Fisetin administration improves LPS-induced acute otitis media in mouse in vivo

Li,Peng; Chen,Dan; Huang,Yang

doi:10.3892/ijmm.2018.3585

Fisetin administration improves LPS-induced acute otitis media in mouse in vivo

Authors:
- Peng Li
- Dan Chen
- Yang Huang
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Affiliations: Department of Otorhinolaryngology, The Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China, Department of Otolaryngology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China, Department of Otolaryngology, The First People's Hospital of Yunnan Province, Xishan, Kunming 650032, P.R. China
Published online on: March 22, 2018 https://doi.org/10.3892/ijmm.2018.3585
Pages: 237-247
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Acute otitis media is one of the most common infectious diseases worldwide in spite of the widespread vaccination. The present study was conducted to explore the effects of fisetin on mouse acute otitis media models. The animal models were established by lipopolysaccharide (LPS) injection into the middle ear of mice via the tympanic membrane. Fisetin was administered to mice for ten days through intragastric administration immediate after LPS application. Hematoxylin and eosin (H&E) staining was performed and the pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6 and VEGF, were measured through enzyme-linked immunosorbent assay (ELISA) method and RT-qPCR analysis. Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway was detected by immunoblotting assays. Reactive oxygen species (ROS) generated levels were determined through assessment of anti-oxidants, and TXNIP/MAPKs signaling pathways were explored to reveal the possible molecular mechanism for acute otitis media progression and the function of fisetin. Fisetin reduced mucosal thickness caused by LPS. In fisetin-treated animals, pro-inflammatory cytokine release was downregulated accompanied with TLR4/NF-κB inactivation. ROS production was significantly decreased in comparison to the LPS-treated group. The TXNIP/MAPKs signaling pathway was inactivated for fisetin treatment in LPS-induced mice with acute otitis media. The above results indicated that fisetin improved acute otitis media through inflammation and ROS suppression via inactivating TLR4/NF-κB and TXNIP/MAPKs signaling pathways.

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1	Morris LM, DeGagne JM, Kempton JB, Hausman F and Trune DR: Mouse middle ear ion homeostasis channels and intercellular junctions. PLoS One. 7:e390042012. View Article : Google Scholar : PubMed/NCBI
2	Darrow DH, Dash N and Derkay CS: Otitis media: Concepts and controversies. Curr Opin Otolaryngol Head Neck Surg. 11:416–423. 2003. View Article : Google Scholar
3	Bluestone CD and Klein JO: Physiology, pathophysiology and pathogenesis. Otitis Media in Infants and Children (4th edition). Decker BC: 41–42. 2007.
4	Post JC: Direct evidence of bacterial biofilms in otitis media. Laryngoscope. 111:2083–2094. 2001. View Article : Google Scholar
5	Topcuoglu N, Keskin F, Ciftci S, Paltura C, Kulekci M, Ustek D and Kulekci G: Relationship between oral anaerobic bacteria and otitis media with effusion. Int J Med Sci. 9:256–261. 2012. View Article : Google Scholar : PubMed/NCBI
6	Hebda PA, Piltcher OB, Swarts JD, Alper CM, Zeevi A and Doyle WJ: Cytokine profiles in a rat model of otitis media with effusion caused by eustachian tube obstruction with and without Streptococcus pneumoniae infection. Laryngoscope. 112:1657–1662. 2002. View Article : Google Scholar : PubMed/NCBI
7	Bouchet V, Hood DW, Li J, Brisson JR, Randle GA, Martin A, Li Z, Goldstein R, Schweda EK, Pelton SI, Richards JC, et al: Host-derived sialic acid is incorporated into Haemophilus influenzae lipopolysaccharide and is a major virulence factor in experimental otitis media(J). Proc Natl Acad Sci USA. 100:8898–8903. 2003. View Article : Google Scholar
8	Gallucci RM, Sugawara T, Yucesoy B, Berryann K, Simeonova PP, Matheson JM and Luster MI: Interleukin-6 treatment augments cutaneous wound healing in immunosuppressed mice. J Interferon Cytokine Res. 21:603–609. 2001. View Article : Google Scholar : PubMed/NCBI
9	Meng Z, Yan C, Deng Q, Gao DF and Niu XL: Curcumin inhibits LPS-induced inflammation in rat vascular smooth muscle cells in vitro via ROS-relative TLR4-MAPK/NF-κB pathways. Acta Pharmacol Sin. 34:901–911. 2013. View Article : Google Scholar : PubMed/NCBI
10	Schwarz JM and Bilbo SD: LPS elicits a much larger and broader inflammatory response than Escherichia coli infection within the hippocampus of neonatal rats. Neurosci Lett. 497:110–115. 2011. View Article : Google Scholar : PubMed/NCBI
11	Niemi K, Teirilä L, Lappalainen J, Rajamäki K, Baumann MH, Öörni K, Wolff H, Kovanen PT, Matikainen S and Eklund KK: Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J Immunol. 186:6119–6128. 2011. View Article : Google Scholar : PubMed/NCBI
12	Gicquel T, Victoni T, Fautrel A, Robert S, Gleonnec F, Guezingar M, Couillin I, Catros V, Boichot E and Lagente V: Involvement of purinergic receptors and NOD-like receptor-family protein 3-inflammasome pathway in the adenosine triphosphate-induced cytokine release from macrophages. Clin Exp Pharmacol Physiol. 41:279–286. 2014. View Article : Google Scholar : PubMed/NCBI
13	Schmitz ML, Bacher S and Kracht M: I kappa B-independent control of NF-kappa B activity by modulatory phosphorylations. Trends Biochem Sci. 26:186–190. 2001. View Article : Google Scholar : PubMed/NCBI
14	Hsieh PF, Hou CW, Yao PW, Wu SP, Peng YF, Shen ML, Lin CH, Chao YY, Chang MH and Jeng KC: Sesamin ameliorates oxidative stress and mortality in kainic acid-induced status epilepticus by inhibition of MAPK and COX-2 activation. J Neuroinflammation. 8:572011. View Article : Google Scholar : PubMed/NCBI
15	Murtaza I, Adhami VM, Hafeez BB, Saleem M and Mukhtar H: Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-kappaB. Int J Cancer. 125:2465–2473. 2009. View Article : Google Scholar : PubMed/NCBI
16	Li J, Cheng Y, Qu W, Sun Y, Wang Z, Wang H and Tian B: Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol. 108:84–93. 2011. View Article : Google Scholar
17	Ying TH, Yang SF, Tsai SJ, Hsieh SC, Huang YC, Bau DT and Hsieh YH: Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8-/caspase-3-dependent pathway. Arch Toxicol. 86:263–273. 2012. View Article : Google Scholar
18	Stol K, Diavatopoulos DA, Graamans K, Engel JA, Melchers WJ, Savelkoul HF, Hays JP, Warris A and Hermans PW: Inflammation in the middle ear of children with recurrent or chronic otitis media is associated with bacterial load. Pediatr Infect Dis J. 31:1128–1134. 2012. View Article : Google Scholar : PubMed/NCBI
19	Tateossian H, Morse S, Parker A, Mburu P, Warr N, Acevedo-Arozena A, Cheeseman M, Wells S and Brown SD: Otitis media in the Tgif knockout mouse implicates TGFβ signalling in chronic middle ear inflammatory disease. Hum Mol Genet. 22:2553–2565. 2013. View Article : Google Scholar : PubMed/NCBI
20	Ferenbach D, Kluth DC and Hughes J: Inflammatory cells in renal injury and repair. Semin Nephrol. 27:250–259. 2007. View Article : Google Scholar : PubMed/NCBI
21	Thieringer R, Fenyk-Melody JE, Le Grand CB, Shelton BA, Detmers PA, Somers EP, Carbin L, Moller DE, Wright SD and Berger J: Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo. J Immunol. 164:1046–1054. 2000. View Article : Google Scholar : PubMed/NCBI
22	Chávez-Sánchez L, Garza-Reyes MG, Espinosa-Luna JE, Chávez-Rueda K, Legorreta-Haquet MV and Blanco-Favela F: The role of TLR2, TLR4 and CD36 in macrophage activation and foam cell formation in response to oxLDL in humans. Hum Immunol. 75:322–329. 2014. View Article : Google Scholar : PubMed/NCBI
23	Wang W, Zhou A, Zhang X, Xiang Y, Huang Y, Wang L, Zhang S, Liu Y, Yin Y and He Y: Interleukin 17A promotes pneumococcal clearance by recruiting neutrophils and inducing apoptosis through a p38 mitogen-activated protein kinase-dependent mechanism in acute otitis media. Infect Immun. 82:2368–2377. 2014. View Article : Google Scholar : PubMed/NCBI
24	Brentnall M, Rodriguez-Menocal L, De Guevara RL, Cepero E and Boise LH: caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol. 14:322013. View Article : Google Scholar : PubMed/NCBI
25	Park J, Min JS, Kim B, Chae UB, Yun JW, Choi MS, Kong IK, Chang KT and Lee DS: Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways. Neurosci Lett. 584:191–196. 2015. View Article : Google Scholar
26	Li W, Wu Z, Ma Q, Liu J, Xu Q, Han L, Duan W, Lv Y, Wang F, Reindl KM, et al: Hyperglycemia regulates TXNIP/TRX/ROS axis via p38 MAPK and ERK pathways in pancreatic cancer. Curr Cancer Drug Targets. 14:348–356. 2014. View Article : Google Scholar : PubMed/NCBI
27	Cao G, Jiang N, Hu Y, Zhang Y, Wang G, Yin M, Ma X, Zhou K, Qi J, Yu B, et al: Ruscogenin attenuates cerebral ischemia-induced blood-brain barrier dysfunction by suppressing TXNIP/NLRP3 inflammasome activation and the MAPK pathway. Int J Mol Sci. 17:14182016. View Article : Google Scholar :
28	Jiang L, Fei D, Gong R, Yang W, Yu W, Pan S and Zhao M and Zhao M: CORM-2 inhibits TXNIP/NLRP3 inflammasome pathway in LPS-induced acute lung injury. Inflamm Res. 65:905–915. 2016. View Article : Google Scholar : PubMed/NCBI
29	Chu TG, Cachola DR III, Regal MA, Llamas AC, Martinez NV and Santos WR: Pneumococcal conjugate vaccine (Non-Typeable Haemophilus influenzae (NTHi) protein D, diphtheria or tetanus toxoid conjugates) in prevention of acute otitis media in children: A Cohort Study. Philipp J Otolaryngol Head Neck Surg. 31:12016.
30	Zhang J, Xu M, Zheng Q, Zhang Y, Ma W and Zhang Z: Blocking macrophage migration inhibitory factor activity alleviates mouse acute otitis media in vivo. Immunol Lett. 162:101–108. 2014. View Article : Google Scholar :
31	Yang PM, Tseng HH, Peng CW, Chen WS and Chiu SJ: Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer MCF-7 cells by induction of caspase-7-associated apoptosis and inhibition of autophagy. Int J Oncol. 40:469–478. 2012.
32	Hafré L, Einarsdottir E, Kentala E, Hammarén-Malmi S, Bhutta MF, MacArthur CJ, Wilmot B, Casselbrant M, Conley YP, Weeks DE, et al: Predisposition to childhood otitis media and genetic polymorphisms within the toll-like receptor 4 (TLR4) locus. PLoS One. 10:e01325512015. View Article : Google Scholar
33	Alladi PA, Roy T, Singh N and Wadhwa S: Prenatal auditory enrichment with species-specific calls and sitar music modulates expression of Bcl-2 and Bax to alter programmed cell death in developing chick auditory nuclei. Int J Dev Neurosci. 23:363–373. 2005. View Article : Google Scholar : PubMed/NCBI
34	Li X, Luo R, Jiang R, Meng X, Wu X, Zhang S and Hua W: The role of the Hsp90/Akt pathway in myocardial calpain-induced caspase-3 activation and apoptosis during sepsis. BMC Cardiovasc Disord. 13:82013. View Article : Google Scholar : PubMed/NCBI
35	Costa SS, Silva MNL, Rosito LPS and Selaimen FA: One case, two lessons: An aberrant internal carotid artery causing acquired cholesteatoma. Braz J Otorhinolaryngol. 80:453–454. 2014.In Portuguese. View Article : Google Scholar : PubMed/NCBI
36	Ha T, Xia Y, Liu X, Lu C, Liu L, Kelley J, Kalbfleisch J, Kao RL, Williams DL and Li C: Glucan phosphate attenuates myocardial HMGB1 translocation in severe sepsis through inhibiting NF-κB activation. Am J Physiol Heart Circ Physiol. 301:H848–H855. 2011. View Article : Google Scholar : PubMed/NCBI
37	Singh AK, Jiang Y, Gupta S, Younus M and Ramzan M: Anti-inflammatory potency of nano-formulated puerarin and curcumin in rats subjected to the lipopolysaccharide-induced inflammation. J Med Food. 16:899–911. 2013. View Article : Google Scholar : PubMed/NCBI
38	Lin J, Wang H, Li J, Wang Q, Zhang S, Feng N, Fan R and Pei J: κ-Opioid receptor stimulation modulates TLR4/NF-κB signaling in the rat heart subjected to ischemia-reperfusion. Cytokine. 61:842–848. 2013. View Article : Google Scholar : PubMed/NCBI
39	Ridder DA and Schwaninger M: NF-kappaB signaling in cerebral ischemia. Neuroscience. 158:995–1006. 2009. View Article : Google Scholar
40	Fan H, Li L, Zhang X, Liu Y, Yang C, Yang Y and Yin J: Oxymatrine downregulates TLR4, TLR2, MyD88, and NF-kappaB and protects rat brains against focal ischemia. Mediators Inflamm. 2009:7047062009. View Article : Google Scholar
41	Elgort MG, O'Shea JM, Jiang Y and Ayer DE: Transcriptional and translational downregulation of thioredoxin interacting protein is required for metabolic reprogramming during G(1). Genes Cancer. 1:893–907. 2010. View Article : Google Scholar
42	Zhou J, Yu Q and Chng WJ: TXNIP (VDUP-1, TBP-2): A major redox regulator commonly suppressed in cancer by epigenetic mechanisms. Int J Biochem Cell Biol. 43:1668–1673. 2011. View Article : Google Scholar : PubMed/NCBI
43	Tschopp J and Schroder K: NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 10:210–215. 2010. View Article : Google Scholar : PubMed/NCBI
44	Ye W, Lei Y, Yu M, Xu Y, Cao M, Yu L, Zhang L, Li P, Bai W and Xu Z: RP3 inflammasome is responsible for Hantavirus inducing interleukin-1β in THP-1 cells. Int J Mol Med. 35:1633–1640. 2015. View Article : Google Scholar : PubMed/NCBI
45	Faber AC, Coffee EM, Costa C, Dastur A, Ebi H, Hata AN, Yeo AT, Edelman EJ, Song Y, Tam AT, et al: mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1. Cancer Discov. 4:42–52. 2014. View Article : Google Scholar :
46	Hata AN, Yeo A, Faber AC, Lifshits E, Chen Z, Cheng KA, Walton Z, Sarosiek KA, Letai A, Heist RS, et al: Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and PI3K inhibitors for KRAS-mutant lung cancers. Cancer Res. 74:3146–3156. 2014. View Article : Google Scholar : PubMed/NCBI
47	He L, Torres-Lockhart K, Forster N, Ramakrishnan S, Greninger P, Garnett MJ, McDermott U, Rothenberg SM, Benes CH and Ellisen LW: Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma. Cancer Discov. 3:324–337. 2013. View Article : Google Scholar : PubMed/NCBI
48	Haroon ZA, Raleigh JA, Greenberg CS and Dewhirst MW: Early wound healing exhibits cytokine surge without evidence of hypoxia. Ann Surg. 231:137–147. 2000. View Article : Google Scholar : PubMed/NCBI
49	Indran IR, Hande MP and Pervaiz S: hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells. Cancer Res. 71:266–276. 2011. View Article : Google Scholar
50	Genestra M: Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cell Signal. 19:1807–1819. 2007. View Article : Google Scholar : PubMed/NCBI
51	Hsin YH, Chen CF, Huang S, Shih TS, Lai PS and Chueh PJ: The apoptotic effect of nanosilver is mediated by a ROS- and JNK-dependent mechanism involving the mitochondrial pathway in NIH3T3 cells. Toxicol Lett. 179:130–139. 2008. View Article : Google Scholar : PubMed/NCBI