cell Mol Med. 21:1058–1072. 2017. View Article : Google Scholar

30 

Schroeder S, Zimmermann A, Carmona-Gutierrez D, Eisenberg T, Ruckenstuhl C, Andryushkova A, Pendl T, Harger A and Madeo F: Metabolites in aging and autophagy. Microb Cell. 1:110–114. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Deretic V and Klionsky DJ: Autophagy and inflammation: A special review issue. Autophagy. 14:179–180. 2018. View Article : Google Scholar : PubMed/NCBI

32 

Shao P, Wu X, Li H, Wu Z, Yang Z and Yao H: Clinical significance of inflammatory cytokine and chemokine expression in hand, foot and mouth disease. Mol Med Rep. 15:2859–2866. 2017. View Article : Google Scholar : PubMed/NCBI

33 

Shang W, Qian S, Fang L, Han Y and Zheng C: Association study of inflammatory cytokine and chemokine expression in hand foot and mouth disease. Oncotarget. 8:79425–79432. 2017. View Article : Google Scholar : PubMed/NCBI

34 

Yi EJ, Shin YJ, Kim JH, Kim TG and Chang SY: Enterovirus 71 infection and vaccines. Clin Exp Vaccine Res. 6:4–14. 2017. View Article : Google Scholar : PubMed/NCBI

35 

Wang M, Tao L and Xu H: Chinese herbal medicines as a source of molecules with anti-enterovirus 71 activity. Chin Med. 11:22016. View Article : Google Scholar : PubMed/NCBI

36 

Shi Y, Li Y, Huang C, Ying L, Xue J, Wu H, Chen Z and Yang Z: Resveratrol enhances HBV replication through activating Sirt1-PGC-1α-PPARα pathway. Sci Rep. 6:247442016. View Article : Google Scholar

37 

Liu T, Zang N, Zhou N, Li W, Xie X, Deng Y, Ren L, Long X, Li S, Zhou L, et al: Resveratrol inhibits the TRIF-dependent pathway by upregulating sterile alpha and armadillo motif protein, contributing to anti-inflammatory effects after respiratory syncytial virus infection. J Virol. 88:4229–4236. 2014. View Article : Google Scholar : PubMed/NCBI

38 

Li X, Huang Y, Sun M, Ji H, Dou H, Hu J, Yan Y, Wang X and Chen L: Honeysuckle-encoded microRNA2911 inhibits enterovirus 71 replication via targeting VP1 gene. Antiviral Res. 152:117–123. 2018. View Article : Google Scholar : PubMed/NCBI

39 

Mihaylova VT, Kong Y, Fedorova O, Sharma L, Dela Cruz CS, Pyle AM, Iwasaki A and Foxman EF: Regional differences in airway epithelial cells reveal tradeoff between defense against oxidative stress and defense against rhinovirus. Cell Rep. 24:3000–3007.e3. 2018. View Article : Google Scholar : PubMed/NCBI

40 

Griffiths C, Drews SJ and Marchant DJ: Respiratory syncytial virus: Infection, detection, and new options for prevention and treatment. Clin Microbiol Rev. 30:277–319. 2017. View Article : Google Scholar :

41 

Cheng ML, Weng SF, Kuo CH and Ho HY: Enterovirus 71 induces mitochondrial reactive oxygen species generation that is required for efficient replication. PLoS One. 9:e1132342014. View Article : Google Scholar : PubMed/NCBI

42 

Guo S, Yao Q, Ke Z, Chen H, Wu J and Liu C: Resveratrol attenuates high glucose-induced oxidative stress and cardio-myocyte apoptosis through AMPK. Mol Cell Endocrinol. 412:85–94. 2015. View Article : Google Scholar : PubMed/NCBI

43 

Yang J, Yin HS, Cao YJ, Jiang ZA, Li YJ, Song MC, Wang YF, Wang ZH, Yang R, Jiang YF, et al: Arctigenin attenuates ischemia/reperfusion induced ventricular arrhythmias by decreasing oxidative stress in rats. Cell Physiol Biochem. 49:728–742. 2018. View Article : Google Scholar : PubMed/NCBI

44 

Hu DD, Mai JN, He LY, Li PQ, Chen WX, Yan JJ, Zhu WD, Deng L, Wei D, Liu DH, et al: Glucocorticoids prevent entero-virus 71 capsid protein VP1 induced calreticulin surface exposure by alleviating neuronal ER stress. Neurotox Res. 31:204–217. 2017. View Article : Google Scholar

45 

Jheng JR, Wang SC, Jheng CR and Horng JT: Enterovirus 71 induces dsRNA/PKR-dependent cytoplasmic redistribution of GRP78/BiP to promote viral replication. Emerg Microbes Infect. 5:e232016.PubMed/NCBI

46 

Hosomi S, Grootjans J, Huang YH, Kaser A and Blumberg RS: New insights into the regulation of natural-killer group 2 member D (NKG2D) and NKG2D-ligands: Endoplasmic reticulum stress and CEA-related cell adhesion molecule 1. Front Immunol. 18:13242018. View Article : Google Scholar

47 

Zhong F, Xie J, Zhang D, Han Y and Wang C: Polypeptide from chlamys farreri suppresses ultraviolet-B irradiation-induced apoptosis through restoring ER redox homeostasis, scavenging ROS generation, and suppressing the PERK-eIF2a-CHOP pathway in HaCaT cells. J Photochem Photobiol B. 151:10–16. 2015. View Article : Google Scholar : PubMed/NCBI

48 

Jung KI, Pyo CW and Choi SY: Influenza A virus-induced autophagy contributes to enhancement of virus infectivity by SOD1 downregulation in alveolar epithelial cells. Biochem Biophys Res Commun. 498:960–966. 2018. View Article : Google Scholar : PubMed/NCBI

49 

Wei Y, Cao XN, Tang XL, Shen LJ, Lin T, He DW, Wu SD and Wei GH: Urban fine particulate matter (PM2.5) exposure destroys blood-testis barrier (BTB) integrity through excessive ROS-mediated autophagy. Toxicol Mech Methods. 28:302–319. 2018. View Article : Google Scholar

50 

Richetta C, Grégoire IP, Verlhac P, Azocar O, Baguet J, Flacher M, Tangy F, Rabourdin-Combe C and Faure M: Sustained autophagy contributes to measles virus infectivity. PLoS Pathog. 9:e10035992013. View Article : Google Scholar : PubMed/NCBI

51 

Rozières A, Viret C and Faure M: Autophagy in measles virus infection. Viruses. 9:pii: E359. 2017. View Article : Google Scholar : PubMed/NCBI

52 

Yan Y, Liu S, Li M, Zhao Y, Shao X, Hang M and Bu X: Recombinant Newcastle disease virus expressing human IFN-λ1 (rL-hIFN-λ1)-induced apoptosis of A549 cells is connected to endoplasmic reticulum stress pathways. Thorac Cancer. 9:1437–1452. 2018. View Article : Google Scholar : PubMed/NCBI

53 

Dash S, Chava S, Aydin Y, Chandra PK, Ferraris P, Chen W, Balart LA, Wu T and Garry RF: Hepatitis C virus infection induces autophagy as a prosurvival mechanism to alleviate hepatic ER-stress response. Viruses. 8:pii: E150. 2016. View Article : Google Scholar : PubMed/NCBI

54 

Lee JY, Son M, Kang JH and Choi UY: Serum interleukin-6 levels as an indicator of aseptic meningitis among children with enterovirus 71-induced hand, foot and mouth disease. Postgrad Med. 130:258–263. 2018. View Article : Google Scholar

55 

Zhu L, Li W, Qi G, Liu N, Sheng L, Shang L and Qi B: The immune mechanism of intestinal tract Toll-like receptor in mediating EV71 virus type severe hand-foot-and-mouth disease and the MAPK pathway. Exp Ther Med. 13:2263–2266. 2017. View Article : Google Scholar : PubMed/NCBI

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August 2019
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Copy and paste a formatted citation
APA
Du, N., Li, X., Bao, W., Wang, B., Xu, G., & Wang, F. (2019). Resveratrol‑loaded nanoparticles inhibit enterovirus 71 replication through the oxidative stress‑mediated ERS/autophagy pathway. International Journal of Molecular Medicine, 44, 737-749. https://doi.org/10.3892/ijmm.2019.4211
MLA
Du, N., Li, X., Bao, W., Wang, B., Xu, G., Wang, F."Resveratrol‑loaded nanoparticles inhibit enterovirus 71 replication through the oxidative stress‑mediated ERS/autophagy pathway". International Journal of Molecular Medicine 44.2 (2019): 737-749.
Chicago
Du, N., Li, X., Bao, W., Wang, B., Xu, G., Wang, F."Resveratrol‑loaded nanoparticles inhibit enterovirus 71 replication through the oxidative stress‑mediated ERS/autophagy pathway". International Journal of Molecular Medicine 44, no. 2 (2019): 737-749. https://doi.org/10.3892/ijmm.2019.4211