2,983
Views
1
CrossRef citations to date
0
Altmetric
Reviews

The promise of endogenous and exogenous riboflavin in anti-infection

, , , &
Pages 2314-2326 | Received 16 Apr 2021, Accepted 29 Jul 2021, Published online: 07 Sep 2021

References

  • Furuya EY, Lowy FD. Antimicrobial-resistant bacteria in the community setting. Nat Rev Microbiol. 2006 4(1):36–45. PMID: 16357859.
  • Xiao YH, Giske CG, Wei ZQ, et al. Epidemiology and characteristics of antimicrobial resistance in China. Drug Resist Updat. 2011 ;14(4–5):236–250. PMID: 21807550.
  • Fisher MC, Hawkins NJ, Sanglard D, et al. Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science. 2018 ;360(6390):739–742. PMID: 29773744.
  • Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management. Lancet Infect Dis. 2017 Dec;17(12):e383–e392. PMID: 28774698.
  • Devi U, Locarnini S. Hepatitis B antivirals and resistance. Curr Opin Virol. 2013 ;3(5):495–500. PMID: 24016777.
  • Lampejo T. Influenza and antiviral resistance: an overview. Eur J Clin Microbiol Infect Dis. 2020;39(7):1201–1208. PMID: 32056049.
  • McKeegan KS, Borges-Walmsley MI, Walmsley AR. Microbial and viral drug resistance mechanisms. Trends Microbiol. 2002;10(10Suppl):S8–14. PMID: 12377562
  • Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance. prevalence, mechanisms, and management. Lancet Infect Dis. 2017;17(12):e383–e392. PMID: 28774698
  • Waglechner N, Wright GD. Antibiotic resistance: it’s bad, but why isn’t it worse? BMC Biol. 2017;15(1):84. PMID: 28915805
  • Berman J, Krysan DJ. Drug resistance and tolerance in fungi. Nat Rev Microbiol. 2020;18(6):319–331. PMID: 32047294
  • Fuller AT. Is p-aminobenzenesulphonamide the active agent of prontosil therapy? Lancet. 1937;229(5917):194–198.
  • Guzzo MB, Nguyen HT, Pham TH, et al. Methylfolate trap promotes bacterial thymineless death by sulfa drugs. PLoS Pathog. 2016;12(10):e1005949. PMID: 27760199
  • Bertacine Dias MV, Santos JC, Libreros-Zúñiga GA, et al. Folate biosynthesis pathway: mechanisms and insights into drug design for infectious diseases. Future Med Chem. 2018;10(8):935–959. PMID: 29629843
  • Parente-Rocha JA, Bailão AM, Amaral AC, et al. Antifungal resistance, metabolic routes as drug targets, and new antifungal agents: an overview about endemic dimorphic fungi. Mediators Inflamm. 2017;2017:1-16. PMID: 28694566.
  • Pedrolli D, Langer S, Hobl B, et al. The ribB FMN riboswitch from Escherichia coli operates at the transcriptional and translational level and regulates riboflavin biosynthesis. FEBS. 2015;282(16):3230–3242. PMID: 25661987
  • Kundu B, Sarkar D, Ray N, et al. Understanding the riboflavin biosynthesis pathway for the development of antimicrobial agents. Med Res Rev. 2019;39(4):1338–1371. PMID: 30927319
  • Pinto JT, Zempleni J. Riboflavin. Adv Nutr. 2016;7(5):973–975. PMID: 27633112
  • Thakur K, Tomar SK, Singh AK, et al. Riboflavin and health: a review of recent human research. Crit Rev Food Sci Nutr. 2017;57(17):3650–3660. PMID: 27029320
  • Flieger M, Bandouchova H, Cerny J, et al. Vitamin B2 as a virulence factor in Pseudogymnoascus destructans skin infection. Sci Rep. 2016;6:33200. PMID: 27620349
  • Toyosawa T, Suzuki M, Kodama K, et al. Effects of intravenous infusion of highly purified vitamin B2 on lipopolysaccharide-induced shock and bacterial infection in mice. Eur J Pharmacol. 2004;492(2–3):273–280. PMID: 15178375
  • Mazur-Bialy AI, Kolaczkowska E, Plytycz B. Modulation of zymosan-induced peritonitis by riboflavin co-injection, pre-injection or post-injection in male Swiss mice. Life Sci. 2012;91(25–26):1351–1357. PMID: 23123448
  • Fischer M, Bacher A. Biosynthesis of flavocoenzymes. Nat Prod Rep. 2005;22(3):324–350. PMID: 25635378
  • Bacher A, Eberhardt S, Fischer M, et al. Biosynthesis of vitamin b2 (riboflavin). Annu Rev Nutr. 2000;20:153–167. PMID: 10940330
  • Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart. 2012;33(7):829–37, 837a-837d. PMID: 21890489
  • Liu S, Hu W, Wang Z, et al. Production of riboflavin and related cofactors by biotechnological processes. Microb Cell Fact. 2020;19(1):31. PMID: 32054466
  • Cecchini G, Perl M, Lipsick J, et al. Transport and binding of riboflavin by Bacillus subtilis. J Biol Chem. 1979 Aug 10;254(15):7295–7301. PMID: 110806.
  • Schneider C, Mack M. A second riboflavin import system is present in flavinogenic Streptomyces davaonensis and supports roseoflavin biosynthesis. Mol Microbiol. 2021 Apr 7. 10.1111/mmi.14726. PMID: 33829573.
  • Vitreschak AG, Rodionov DA, Mironov AA, et al. Regulation of riboflavin biosynthesis and transport genes in bacteria by transcriptional and translational attenuation. Nucleic Acids Res. 2002 Jul 15;30(14):3141–3151. PMID: 12136096.
  • Gutiérrez-Preciado A, Torres AG, Merino E, et al. Extensive Identification of Bacterial Riboflavin Transporters and Their Distribution across Bacterial Species. PLoS One. 2015 May 4;10(5):e0126124. PMID: 25938806.
  • Abbas CA, Sibirny AA. Genetic control of biosynthesis and transport of riboflavin and flavin nucleotides and construction of robust biotechnological producers. Microbiol Mol Biol Rev. 2011;75(2):321–360. PMID: 21646432
  • Perl M, Kearney EB, Singer TP. Transport of riboflavin into yeast cells. J Biol Chem. 1976 Jun 10;251(11):3221–3228. PMID: 6447.
  • Reihl P, Stolz J. The monocarboxylate transporter homolog Mch5p catalyzes riboflavin (vitamin B2) uptake in Saccharomyces cerevisiae. J Biol Chem. 2005 Dec 2; Epub 2005 Oct 4. 280(48):39809–39817. PMID: 16204239.
  • Barile M, Giancaspero TA, Leone P, et al. Riboflavin transport and metabolism in humans. J Inherit Metab Dis. 2016 Jul;39(4):545–557; Epub 2016 Jun 6. PMID: 27271694.
  • Krajewski SS, Ignatov D, Johansson J. Two are better than one: dual targeting of riboswitches by metabolite analogs. Cell Chem Biol. 2017;24(5):535–537. PMID: 28525764
  • Blount KF, Breaker RR. Riboswitches as antibacterial drug targets. Nat Biotechnol. 2006;24(12):1558–1564. PMID: 17160062
  • Panchal V, Brenk R. Riboswitches as drug targets for antibiotics. Antibiotics. 2021;10(1):45. PMID: 33466288
  • Howe JA, Wang H, Fischmann TO, et al. Selective small-molecule inhibition of an RNA structural element. Nature. 2015;526(7575):672–677. PMID: 26416753
  • Balibar CJ, Villafania A, Barbieri CM, et al. Validation and development of an Escherichia coli riboflavin pathway phenotypic screen hit as a small-molecule ligand of the flavin mononucleotide riboswitch. Methods Mol Biol. 2018;1787:19–40. PMID: 29736707
  • Motika SE, Ulrich RJ, Geddes EJ, et al. Gram-negative antibiotic active through inhibition of an essential riboswitch. J Am Chem Soc. 2020;142(24):10856–10862. PMID: 32432858
  • Wang H, Mann PA, L X, et al. Dual-targeting small-molecule inhibitors of the Staphylococcus aureus FMN riboswitch disrupt riboflavin homeostasis in an infectious setting. Cell Chem Biol. 2017;24(5):576–588.e6.
  • Jankowitsch F, Schwarz J, Rückert C, et al. Genome sequence of the bacterium Streptomyces davawensis JCM 4913 and heterologous production of the unique antibiotic roseoflavin. Genome sequence of the bacterium Streptomyces davawensis JCM 4913 and heterologous production of the unique antibiotic roseoflavin. J Bacteriol. 2012;194(24):6818–6827. PMID: 23043000
  • Lee ER, Blount KF, Breaker RR. Roseoflavin is a natural antibacterial compound that binds to FMN riboswitches and regulates gene expression. RNA Biol. 2009;6(2):187–194. PMID: 19246992
  • Serganov A, Huang L, Patel DJ. Coenzyme recognition and gene regulation by a flavin mononucleotide riboswitch. Nature. 2009;458(7235):233–237. PMID: 19169240
  • Mansjö M, Johansson J. The riboflavin analog roseoflavin targets an FMN-riboswitch and blocks Listeria monocytogenes growth, but also stimulates virulence gene-expression and infection. RNA Biol. 2011;8(4):674–680. PMID: 21593602
  • Matern A, Pedrolli D, Großhennig S, et al. Uptake and metabolism of antibiotics roseoflavin and 8-Demethyl-8-Aminoriboflavin in riboflavin-auxotrophic Listeria monocytogenes. J Bacteriol. 2016;198(23):3233–3243. PMID: 27672192
  • Pedrolli DB, Mack M. Bacterial flavin mononucleotide riboswitches as targets for flavin analogs. Methods Mol Biol. 2014;1103:165–176. PMID: 24318894
  • Ott E, Stolz J, Lehmann M, et al. RFN riboswitch of Bacillus subtilis is a target for the antibiotic roseoflavin produced by Streptomyces davawensis. RNA Biol. 2009;6(3):276–280. PMID: 19333008
  • Grill S, Busenbender S, Pfeiffer M, et al. The bifunctional flavokinase/flavin adenine dinucleotide synthetase from Streptomyces davawensis produces inactive flavin cofactors and is not involved in resistance to the antibiotic roseoflavin. J Bacteriol. 2008;190(5):1546–1553. PMID: 18156273
  • Pedrolli DB, Matern A, Wang J, et al. A highly specialized flavin mononucleotide riboswitch responds differently to similar ligands and confers roseoflavin resistance to Streptomyces davawensis. Nucleic Acids Res. 2012;40(17):8662–8673. PMID: 22740651
  • Langer S, Hashimoto M, Hobl B, et al. Flavoproteins are potential targets for the antibiotic roseoflavin in Escherichia coli. J Bacteriol. 2013;195(18):4037–4045. PMID: 23836860
  • Pedrolli DB, Nakanishi S, Barile M, et al. The antibiotics roseoflavin and 8-demethyl-8-amino-riboflavin from Streptomyces davawensis are metabolized by human flavokinase and human FAD synthetase. Biochem Pharmacol. 2011;82(12):1853–1859. PMID: 21924249
  • Blount KF, Megyola C, Plummer M, et al. Novel riboswitch-binding flavin analog that protects mice against Clostridium difficile infection without inhibiting cecal flora. Antimicrob Agents Chemother. 2015;59(9):5736–5746. PMID: 26169403
  • Long Q, Ji L, Wang H, et al. Riboflavin biosynthetic and regulatory factors as potential novel anti-infective drug targets. Chem Biol Drug Des. 2010;75(4):339–347. PMID: 20148904
  • Bonomi HR, Marchesini MI, Klinke S, et al. An atypical riboflavin pathway is essential for Brucella abortus virulence. PLoS One. 2010;5(2):e9435. PMID: 20195542
  • Morgunova E, Saller S, Haase I, et al. Lumazine synthase from Candida albicans as an anti-fungal target enzyme: structural and biochemical basis for drug design. J Biol Chem. 2007;282(23):17231–17241. PMID: 17446177
  • Kumar P, Singh M, Karthikeyan S. Crystal structure analysis of icosahedral lumazine synthase from Salmonella typhimurium, an antibacterial drug target. Acta Crystallogr D Biol Crystallogr. 2011;67(Pt2):131–139. PMID: 21245535
  • Chen J, Illarionov B, Bacher A, et al. A high-throughput screen utilizing the fluorescence of riboflavin for identification of lumazine synthase inhibitors. Anal Biochem. 2005;338(1):124–130. PMID: 15707942
  • Meir Z, Osherov N. Vitamin biosynthesis as an antifungal target. J Fungi. 2018;4(2):72. PMID: 29914189
  • Zhao Y, Bacher A, Illarionov B, et al. Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis. J Org Chem. 2009;74(15):5297–5303. PMID: 19545132
  • Serer MI, Carrica MDC, Trappe J, et al. A high-throughput screening for inhibitors of riboflavin synthase identifies novel antimicrobial compounds to treat brucellosis. FEBS J. 2019;286(13):2522–2535. PMID: 30927485
  • Cushman M, Jin G, Sambaiah T, et al. Design, synthesis, and biochemical evaluation of 1,5,6,7-tetrahydro-6,7-dioxo-9-D-ribitylaminolumazines bearing alkyl phosphate substituents as inhibitors of lumazine synthase and riboflavin synthase. J Org Chem. 2005;70(20):8162–8170. PMID: 16277343
  • Islam Z, Kumar A, Singh S, et al. Structural basis for competitive inhibition of 3,4-dihydroxy-2-butanone-4-phosphate synthase from Vibrio cholerae. J Biol Chem. 2015;290(18):11293–11308. PMID: 25792735
  • Jin L, Zhou H, Zhao S, et al. Cloning and characterization of a new antibacterial target, 3,4-dihydroxy-2-butanone-4-phosphate synthase. Acta Microbiologica Sinica. 2012;52(11):1415–1420. PMID: 23383514.
  • Li J, Hua Z, Miao L, et al. The crystal structure and biochemical properties of DHBPS from Streptococcus pneumoniae, a potential anti-infective target for Gram-positive bacteria. Protein Expr Purif. 2013;91(2):161–168. PMID: 23954596
  • Sebastián M, Velázquez-Campoy A, The MM. RFK catalytic cycle of the pathogen Streptococcus pneumoniae shows species-specific features in prokaryotic FMN synthesis. J Enzyme Inhib Med Chem. 2018;33(1):842–849. PMID: 29693467
  • Lans I, Anoz-Carbonell E, Palacio-Rodríguez K, et al. In silico discovery and biological validation of ligands of FAD synthase, a promising new antimicrobial target. PLoS Computational Biology. 2020;16(8):e1007898. PMID: 32797038.
  • Dietl AM, Meir Z, Shadkchan Y, et al. Riboflavin and pantothenic acid biosynthesis are crucial for iron homeostasis and virulence in the pathogenic mold Aspergillus fumigatus. Virulence. 2018;9(1):1036–1049. PMID: 30052132
  • Demuyser L, Palmans I, Vandecruys P, et al. Molecular elucidation of riboflavin production and regulation in Candida albicans, toward a novel antifungal drug target. mSphere. 2020;5(4):e00714–20. PMID: 32759338
  • Becker JM, Kauffman SJ, Hauser M, et al. Pathway analysis of Candida albicans survival and virulence determinants in a murine infection model. Proc Natl Acad Sci USA. 2010;107(51):22044–22049. PMID: 21135205
  • Garfoot AL, Zemska O, Rappleye CA. Histoplasma capsulatum depends on de novo vitamin biosynthesis for intraphagosomal proliferation. Infect Immun. 2014 Jan;82(1):393–404; Epub 2013 Nov 4. PMID: 24191299.
  • de Castro PA, Chiaratto J, Morais ER, et al. The putative flavin carrier family FlcA-C is important for Aspergillus fumigatus virulence. Virulence. 2017;8(6):797–809. PMID: 27652896
  • Ussher JE, Klenerman P, Willberg CB. Mucosal-associated invariant T-cells: new players in anti-bacterial immunity. Front Immunol. 2014;5:450. PMID: 25339949
  • Eckle SB, Corbett AJ, Keller AN, et al. Recognition of Vitamin B precursors and byproducts by mucosal associated invariant T cells. J Biol Chem. 2015;290(51):30204–30211. PMID: 26468291
  • Franciszkiewicz K, Salou M, Legoux F, et al. MHC class I-related molecule, MR1, and mucosal-associated invariant T cells. Immunol Rev. 2016;272(1):120–138. PMID: 27319347
  • Keller AN, Corbett AJ, Wubben JM, et al. MAIT cells and MR1-antigen recognition. Curr Opin Immunol. 2017;46:66–74. PMID: 28494326
  • Constantinides MG, Link VM, Tamoutounour S, et al. MAIT cells are imprinted by the microbiota in early life and promote tissue repair. Science. 2019;366(6464):eaax6624. PMID: 31649166
  • Chen Z, Wang H, D’Souza C, et al. Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals. Mucosal Immunol. 2017;10(1):58–68. PMID: 27143301
  • Wang H, D’Souza C, Lim XY et al. MAIT cells protect against pulmonary Legionella longbeachae infection. Nature Communucations.2018;9(1):3350.
  • Kurioka A, Ussher JE, Cosgrove C, et al. MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets. Mucosal Immunol. 2015;8(2):429–440. PMID: 25269706
  • Sakala IG, Kjer-Nielsen L, Eickhoff CS, et al. Functional heterogeneity and antimycobacterial effects of mouse mucosal-associated invariant T Cells specific for riboflavin metabolites. J Immunol. 2015;195(2):587–601. PMID: 26063000
  • Bucsan AN, Rout N, Foreman TW, et al. Mucosal-activated invariant T cells do not exhibit significant lung recruitment and proliferation profiles in macaques in response to infection with Mycobacterium tuberculosis CDC1551. Tuberculosis. 2019;116S:S11–S18. PMID: 31072689
  • Napier RJ, Adams EJ, Gold MC, et al. The role of mucosal associated invariant T Cells in antimicrobial immunity. Front Immunol. 2015;6:344. PMID: 26217338
  • Le Bourhis L, Martin E, Péguillet I, et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat Immunol. 2010;11(8):701–708. PMID: 20581831
  • Jahreis S, Böttcher S, Hartung S, et al. Human MAIT cells are rapidly activated by Aspergillus spp. in an APC-dependent manner. Eur J Immunol. 2018;48(10):1698–1706. PMID: 30059139
  • Böttcher S, Hartung S, Meyer F, et al. Human mucosal-associated invariant T cells respond to Mucorales species in a MR1-dependent manner. Med Mycol. 2020:myaa103. DOI:10.1093/mmy/myaa103. PMID: 33336238.
  • Dias J, Leeansyah E, Sandberg JK. Multiple layers of heterogeneity and subset diversity in human MAIT cell responses to distinct microorganisms and to innate cytokines. Proc Natl Acad Sci USA. 2017;114(27):E5434–E5443. PMID: 28630305
  • van Wilgenburg B, Loh L, Chen Z, et al. MAIT cells contribute to protection against lethal influenza infection in vivo. Nat Commun. 2018;9(1):4706. PMID: 30413689
  • van Wilgenburg B, Scherwitzl I, Hutchinson EC, et al. MAIT cells are activated during human viral infections. Nat Commun. 2016;7:11653. PMID: 27337592
  • Ussher JE, Willberg CB, Klenerman P. MAIT cells and viruses. Immunol Cell Biol. 2018;96(6):630–641. PMID: 29350807
  • Huang W, He W, Shi X, et al. Mucosal-associated invariant T-cells are severely reduced and exhausted in humans with chronic HBV infection. J Viral Hepat. 2020;27(11):1096–1107. PMID: 32510704
  • Leeansyah E, Ganesh A, Quigley MF. Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell population in chronic HIV-1 infection. Blood. 2013;121(7):1124–1135. PMID: 23243281
  • Leeansyah E, Svärd J, Dias J. Arming of MAIT cell cytolytic antimicrobial activity is induced by IL-7 and defective in HIV-1 infection. PLoS Pathog. 2015;11(8):e1005072. PMID: 26295709
  • Tang X, Zhang S, Sustained PQ. IFN-I stimulation impairs MAIT cell responses to bacteria by inducing IL-10 during chronic HIV-1 infection. Sci Adv. 2020;6(8):eaaz0374. PMID: 32128419
  • Shih CK, Chen CM, Chen CY, et al. Riboflavin protects mice against liposaccharide-induced shock through expression of heat shock protein 25. Food Chem Toxicol. 2010;48(7):1913–1918. PMID: 20430062
  • Toyosawa T, Suzuki M, Kodama K, et al. Potentiation by amino acid of the therapeutic effect of highly purified vitamin B2 in mice with lipopolysaccharide-induced shock. Eur J Pharmacol. 2004;493(1–3):177–182. PMID: 15189780
  • Kodama K, Suzuki M, Toyosawa T, et al. Inhibitory mechanisms of highly purified vitamin B2 on the productions of proinflammatory cytokine and NO in endotoxin-induced shock in mice. Life Sci. 2005;78(2):134–139. PMID: 16112685
  • Mazur-Bialy AI, Pochec E, Plytycz B. Immunomodulatory effect of riboflavin deficiency and enrichment-reversible pathological response versus silencing of inflammatory activation. J Physiol Pharmacol. 2015;66(6):793–802. PMID: 26769828
  • Mazur-Bialy AI, Majka A, Wojtas L, et al. Strain-specific effects of riboflavin supplementation on zymosan-induced peritonitis in C57BL/6J, BALB/c and CBA mice. Life Sci. 2011;88(5–6):265–271. PMID: 21115019
  • Mazur-Bialy AI, Pocheć E. HMGB1 inhibition during zymosan-induced inflammation: the potential therapeutic action of riboflavin. Arch Immunol Ther Exp. 2016;64(2):171–176. PMID: 26445809
  • Saito H, Ebinuma H, Tada S, et al. Enhancing effect of the liver extract and flavin adenin dinucleotide mixture on anti-viral efficacy of interferon in patients with chronic hepatitis C. Keio J Med. 1996;45(1):48–53. PMID: 8882468
  • Shahzad S, Ashraf MA, Sajid M, et al. Evaluation of synergistic antimicrobial effect of vitamins (A, B1, B2, B6, B12, C, D, E and K) with antibiotics against resistant bacterial strains. Journal of Global Antimicrobial Resistance. 2018(13):231–236.PMID: 29408383.
  • Mal P, Dutta K, Bandyopadhyay D, et al. Azithromycin in combination with riboflavin decreases the severity of Staphylococcus aureus infection induced septic arthritis by modulating the production of free radicals and endogenous cytokines. Inflamm Res. 2013;62(3):259–273. PMID: 23229721
  • Banerjee S, Ghosh D, Vishakha K, et al. Photodynamic antimicrobial chemotherapy (PACT) using riboflavin inhibits the mono and dual species biofilm produced by antibiotic resistant Staphylococcus aureus and Escherichia coli. Photodiagnosis Photodyn Ther. 2020;32:102002. PMID: 32916327
  • Rivas Aiello MB, Ghilini F, Martínez Porcel JE, et al. Riboflavin-mediated photooxidation of gold nanoparticles and its effect on the inactivation of bacteria. Langmuir. 2020;36(28):8272–8281. PMID: 32569473
  • Schrier A, Greebel G, Attia H, et al. In vitro antimicrobial efficacy of riboflavin and ultraviolet light on Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa. J Refract Surg. 2009;25(9):S799–802. PMID: 19772254
  • Hiraku Y, Ito K, Hirakawa K, et al. Photosensitized DNA damage and its protection via a novel mechanism. Photochem Photobiol. 2007;83(1):205–212. PMID: 16965181
  • Baier J, Maisch T, Maier M, et al. Singlet oxygen generation by UVA light exposure of endogenous photosensitizers. Biophys J. 2006;91(4):1452–1459. PMID: 16751234
  • Bäckman A, Makdoumi K, Mortensen J, et al. The efficiency of cross-linking methods in eradication of bacteria is influenced by the riboflavin concentration and the irradiation time of ultraviolet light. Acta Ophthalmol. 2014;92(7). PMID: 25493311
  • Sauer A, Letscher-Bru V, Speeg-Schatz C, et al. In vitro efficacy of antifungal treatment using riboflavin/UV-A (365 nm) combination and amphotericin B. Invest Ophthalmol Vis Sci. 2010;51(8):3950–3953. PMID: 20335618
  • Davis SA, Bovelle R, Han G, et al. Corneal collagen cross-linking for bacterial infectious keratitis. Cochrane Database Syst Rev. 2020;6(6):CD013001. PMID: 32557558
  • Li Z, Jhanji V, Tao X, et al. Riboflavin/ultravoilet light-mediated crosslinking for fungal keratitis. Br J Ophthalmol. 2013;97(5):669–671. PMID: 23355529
  • Said DG, Elalfy MS, Gatzioufas Z, et al. Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting. Ophthalmology. 2014;121(7):1377–1382. PMID: 24576886
  • Bilgihan K, Kalkanci A, Ozdemir HB, et al. Evaluation of antifungal efficacy of 0.1% and 0.25% riboflavin with UVA: a comparative in vitro study. Curr Eye Res. 2016;41(8):1050–1056. PMID: 26644282
  • Prajna NV, Radhakrishnan N, Lalitha P, et al. Cross-linking-assisted infection reduction: a randomized clinical trial evaluating the effect of adjuvant cross-linking on outcomes in fungal keratitis. Ophthalmology. 2020;127(2):159–166. PMID: 31619359
  • Kashiwabuchi RT, Carvalho FR, Khan YA, et al. Assessment of fungal viability after long-wave ultraviolet light irradiation combined with riboflavin administration. Graefes Arch Clin Exp Ophthalmol. 2013;251(2):521–527. PMID: 23180236
  • Chan TC, Lau TW, Lee JW, et al. Corneal collagen cross-linking for infectious keratitis: an update of clinical studies. Acta Ophthalmol. 2015;93(8):689–696. PMID: 25990098
  • Arboleda A, Miller D, Cabot F, et al. Assessment of rose bengal versus riboflavin photodynamic therapy for inhibition of fungal keratitis isolates. Am J Ophthalmol. 2014;158(1):64–70.e2. PMID: 24792103
  • Ragan I, Hartson L, Pidcoke H, et al. Pathogen reduction of SARS-CoV-2 virus in plasma and whole blood using riboflavin and UV light. PLoS One. 2020;15(5):e0233947. PMID: 32470046
  • Keil SD, Ragan I, Yonemura S, et al. Inactivation of severe acute respiratory syndrome coronavirus 2 in plasma and platelet products using a riboflavin and ultraviolet light-based photochemical treatment. Vox Sang. 2020;115(6):495–501. PMID: 32311760
  • Keil SD, Bowen R, Marschner S. Inactivation of middle east respiratory syndrome coronavirus (MERS-CoV) in plasma products using a riboflavin-based and ultraviolet light-based photochemical treatment. Transfusion. 2016;56(12) PMID: 27805261
  • Faddy HM, Fryk JJ, Watterson D, et al. Riboflavin and ultraviolet light. impact on dengue virus infectivity. Vox Sang. 2016;111(3):235–241. PMID: 27281512
  • Cap AP, Pidcoke HF, Keil SD, et al. Treatment of blood with a pathogen reduction technology using ultraviolet light and riboflavin inactivates Ebola virus in vitro. Transfusion. 2016;56:S6–15. Suppl 1 (Suppl1). PMID: 27001363.
  • Dey S, Bishayi B. Riboflavin along with antibiotics balances reactive oxygen species and inflammatory cytokines and controls Staphylococcus aureus infection by boosting murine macrophage function and regulates inflammation. J Inflamm. 2016;13(36). DOI:10.1186/s12950-016-0145-0. PMID: 27932936
  • Tran JQ, Muench MO, Heitman JW, et al. Pathogen reduction with riboflavin and ultraviolet light induces a quasi-apoptotic state in blood leukocytes. Transfusion. 2019;59(11):3501–3510. PMID: 31599981
  • Van Dyck K, Viela F, Mathelié-Guinlet M, et al. Adhesion of Staphylococcus aureus to Candida albicans During Co-Infection Promotes Bacterial Dissemination Through the Host Immune Response. Front Cell Infect Microbiol. 2021 Feb;2(10):624839. PMID: 33604309.
  • Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011;29:139–162. PMID: 21219181
  • Karki R, Sharma BR, Tuladhar S, et al. Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes. Cell. 2021;184(1):149–168.e17. PMID: 33278357
  • Salkowski CA, Detore G, McNally R, et al. Regulation of inducible nitric oxide synthase messenger RNA expression and nitric oxide production by lipopolysaccharide in vivo: the roles of macrophages, endogenous IFN-gamma, and TNF receptor-1-mediated signaling. J Immunol. 1997;158(2):905–912. PMID: 8993010
  • Popescu M, Cabrera-Martinez B, Winslow GMTNF-Α. contributes to lymphoid tissue disorganization and germinal center B cell suppression during intracellular bacterial infection. J Immunol. 2019;203(9):2415–2424. PMID: 31570507
  • de Waal Malefyt R, Abrams J, Bennett B, et al. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991;174(5). PMID: 1940799
  • De Maio A. Heat shock proteins : facts, thoughts, and dreams.  Shock. 1999;11(1):1–12. PMID: 9921710.
  • Parameswaran N, Patial S. Tumor necrosis factor-α signaling in macrophages. Crit Rev Eukaryot Gene Expr. 2010;20(2):87–103. PMID: 21133840
  • Ouyang W, O’Garra A. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. immunity. 2019;50(4):871–891. PMID: 30995504