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Applied Microbiology and Biotechnology

, Volume 103, Issue 21–22, pp 9037–9055 | Cite as

Cinnamaldehyde inhibits Candida albicans growth by causing apoptosis and its treatment on vulvovaginal candidiasis and oropharyngeal candidiasis

  • Lei Chen
  • Zhen Wang
  • Liang Liu
  • Su Qu
  • Yuanyuan Mao
  • Xue PengEmail author
  • Yong-xin LiEmail author
  • Jun TianEmail author
Applied microbial and cell physiology
  • 155 Downloads

Abstract

The invasion of Candida albicans is one of the most common fungal infections seen in clinical practice, and serious drug resistance has been reported in recent years. Therefore, new anti-C. albicans drugs must be introduced. In this research, it was demonstrated that cinnamaldehyde (CA) shows strong antimicrobial activity, with 0.26 mg/mL CA being the minimum inhibitory concentration to manage C. albicans. Extraordinarily, we detected that CA accumulated the intracellular reactive oxygen species (ROS) and enhanced the calcium concentration in the cytoplasm and mitochondria through flow cytometry. In addition, we observed that C. albicans cells released Cytochrome c from the mitochondria to the cytoplasm, depolarized the mitochondrial membrane potential, and activated the metacaspase when exposed to 0.065, 0.13, 0.26, and 0.52 mg/mL CA. Furthermore, to confirm that CA introduces the C. albicans apoptosis, we discovered that when the phosphatidylserine was exposed, DNA damage and chromatin condensation occurred, which were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and 4′,6-diamidino-2-phenylindole (DAPI) staining. Finally, demonstrations of phenotype investigation, colony-forming unit (CFU) counts, and periodic acid–Schiff (PAS) staining were conducted to prove that CA possessed the ability to treat oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC). From the above, our research indicates that CA is a promising antifungal candidate when applied to C. albicans infections.

Keywords

Candida albicans Cinnamaldehyde Reactive oxygen species Apoptosis Vulvovaginal candidiasis Oropharyngeal candidiasis 

Notes

Authors’ contributions

JT and XP designed the experiments. LC, ZW, and LL performed the experiments. SQ and YM analyzed the data. LC and YL drafted the manuscript. All authors read and approved the final manuscript.

Funding information

This study was funded by National Natural Science Foundation of China (31972171, 31671944, 31570028), Six Talent Peaks Project of Jiangsu Province (SWYY-026), Qing Lan Project of Jiangsu Province, Natural Science Foundation by Xuzhou City (KC17053), Jiangsu Science and Technology Agency Project (BK20141148) and the PAPD of Jiangsu Higher Education Institutions.

Compliance with ethical standards

Ethical approval

All animal or human experiments in this study were performed in strict accordance with the Guide for the Care and Use of Chinese legislation, the Ministry of Science and Technology of China and were approved by the Institutional Jiangsu Normal University Committee for Animal Experiments.

Competing interests

The authors declare that they have no competing interests.

References

  1. Aguirre J, Rios-Momberg M, Hewitt D, Hansberg W (2005) Reactive oxygen species and development in microbial eukaryotes. Trends Microbiol 13(3):111–118.  https://doi.org/10.1016/j.tim.2005.01.007 CrossRefPubMedGoogle Scholar
  2. Alonso-Monge R, Carvaihlo S, Nombela C, Rial E, Pla J (2009) The hog1 MAP kinase controls respiratory metabolism in the fungal pathogen Candida albicans. Microbiology 155(Pt 2):413–423.  https://doi.org/10.1099/mic.0.023309-0 CrossRefPubMedGoogle Scholar
  3. Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H (2015) Discovery and resupply of pharmacologically active plant-derived natural products: a review. Biotechnol Adv 33(8):1582–1614.  https://doi.org/10.1016/j.biotechadv.2015.08.001 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bagur R, Hajnoczky G (2017) Intracellular Ca2+ sensing: its role in calcium homeostasis and signaling. Mol Cell 66(6):780–788.  https://doi.org/10.1016/j.molcel.2017.05.028 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Ben Yaakov D, Shadkchan Y, Albert N, Kontoyiannis DP, Osherov N (2017) The quinoline bromoquinol exhibits broad-spectrum antifungal activity and induces oxidative stress and apoptosis in Aspergillus fumigatus. J Antimicrob Chemother 72(8):2263–2272.  https://doi.org/10.1093/jac/dkx117 CrossRefPubMedGoogle Scholar
  6. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC (2012) Hidden killers: human fungal infections. Sci Transl Med 4(165):165rv13.  https://doi.org/10.1126/scitranslmed.3004404 CrossRefPubMedGoogle Scholar
  7. Buglak NE, Jiang W, Bahnson ESM (2018) Cinnamic aldehyde inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia in zucker diabetic fatty rats. Redox Biol 19:166–178.  https://doi.org/10.1016/j.redox.2018.08.013 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Burke PJ (2017) Mitochondria, bioenergetics and apoptosis in cancer. Trends Cancer 3(12):857–870.  https://doi.org/10.1016/j.trecan.2017.10.006 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Burt SA, Adolfse SJM, Ahad DSA, Tersteeg-Zijderveld MHG, Jongerius-Gortemaker BGM, Post JA, Bruggemann H, Santos RR (2016) Cinnamaldehyde, carvacrol and organic acids affect gene expression of selected oxidative stress and inflammation markers in ipec-j2 cells exposed to salmonella typhimurium. Phytother Res 30(12):1988–2000.  https://doi.org/10.1002/ptr.5705 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cao YY, Huang S, Dai BD, Zhu ZY, Lu H, Dong LL, Cao YB, Wang Y, Gao PH, Chai YF, Jiang YY (2009) Candida albicans cells lacking camca1-encoded metacaspase show resistance to oxidative stress-induced death and change in energy metabolism. Fungal Genet Biol 46(2):183–189.  https://doi.org/10.1016/j.fgb.2008.11.001 CrossRefPubMedGoogle Scholar
  11. Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, Ho AW, Hai JH, Yu JJ, Jung JW, Filler SG, Masso-Welch P, Edgerton M, Gaffen SL (2009) Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med 206(2):299–311.  https://doi.org/10.1084/jem.20081463 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, Saul RL, McCord JM, Harman D (1987) Oxygen radicals and human disease. Ann Intern Med 107(4):526–545CrossRefGoogle Scholar
  13. Degterev A, Yuan J (2008) Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol 9(5):378–390.  https://doi.org/10.1038/nrm2393 CrossRefPubMedGoogle Scholar
  14. Degterev A, Boyce M, Yuan J (2003) A decade of caspases. Oncogene 22(53):8543–8567.  https://doi.org/10.1038/sj.onc.1207107 CrossRefPubMedGoogle Scholar
  15. Demaurex N, Rosselin M (2017) Redox control of mitochondrial calcium uptake. Mol Cell 65(6):961–962.  https://doi.org/10.1016/j.molcel.2017.02.029 CrossRefPubMedGoogle Scholar
  16. Feissner RF, Skalska J, Gaum WE, Sheu SS (2009) Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci-Landmrk 14:1197–1218.  https://doi.org/10.2741/3303 CrossRefGoogle Scholar
  17. Fidel PL Jr (2011) Candida-host interactions in HIV disease: implications for oropharyngeal candidiasis. Adv Dent Res 23(1):45–49.  https://doi.org/10.1177/0022034511399284 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Fuchs Y, Steller H (2011) Programmed cell death in animal development and disease. Cell 147(4):742–758.  https://doi.org/10.1016/j.cell.2011.10.033 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Giacomello M, Drago I, Pizzo P, Pozzan T (2007) Mitochondrial Ca2+ as a key regulator of cell life and death. Cell Death Differ 14(7):1267–1274.  https://doi.org/10.1038/sj.cdd.4402147 CrossRefPubMedGoogle Scholar
  20. Gottlieb E, Armour SM, Harris MH, Thompson CB (2003) Mitochondrial membrane potential regulates matrix configuration and cytochrome c release during apoptosis. Cell Death Differ 10(6):709–717.  https://doi.org/10.1038/sj.cdd.4401231 CrossRefPubMedGoogle Scholar
  21. Hise AG, Tomalka J, Ganesan S, Patel K, Hall BA, Brown GD, Fitzgerald KA (2009) An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. Cell Host Microbe 5(5):487–497.  https://doi.org/10.1016/j.chom.2009.05.002 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hwang JH, Hwang IS, Liu QH, Woo ER, Lee DG (2012) Medioresinol leads to intracellular ROS accumulation and mitochondria-mediated apoptotic cell death in Candida albicans. Biochimie 94(8):1784–1793.  https://doi.org/10.1016/j.biochi.2012.04.010 CrossRefPubMedGoogle Scholar
  23. Jou MJ (2008) Pathophysiological and pharmacological implications of mitochondria-targeted reactive oxygen species generation in astrocytes. Adv Drug Deliv Rev 60(13–14):1512–1526.  https://doi.org/10.1016/j.addr.2008.06.004 CrossRefPubMedGoogle Scholar
  24. Kang LL, Zhang DM, Ma CH, Zhang JH, Jia KK, Liu JH, Wang R, Kong LD (2016) Cinnamaldehyde and allopurinol reduce fructose-induced cardiac inflammation and fibrosis by attenuating CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation. Sci Rep 6:27460.  https://doi.org/10.1038/srep27460 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Khan SN, Khan S, Iqbal J, Khan R, Khan AU (2017) Enhanced killing and antibiofilm activity of encapsulated cinnamaldehyde against Candida albicans. Front Microbiol 8:1641.  https://doi.org/10.3389/fmicb.2017.01641 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Khoo KH, Verma CS, Lane DP (2014) Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov 13(3):217–236.  https://doi.org/10.1038/nrd4236 CrossRefPubMedGoogle Scholar
  27. Kuang S, Liu G, Cao R, Zhang L, Yu Q, Sun C (2017) Mansouramycin C kills cancer cells through reactive oxygen species production mediated by opening of mitochondrial permeability transition pore. Oncotarget 8(61):104057–104071.  https://doi.org/10.18632/oncotarget.22004 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Liao JC, Deng JS, Chiu CS, Hou WC, Huang SS, Shie PH, Huang GJ (2012) Anti-inflammatory activities of cinnamomum cassia constituents in vitro and in vivo. Evid Based Complement Alternat Med 2012:429320–429312.  https://doi.org/10.1155/2012/429320 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Logan A, Pell VR, Shaffer KJ, Evans C, Stanley NJ, Robb EL, Prime TA, Chouchani ET, Cocheme HM, Fearnley IM, Vidoni S, James AM, Porteous CM, Partridge L, Krieg T, Smith RAJ, Murphy MP (2016) Assessing the mitochondrial membrane potential in cells and in vivo using targeted click chemistry and mass spectrometry. Cell Metab 23(2):379–385.  https://doi.org/10.1016/j.cmet.2015.11.014 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Long M, Tao S, Rojo de la Vega M, Jiang T, Wen Q, Park SL, Zhang DD, Wondrak GT (2015) Nrf2-dependent suppression of azoxymethane/dextran sulfate sodium-induced colon carcinogenesis by the cinnamon-derived dietary factor cinnamaldehyde. Cancer Prev Res (Phila) 8(5):444–454.  https://doi.org/10.1158/1940-6207.CAPR-14-0359 CrossRefGoogle Scholar
  31. Machida K, Tanaka T, Fujita K, Taniguchi M (1998) Farnesol-induced generation of reactive oxygen species via indirect inhibition of the mitochondrial electron transport chain in the yeast Saccharomyces cerevisiae. J Bacteriol 180(17):4460–4465PubMedPubMedCentralGoogle Scholar
  32. Madeo F, Frohlich E, Frohlich KU (1997) A yeast mutant showing diagnostic markers of early and late apoptosis. J Cell Biol 139(3):729–734CrossRefGoogle Scholar
  33. Madeo F, Frohlich E, Ligr M, Grey M, Sigrist SJ, Wolf DH, Frohlich KU (1999) Oxygen stress: a regulator of apoptosis in yeast. J Cell Biol 145(4):757–767CrossRefGoogle Scholar
  34. Mukherjee PK, Chandra J, Retuerto M, Sikaroodi M, Brown RE, Jurevic R, Salata RA, Lederman MM, Gillevet PM, Ghannoum MA (2014) Oral mycobiome analysis of HIV-infected patients: identification of Pichia as an antagonist of opportunistic fungi. PLoS Pathog 10(3):e1003996.  https://doi.org/10.1371/journal.ppat.1003996 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13.  https://doi.org/10.1042/Bj20081386 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Muzaffar S, Bose C, Banerji A, Nair BG, Chattoo BB (2016) Anacardic acid induces apoptosis-like cell death in the rice blast fungus Magnaporthe oryzae. Appl Microbiol Biotechnol 100(1):323–335.  https://doi.org/10.1007/s00253-015-6915-4 CrossRefPubMedGoogle Scholar
  37. Nucci M, Queiroz-Telles F, Alvarado-Matute T, Tiraboschi IN, Cortes J, Zurita J, Guzman-Blanco M, Santolaya ME, Thompson L, Sifuentes-Osornio J, Echevarria JI, Colombo AL, Latin American Invasive Mycosis N (2013) Epidemiology of candidemia in Latin America: a laboratory-based survey. PLoS One 8(3):e59373.  https://doi.org/10.1371/journal.pone.0059373 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Orrenius S, Zhivotovsky B, Nicotera P (2003) Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4(7):552–565.  https://doi.org/10.1038/nrm1150 CrossRefPubMedGoogle Scholar
  39. Phaniendra A, Jestadi DB, Periyasamy L (2015) Free radicals: properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem 30(1):11–26.  https://doi.org/10.1007/s12291-014-0446-0 CrossRefPubMedGoogle Scholar
  40. Phillips AJ, Sudbery I, Ramsdale M (2003) Apoptosis induced by environmental stresses and amphotericin B in Candida albicans. Proc Natl Acad Sci U S A 100(24):14327–14332.  https://doi.org/10.1073/pnas.2332326100 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Qu S, Chen L, Tian H, Wang Z, Wang F, Wang L, Li J, Ji H, Xi L, Feng Z, Tian J, Feng Z (2019) Effect of perillaldehyde on prophylaxis and treatment of vaginal candidiasis in a murine model. Front Microbiol 10:1466.  https://doi.org/10.3389/fmicb.2019.01466 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Sawicki R, Golus J, Przekora A, Ludwiczuk A, Sieniawska E, Ginalska G (2018) Antimycobacterial activity of cinnamaldehyde in a Mycobacterium tuberculosis(H37Ra) model. Molecules 23(9).  https://doi.org/10.3390/molecules23092381 CrossRefGoogle Scholar
  43. Shi M, Chen L, Wang XW, Zhang T, Zhao PB, Song XY, Sun CY, Chen XL, Zhou BC, Zhang YZ (2012) Antimicrobial peptaibols from Trichoderma pseudokoningii induce programmed cell death in plant fungal pathogens. Microbiology 158(Pt 1):166–175.  https://doi.org/10.1099/mic.0.052670-0 CrossRefPubMedGoogle Scholar
  44. Sobel JD (2007) Vulvovaginal candidosis. Lancet 369(9577):1961–1971.  https://doi.org/10.1016/S0140-6736(07)60917-9 CrossRefPubMedGoogle Scholar
  45. Solis NV, Swidergall M, Bruno VM, Gaffen SL, Filler SG (2017) The aryl hydrocarbon receptor governs epithelial cell invasion during oropharyngeal candidiasis. MBio 8(2).  https://doi.org/10.1128/mBio.00025-17
  46. Sukumar M, Liu J, Mehta GU, Patel SJ, Roychoudhuri R, Crompton JG, Klebanoff CA, Ji Y, Li P, Yu Z, Whitehill GD, Clever D, Eil RL, Palmer DC, Mitra S, Rao M, Keyvanfar K, Schrump DS, Wang E, Marincola FM, Gattinoni L, Leonard WJ, Muranski P, Finkel T, Restifo NP (2016) Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell Metab 23(1):63–76.  https://doi.org/10.1016/j.cmet.2015.11.002 CrossRefPubMedGoogle Scholar
  47. Swerdlow S, Distelhorst CW (2007) Bcl-2-regulated calcium signals as common mediators of both apoptosis and autophagy. Dev Cell 12(2):178–179.  https://doi.org/10.1016/j.devcel.2007.01.008 CrossRefPubMedGoogle Scholar
  48. Taguchi Y, Hasumi Y, Abe S, Nishiyama Y (2013) The effect of cinnamaldehyde on the growth and the morphology of Candida albicans. Med Mol Morphol 46(1):8–13.  https://doi.org/10.1007/s00795-012-0001-0 CrossRefPubMedGoogle Scholar
  49. Tian J, Wang Y, Lu Z, Sun C, Zhang M, Zhu A, Peng X (2016) Perillaldehyde, a promising antifungal agent used in food preservation, triggers apoptosis through a metacaspase-dependent pathway in Aspergillus flavus. J Agric Food Chem 64(39):7404–7413.  https://doi.org/10.1021/acs.jafc.6b03546 CrossRefPubMedGoogle Scholar
  50. Tian H, Qu S, Wang Y, Lu Z, Zhang M, Gan Y, Zhang P, Tian J (2017a) Erratum to: calcium and oxidative stress mediate perillaldehyde-induced apoptosis in Candida albicans. Appl Microbiol Biotechnol 101(8):3347–3348.  https://doi.org/10.1007/s00253-017-8217-5 CrossRefPubMedGoogle Scholar
  51. Tian J, Lu Z, Wang Y, Zhang M, Wang X, Tang X, Peng X, Zeng H (2017b) Nerol triggers mitochondrial dysfunction and disruption via elevation of Ca2+ and ROS in Candida albicans. Int J Biochem Cell Biol 85:114–122.  https://doi.org/10.1016/j.biocel.2017.02.006 CrossRefPubMedGoogle Scholar
  52. Tian J, Gan Y, Pan C, Zhang M, Wang X, Tang X, Peng X (2018) Nerol-induced apoptosis associated with the generation of ROS and Ca2+ overload in saprotrophic fungus Aspergillus flavus. Appl Microbiol Biotechnol 102(15):6659–6672.  https://doi.org/10.1007/s00253-018-9125-z CrossRefPubMedGoogle Scholar
  53. Uemura T, Yashiro T, Oda R, Shioya N, Nakajima T, Hachisu M, Kobayashi S, Nishiyama C, Arimura GI (2018) Intestinal anti-inflammatory activity of perillaldehyde. J Agric Food Chem 66(13):3443–3448.  https://doi.org/10.1021/acs.jafc.8b00353 CrossRefPubMedGoogle Scholar
  54. Utchariyakiat I, Surassmo S, Jaturanpinyo M, Khuntayaporn P, Chomnawang MT (2016) Efficacy of cinnamon bark oil and cinnamaldehyde on anti-multidrug resistant Pseudomonas aeruginosa and the synergistic effects in combination with other antimicrobial agents. BMC Complement Altern Med 16:158.  https://doi.org/10.1186/s12906-016-1134-9 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Wang C, Youle RJ (2009) The role of mitochondria in apoptosis. Annu Rev Genet 43:95–118.  https://doi.org/10.1146/annurev-genet-102108-134850 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39(3):309–317.  https://doi.org/10.1086/421946 CrossRefGoogle Scholar
  57. Xu H, Sobue T, Bertolini M, Thompson A, Dongari-Bagtzoglou A (2016) Streptococcus oralis and Candida albicans synergistically activate mu-calpain to degrade E-cadherin from oral epithelial junctions. J Infect Dis 214(6):925–934.  https://doi.org/10.1093/infdis/jiw201 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Youn HS, Lee JK, Choi YJ, Saitoh SI, Miyake K, Hwang DH, Lee JY (2008) Cinnamaldehyde suppresses toll-like receptor 4 activation mediated through the inhibition of receptor oligomerization. Biochem Pharmacol 75(2):494–502.  https://doi.org/10.1016/j.bcp.2007.08.033 CrossRefPubMedGoogle Scholar
  59. Yu XY, Fu F, Kong WN, Xuan QK, Wen DH, Chen XQ, He YM, He LH, Guo J, Zhou AP, Xi YH, Ni LJ, Yao YF, Wu WJ (2018) Streptococcus agalactiae inhibits Candida albicans hyphal development and diminishes host vaginal mucosal TH17 response. Front Microbiol 9:198.  https://doi.org/10.3389/fmicb.2018.00198 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Yuan J, Najafov A, Py BF (2016) Roles of caspases in necrotic cell death. Cell 167(7):1693–1704.  https://doi.org/10.1016/j.cell.2016.11.047 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Yun DG, Lee DG (2016) Silibinin triggers yeast apoptosis related to mitochondrial Ca2+ influx in Candida albicans. Int J Biochem Cell Biol 80:1–9.  https://doi.org/10.1016/j.biocel.2016.09.008 CrossRefPubMedGoogle Scholar
  62. Yun X, Rao W, Xiao C, Huang Q (2017) Apoptosis of leukemia K562 and Molt-4 cells induced by emamectin benzoate involving mitochondrial membrane potential loss and intracellular Ca2+ modulation. Environ Toxicol Pharmacol 52:280–287.  https://doi.org/10.1016/j.etap.2017.04.013 CrossRefPubMedGoogle Scholar
  63. Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C (2005) The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis 41(9):1232–1239.  https://doi.org/10.1086/496922 CrossRefPubMedGoogle Scholar
  64. Zhao J, Zhang X, Dong L, Wen Y, Zheng X, Zhang C, Chen R, Zhang Y, Li Y, He T, Zhu X, Li L (2015) Cinnamaldehyde inhibits inflammation and brain damage in a mouse model of permanent cerebral ischaemia. Br J Pharmacol 172(20):5009–5023.  https://doi.org/10.1111/bph.13270 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.College of Life ScienceJiangsu Normal UniversityJiangsu ProvincePeople’s Republic of China
  2. 2.Beijing Advanced Innovation Center for Food Nutrition and Human HealthBeijing Technology and Business UniversityBeijingPeople’s Republic of China

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