Abstract
Patulin (PAT) is a fungi-derived secondary metabolite produced by numerous fungal species, especially within Aspergillus, Byssochlamys, and Penicillium genera, amongst which P. expansum is the foremost producer. Similar to other fungi-derived metabolites, PAT has been shown to have diverse biological features. Initially, PAT was used as an effective antimicrobial agent against Gram-negative and Gram-positive bacteria. Then, PAT has been shown to possess immunosuppressive properties encompassing humoral and cellular immune response, immune cell function and activation, phagocytosis, nitric oxide and reactive oxygen species production, cytokine release, and nuclear factor-κB and mitogen-activated protein kinases activation. Macrophages are a heterogeneous population of immune cells widely distributed throughout organs and connective tissue. The chief function of macrophages is to engulf and destroy foreign bodies through phagocytosis; this ability was fundamental to his discovery. However, macrophages play other well-established roles in immunity. Thus, considering the central role of macrophages in the immune response, we review the immunosuppressive effects of PAT in macrophages and provide the possible mechanisms of action.
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References
Ajizian SJ, English BK, Meals EA (1999) Specific inhibitors of p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways block inducible nitric oxide synthase and tumor necrosis factor accumulation in murine macrophages stimulated with lipopolysaccharide and interferon-γ. J Infect Dis 179:939–944. https://doi.org/10.1086/314659
Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801. https://doi.org/10.1016/j.cell.2006.02.015
Alexanian A, Sorokin A (2017) Cyclooxygenase 2: protein-protein interactions and posttranslational modifications. Physiol Genomics 49:667–681. https://doi.org/10.1152/physiolgenomics.00086.2017
Artigot MP, Loiseau N, Laffitte J, Mas-Reguieg L, Tadrist S, Oswald IP, Puel O (2009) Molecular cloning and functional characterization of two CYP619 cytochrome P450s involved in biosynthesis of patulin in aspergillus clavatus. Microbiol (Reading) 155:1738–1747. https://doi.org/10.1099/mic.0.024836-0
Arulselvan P, Fard MT, Tan WS, Gothai S, Fakurazi S, Norhaizan ME, Kumar SS (2016) Role of antioxidants and natural products in inflammation. Oxid Med Cell Longev 2016:5276130 https://doi.org/10.1155/2016/5276130
Arzu Kockaya E, Selmanoglu G, Ozsoy N, Gul N (2009) Evaluation of patulin toxicity in the thymus of growing male rats. Arh Hig Rada Toksikol 60:411–418. https://doi.org/10.2478/10004-1254-60-2009-1973
Beck J, Ripka S, Siegner A, Schiltz E, Schweizer E (1990) The multifunctional 6-methylsalicylic acid synthase gene of Penicillium patulum. Its gene structure relative to that of other polyketide synthases. Eur J Biochem 192:487–498. https://doi.org/10.1111/j.1432-1033.1990.tb19252.x
Beinke S, Robinson MJ, Hugunin M, Ley SC (2004) Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IκB kinase-induced proteolysis of NF-κB1 p105. Mol Cell Biol 24:9658–9667. https://doi.org/10.1128/MCB.24.21.9658-9667.2004
Beutler B (2002) TLR4 as the mammalian endotoxin sensor. Curr Top Microbiol Immunol 270:109–120. https://doi.org/10.1007/978-3-642-59430-4_7
Beutler B, Du X, Poltorak A (2001) Identification of toll-like receptor 4 (TLR4) as the sole conduit for LPS signal transduction: genetic and evolutionary studies. J Endotoxin Res 7:277–280
Bhat R, Rai RV, Karim AA (2010) Mycotoxins in food and feed: present status and future concerns. Compr Rev Food Sci Food Saf 9:57–81. https://doi.org/10.1111/j.1541-4337.2009.00094.x
Bhatt A (2010) Evolution of clinical research: a history before and beyond james lind. Perspect Clin Res 1:6–10
Bhattacharyya S, Midwood KS, Yin H, Varga J (2017) Toll-like receptor-4 signaling drives persistent fibroblast activation and prevents fibrosis resolution in scleroderma. Adv Wound Care (New Rochelle) 6:356–369. https://doi.org/10.1089/wound.2017.0732
Birkinshaw JH, Bracken A, Michael SE, Raistrick H (1943) Patulin in the common cold collaborative research on a derivative of Penicillium Patulum Bainier: II. Biochemistry and chemistry. Lancet 242:625–630. https://doi.org/10.1016/s0140-6736(00)88177-5
Bogdan C (2015) Nitric oxide synthase in innate and adaptive immunity: an update. Trends Immunol 36:161–178. https://doi.org/10.1016/j.it.2015.01.003
Bondy GS, Pestka JJ (2000) Immunomodulation by fungal toxins. J Toxicol Environ Health B Crit Rev 3:109–143. https://doi.org/10.1080/109374000281113
Bourdiol D, Escoula L, Salvayre R (1990) Effect of patulin on microbicidal activity of mouse peritoneal macrophages. Food Chem Toxicol 28:29–33. https://doi.org/10.1016/0278-6915(90)90132-7
Bräse S, Encinas A, Keck J, Nising CF (2009) Chemistry and biology of mycotoxins and related fungal metabolites. Chem Rev 109:3903–3990. https://doi.org/10.1021/cr050001f
Brown R, Priest E, Naglik JR, Richardson JP (2021) Fungal toxins and host immune responses. Front Microbiol 12:643639. https://doi.org/10.3389/fmicb.2021.643639
Bulgaru CV, Marin DE, Pistol GC, Taranu I (2021) Zearalenone and the immune response. Toxins (Basel) 13. https://doi.org/10.3390/toxins13040248
Chalmers I, Clarke M (2004) Commentary: the 1944 patulin trial: the first properly controlled multicentre trial conducted under the aegis of the British Medical Research Council. Int J Epidemiol 33:253–260. https://doi.org/10.1093/ije/dyh162
Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L (2018) Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 9:7204–7218. https://doi.org/10.18632/oncotarget.23208
Conti B, Tabarean I, Andrei C, Bartfai T (2004) Cytokines and fever. Front Biosci 9:1433–1449. https://doi.org/10.2741/1341
D’Arcy Hart P (1999) A change in scientific approach: from alternation to randomised allocation in clinical trials in the 1940s. BMJ 319:572–573. https://doi.org/10.1136/bmj.319.7209.572
Dai Y, Huang K, Zhang B, Zhu L, Xu W (2017) Aflatoxin B1-induced epigenetic alterations: an overview. Food Chem Toxicol 109:683–689. https://doi.org/10.1016/j.fct.2017.06.034
De Maria R, Cifone MG, Trotta R, Rippo MR, Festuccia C, Santoni A, Testi R (1994) Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors. J Exp Med 180:1999–2004. https://doi.org/10.1084/jem.180.5.1999
Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095–2147
Dinarello CA (1997) Interleukin-1. Cytokine Growth Factor Rev 8:253–265. https://doi.org/10.1016/s1359-6101(97)00023-3
Dinarello CA (2018) Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 281:8–27. https://doi.org/10.1111/imr.12621
Dombrink-Kurtzman MA (2007) The sequence of the isoepoxydon dehydrogenase gene of the patulin biosynthetic pathway in Penicillium species. Antonie Van Leeuwenhoek 91:179–189. https://doi.org/10.1007/s10482-006-9109-3
Dombrink-Kurtzman MA, Engberg AE (2006) Byssochlamys nivea with patulin-producing capability has an isoepoxydon dehydrogenase gene (idh) with sequence homology to Penicillium expansum and P. griseofulvum. Mycol Res 110:1111–1118 https://doi.org/10.1016/j.mycres.2006.05.008
Epelman S, Lavine KJ, Randolph GJ (2014) Origin and functions of tissue macrophages. Immunity 41:21–35. https://doi.org/10.1016/j.immuni.2014.06.013
Escoula L, Bourdiol D, Linas MD, Recco P, Seguela JP (1988a) Enhancing resistance and modulation of humoral immune response to experimental Candida albicans infection by patulin. Mycopathologia 103:153–156. https://doi.org/10.1007/BF00436814
Escoula L, Thomsen M, Bourdiol D, Pipy B, Peuriere S, Roubinet F (1988b) Patulin immunotoxicology: effect on phagocyte activation and the cellular and humoral immune system of mice and rabbits. Int J Immunopharmacol 10:983–989. https://doi.org/10.1016/0192-0561(88)90045-8
Fan X, Jin T (2019) Structures of RIG-I-like receptors and insights into viral RNA sensing. Adv Exp Med Biol 1172:157–188. https://doi.org/10.1007/978-981-13-9367-9_8
Feghali CA, Wright TM (1997) Cytokines in acute and chronic inflammation. Front Biosci 2:d12–26. https://doi.org/10.2741/a171
Ferrante MC, Raso GM, Bilancione M, Esposito E, Iacono A, Meli R (2008) Differential modification of inflammatory enzymes in J774A.1 macrophages by ochratoxin A alone or in combination with lipopolysaccharide. Toxicol Lett 181:40–46. https://doi.org/10.1016/j.toxlet.2008.06.866
Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247. https://doi.org/10.1038/35041687
Fitzgerald KA, Kagan JC (2020) Toll-like receptors and the control of immunity. Cell 180:1044–1066. https://doi.org/10.1016/j.cell.2020.02.041
Fliege R, Metzler M (1999) The mycotoxin patulin induces intra- and intermolecular protein crosslinks in vitro involving cysteine, lysine, and histidine side chains, and α-amino groups. Chem Biol Interact 123:85–103. https://doi.org/10.1016/s0009-2797(99)00123-4
Forrester PI, Gaucher GM (1972) m-Hydroxybenzyl alcohol dehydrogenase from Penicillium Urticae. Biochemistry 11:1108–1114. https://doi.org/10.1021/bi00756a026
Frank HK (1977) Occurrence of patulin in fruit and vegetables. Ann Nutr Aliment 31:459–465
Fujiwara N, Kobayashi K (2005) Macrophages in inflammation. Curr Drug Targets Inflamm Allergy 4:281–286. https://doi.org/10.2174/1568010054022024
Gaucher GM (1975) m-Hydroxybenzyl-alcohol dehydrogenase. Methods Enzymol 43:540–548. https://doi.org/10.1016/0076-6879(75)43116-0
Geller DA, Billiar TR (1998) Molecular biology of nitric oxide synthases. Cancer Metastasis Rev 17:7–23. https://doi.org/10.1023/a:1005940202801
Gordon S, Pluddemann A (2018) Macrophage clearance of apoptotic cells: a critical assessment. Front Immunol 9:127. https://doi.org/10.3389/fimmu.2018.00127
Harding CV, Canaday D, Ramachandra L (2010) Choosing and preparing antigen-presenting cells. Curr Protoc Immunol Chap 16:16 11 11–16 11 30. https://doi.org/10.1002/0471142735.im1601s88
Harington CR (1949) The work of the National Institute for Medical Research. Proc R Soc Lond B 136:333–348
Hirayama D, Iida T, Nakase H (2017) The phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis. Int J Mol Sci 19. https://doi.org/10.3390/ijms19010092
Hmama Z, Pena-Diaz S, Joseph S, Av-Gay Y (2015) Immunoevasion and immunosuppression of the macrophage by Mycobacterium tuberculosis. Immunol Rev 264:220–232. https://doi.org/10.1111/imr.12268
Hong S, Park SK, Lee J, Park SH, Kim YS, Park JH, Yu S, Lee YG (2023) Patulin ameliorates hypertrophied lipid accumulation and lipopolysaccharide-induced inflammatory response by modulating mitochondrial respiration. Antioxid (Basel) 12. https://doi.org/10.3390/antiox12091750
Hou L, Gan F, Zhou X, Zhou Y, Qian G, Liu Z, Huang K (2018) Immunotoxicity of ochratoxin A and aflatoxin B1 in combination is associated with the nuclear factor κ B signaling pathway in 3D4/21cells. Chemosphere 199:718–727. https://doi.org/10.1016/j.chemosphere.2018.02.009
Hughes MM, O’Neill LAJ (2018) Metabolic regulation of NLRP3. Immunol Rev 281:88–98. https://doi.org/10.1111/imr.12608
Hunter CA, Jones SA (2015) IL-6 as a keystone cytokine in health and disease. Nat Immunol 16:448–457. https://doi.org/10.1038/ni.3153
Iijima H, Ebizuka Y, Sankawa U (1986) Biosynthesis of patulin; in vitro conversion of gentisyl alcohol into patulin by microsomal enzyme(s) and retention of one of the carbinol protons in this reaction. Chem Pharm Bull (Tokyo) 34:3534–3537. https://doi.org/10.1248/cpb.34.3534
Kamle M, Mahato DK, Devi S, Lee KE, Kang SG, Kumar P (2019) Fumonisins: impact on agriculture, food, and human health and their management strategies. Toxins (Basel) 11. https://doi.org/10.3390/toxins11060328
Kang S, Narazaki M, Metwally H, Kishimoto T (2020) Historical overview of the interleukin-6 family cytokine. J Exp Med 217. https://doi.org/10.1084/jem.20190347
Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650. https://doi.org/10.1016/j.immuni.2011.05.006
Kell AM, Gale M Jr. (2015) RIG-I in RNA virus recognition. Virology 479–480:110–121. https://doi.org/10.1016/j.virol.2015.02.017
Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802:396–405. https://doi.org/10.1016/j.bbadis.2009.12.009
Kim EK, Choi EJ (2015) Compromised MAPK signaling in human diseases: an update. Arch Toxicol 89:867–882. https://doi.org/10.1007/s00204-015-1472-2
Kishimoto T (2010) IL-6: from its discovery to clinical applications. Int Immunol 22:347–352. https://doi.org/10.1093/intimm/dxq030
Kleinert H, Schwarz PM, Forstermann U (2003) Regulation of the expression of inducible nitric oxide synthase. Biol Chem 384:1343–1364. https://doi.org/10.1515/BC.2003.152
Kourtzelis I, Hajishengallis G, Chavakis T (2020) Phagocytosis of apoptotic cells in resolution of inflammation. Front Immunol 11:553. https://doi.org/10.3389/fimmu.2020.00553
Kumar P, Mahato DK, Kamle M, Mohanta TK, Kang SG (2016) Aflatoxins: a global concern for food safety, human health and their management. Front Microbiol 7:2170. https://doi.org/10.3389/fmicb.2016.02170
Kumar P, Mahato DK, Sharma B, Borah R, Haque S, Mahmud MMC, Shah AK, Rawal D, Bora H, Bui S (2020) Ochratoxins in food and feed: occurrence and its impact on human health and management strategies. Toxicon 187:151–162. https://doi.org/10.1016/j.toxicon.2020.08.031
Lahti A, Lahde M, Kankaanranta H, Moilanen E (2000) Inhibition of extracellular signal-regulated kinase suppresses endotoxin-induced nitric oxide synthesis in mouse macrophages and in human colon epithelial cells. J Pharmacol Exp Ther 294:1188–1194
Lam KS, Neway JO, Gaucher GM (1988) In vitro stabilization of 6-methylsalicylic acid synthetase from Penicillium Urticae. Can J Microbiol 34:30–37. https://doi.org/10.1139/m88-006
Lavoie H, Gagnon J, Therrien M (2020) ERK signalling: a master regulator of cell behaviour, life and fate. Nat Rev Mol Cell Biol 21:607–632. https://doi.org/10.1038/s41580-020-0255-7
Lawrence T (2009) The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651. https://doi.org/10.1101/cshperspect.a001651
Lewellyn GC, McCay JA, Brown RD, Musgrove DL, Butterworth LF, Munson AE, White KL Jr. (1998) Immunological evaluation of the mycotoxin patulin in female B6C3F1 mice. Food Chem Toxicol 36:1107–1115. https://doi.org/10.1016/s0278-6915(98)00084-2
Li B, Chen Y, Zhang Z, Qin G, Chen T, Tian S (2020) Molecular basis and regulation of pathogenicity and patulin biosynthesis in Penicillium Expansum. Compr Rev Food Sci Food Saf 19:3416–3438. https://doi.org/10.1111/1541-4337.12612
Light RJ (1969) 6-methylsalicylic acid decarboxylase from Penicillium Patulum. Biochim Biophys Acta 191:430–438. https://doi.org/10.1016/0005-2744(69)90262-9
Lynen F, Tada M (1961) Die biochemischen grundlagen Der „polyacetat-regel. Angew Chem 73:513–519. https://doi.org/10.1002/ange.19610731502
MacMicking J, Xie QW, Nathan C (1997) Nitric oxide and macrophage function. Annu Rev Immunol 15:323–350. https://doi.org/10.1146/annurev.immunol.15.1.323
Mahato DK, Lee KE, Kamle M, Devi S, Dewangan KN, Kumar P, Kang SG (2019) Aflatoxins in food and feed: an overview on prevalence, detection and control strategies. Front Microbiol 10:2266. https://doi.org/10.3389/fmicb.2019.02266
Mahato DK, Devi S, Pandhi S, Sharma B, Maurya KK, Mishra S, Dhawan K, Selvakumar R, Kamle M, Mishra AK, Kumar P (2021a) Occurrence, impact on agriculture, human health, and management strategies of zearalenone in food and feed: a review. Toxins (Basel) 13. https://doi.org/10.3390/toxins13020092
Mahato DK, Kamle M, Sharma B, Pandhi S, Devi S, Dhawan K, Selvakumar R, Mishra D, Kumar A, Arora S, Singh NA, Kumar P (2021b) Patulin in food: a mycotoxin concern for human health and its management strategies. Toxicon 198:12–23. https://doi.org/10.1016/j.toxicon.2021.04.027
Manohar M, Verma AK, Venkateshaiah SU, Sanders NL, Mishra A (2017) Pathogenic mechanisms of pancreatitis. World J Gastrointest Pharmacol Ther 8:10–25. https://doi.org/10.4292/wjgpt.v8.i1.10
Marzio R, Jirillo E, Ransijn A, Mauel J, Corradin SB (1997) Expression and function of the early activation antigen CD69 in murine macrophages. J Leukoc Biol 62:349–355. https://doi.org/10.1002/jlb.62.3.349
Mayer E, Novak B, Springler A, Schwartz-Zimmermann HE, Nagl V, Reisinger N, Hessenberger S, Schatzmayr G (2017) Effects of deoxynivalenol (DON) and its microbial biotransformation product deepoxy-deoxynivalenol (DOM-1) on a trout, pig, mouse, and human cell line. Mycotoxin Res 33:297–308. https://doi.org/10.1007/s12550-017-0289-7
Medzhitov R (2007) Recognition of microorganisms and activation of the immune response. Nature 449:819–826. https://doi.org/10.1038/nature06246
Möller B, Villiger PM (2006) Inhibition of IL-1, IL-6, and TNF-α in immune-mediated inflammatory diseases. Springer Semin Immunopathol 27:391–408. https://doi.org/10.1007/s00281-006-0012-9
Möller M, Botti H, Batthyany C, Rubbo H, Radi R, Denicola A (2005) Direct measurement of nitric oxide and oxygen partitioning into liposomes and low density lipoprotein. J Biol Chem 280:8850–8854. https://doi.org/10.1074/jbc.M413699200
Moncada S (1999) Nitric oxide: discovery and impact on clinical medicine. J R Soc Med 92:164–169. https://doi.org/10.1177/014107689909200402
Murphy G, Lynen F (1975) Patulin biosynthesis: the metabolism of m-hydroxybenzyl alcohol and m-hydroxybenzaldehyde by particulate preparations from Penicillium Patulum. Eur J Biochem 58:467–475. https://doi.org/10.1111/j.1432-1033.1975.tb02394.x
Nagata S (2018) Apoptosis and clearance of apoptotic cells. Annu Rev Immunol 36:489–517. https://doi.org/10.1146/annurev-immunol-042617-053010
Neway J, Gaucher GM (1981) Intrinsic limitations on the continued production of the antibiotic patulin by Penicillium Urticae. Can J Microbiol 27:206–215. https://doi.org/10.1139/m81-032
Oh SY, Boermans HJ, Swamy HVLN, Sharma BS, Karrow NA (2012) Immunotoxicity of Penicillium mycotoxins on viability and proliferation of bovine macrophage cell line (BOMACs). Open Mycol J 6:11–16
Oh SY, Balch CG, Cliff RL, Sharma BS, Boermans HJ, Swamy HV, Quinton VM, Karrow NA (2013) Exposure to Penicillium mycotoxins alters gene expression of enzymes involved in the epigenetic regulation of bovine macrophages (BoMacs). Mycotoxin Res 29:235–243. https://doi.org/10.1007/s12550-013-0174-y
Oh SY, Mead PJ, Sharma BS, Quinton VM, Boermans HJ, Smith TK, Swamy HV, Karrow NA (2015a) Effect of Penicillium mycotoxins on the cytokine gene expression, reactive oxygen species production, and phagocytosis of bovine macrophage (BoMacs) function. Toxicol Vitro 30:446–453. https://doi.org/10.1016/j.tiv.2015.09.017
Oh SY, Quinton VM, Boermans HJ, Swamy HV, Karrow NA (2015b) In vitro exposure of Penicillium mycotoxins with or without a modified yeast cell wall extract (mYCW) on bovine macrophages (BoMacs). Mycotoxin Res 31:167–175. https://doi.org/10.1007/s12550-015-0227-5
Oh SY, Cedergreen N, Yiannikouris A, Swamy HV, Karrow NA (2017) Assessing interactions of binary mixtures of Penicillium mycotoxins (PMs) by using a bovine macrophage cell line (BoMacs). Toxicol Appl Pharmacol 318:33–40. https://doi.org/10.1016/j.taap.2017.01.015
Ozsoy N, Selmanoglu G, Kockaya EA, Gul N, Cebesoy S (2008) Effect of patulin on the interdigitating dendritic cells (IDCs) of rat thymus. Cell Biochem Funct 26:192–196. https://doi.org/10.1002/cbf.1431
Parham P (2005) Putting a face to MHC restriction. J Immunol 174:3–5. https://doi.org/10.4049/jimmunol.174.1.3
Paucod JC, Krivobok S, Vidal D (1990) Immunotoxicity testing of mycotoxins T-2 and patulin on Balb/c mice. Acta Microbiol Hung 37:331–339
Pestka JJ (2008) Mechanisms of deoxynivalenol-induced gene expression and apoptosis. Food Addit Contam Part Chem Anal Control Expo Risk Assess 25:1128–1140. https://doi.org/10.1080/02652030802056626
Pestka JJ, Zhou HR, Moon Y, Chung YJ (2004) Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox. Toxicol Lett 153:61–73. https://doi.org/10.1016/j.toxlet.2004.04.023
Pleadin J, Frece J, Markov K (2019) Mycotoxins in food and feed. Adv Food Nutr Res 89:297–345. https://doi.org/10.1016/bs.afnr.2019.02.007
Poon IK, Hulett MD, Parish CR (2010) Molecular mechanisms of late apoptotic/necrotic cell clearance. Cell Death Differ 17:381–397. https://doi.org/10.1038/cdd.2009.195
Poveda J, Sanz AB, Rayego-Mateos S, Ruiz-Ortega M, Carrasco S, Ortiz A, Sanchez-Nino MD (2016) NFκBiz protein downregulation in acute kidney injury: modulation of inflammation and survival in tubular cells. Biochim Biophys Acta 1862:635–646. https://doi.org/10.1016/j.bbadis.2016.01.006
Puel O, Galtier P, Oswald IP (2010) Biosynthesis and toxicological effects of patulin. Toxins (Basel) 2:613–631. https://doi.org/10.3390/toxins2040613
Raistrick H (1943) Patulin in the common cold collaborative research on a derivative of Penicillium Patulum Bainier: i. introduction. Lancet 242:625. https://doi.org/10.1016/s0140-6736(00)88176-3
Ramachandran RA, Lupfer C, Zaki H (2018) The inflammasome: regulation of nitric oxide and antimicrobial host defence. Adv Microb Physiol 72:65–115. https://doi.org/10.1016/bs.ampbs.2018.01.004
Rathinam VA, Vanaja SK, Fitzgerald KA (2012) Regulation of inflammasome signaling. Nat Immunol 13:333–342. https://doi.org/10.1038/ni.2237
Rosales C, Uribe-Querol E (2017) Phagocytosis: a fundamental process in immunity. Biomed Res Int 2017:9042851. https://doi.org/10.1155/2017/9042851
Rose-John S (2018) Interleukin-6 family cytokines. Cold Spring Harb Perspect Biol 10. https://doi.org/10.1101/cshperspect.a028415
Sajid M, Mehmood S, Yuan Y, Yue T (2019) Mycotoxin patulin in food matrices: occurrence and its biological degradation strategies. Drug Metab Rev 51:105–120. https://doi.org/10.1080/03602532.2019.1589493
Saleh I, Goktepe I (2019) The characteristics, occurrence, and toxicological effects of patulin. Food Chem Toxicol 129:301–311. https://doi.org/10.1016/j.fct.2019.04.036
Sales-Neto JM, da Silva JSF, Carvalho DCM, Lima ÉA, Cavalcante-Silva LHA, Lettnin AP, Votto APS, Vasconcelos U, Rodrigues-Mascarenhas S (2022) Patulin inhibits LPS-induced nitric oxide production by suppressing MAPKs signaling pathway. Nat Prod Res 36:5879–5883. https://doi.org/10.1080/14786419.2021.2021516
Salvemini D (1997) Regulation of cyclooxygenase enzymes by nitric oxide. Cell Mol Life Sci 53:576–582. https://doi.org/10.1007/s000180050074
Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P (1993) Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci U S A 90:7240–7244. https://doi.org/10.1073/pnas.90.15.7240
Salvemini D, Kim SF, Mollace V (2013) Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: relevance and clinical implications. Am J Physiol Regul Integr Comp Physiol 304:R473–487. https://doi.org/10.1152/ajpregu.00355.2012
Schutze N, Lehmann I, Bonisch U, Simon JC, Polte T (2010) Exposure to mycotoxins increases the allergic immune response in a murine asthma model. Am J Respir Crit Care Med 181:1188–1199. https://doi.org/10.1164/rccm.200909-1350OC
Scott A, Khan KM, Cook JL, Duronio V (2004) What is inflammation? Are we ready to move beyond Celsus? Br J Sports Med 38:248–249. https://doi.org/10.1136/bjsm.2003.011221
Seeboth J, Solinhac R, Oswald IP, Guzylack-Piriou L (2012) The fungal T-2 toxin alters the activation of primary macrophages induced by TLR-agonists resulting in a decrease of the inflammatory response in the pig. Vet Res 43:35. https://doi.org/10.1186/1297-9716-43-35
Sekiguchi J, Gaucher GM (1977) Conidiogenesis and secondary metabolism in Penicillium Urticae. Appl Environ Microbiol 33:147–158. https://doi.org/10.1128/aem.33.1.147-158.1977
Sekiguchi J, Gaucher GM (1978) Identification of phyllostine as an intermediate of the patulin pathway in Penicillium Urticae. Biochemistry 17:1785–1791. https://doi.org/10.1021/bi00602a033
Sekiguchi J, Gaucher GM (1979) Isoepoxydon, a new metabolite of the patulin pathway in Penicillium Urticae. Biochem J 182:445–453. https://doi.org/10.1042/bj1820445
Sekiguchi J, Gaucher GM, Yamada Y (1979) Biosynthesis of patulin in Penicillium Urticae: identification of isopatulin as a new intermediate. Tetrahedron Lett :41–42
Sekiguchi J, Shimamoto T, Yamada Y, Gaucher GM (1983) Patulin biosynthesis: enzymatic and nonenzymatic transformations of the mycotoxin E-ascladiol. Appl Environ Microbiol 45:1939–1942. https://doi.org/10.1128/aem.45.6.1939-1942.1983
Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, Seifi B, Mohammadi A, Afshari JT, Sahebkar A (2018) Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 233:6425–6440. https://doi.org/10.1002/jcp.26429
Shiratsuchi A, Nakanishi Y (2006) Elimination of influenza virus-infected cells by phagocytosis. Yakugaku Zasshi 126:1245–1251. https://doi.org/10.1248/yakushi.126.1245
Snini SP, Tadrist S, Laffitte J, Jamin EL, Oswald IP, Puel O (2014) The gene PatG involved in the biosynthesis pathway of patulin, a food-borne mycotoxin, encodes a 6-methylsalicylic acid decarboxylase. Int J Food Microbiol 171:77–83. https://doi.org/10.1016/j.ijfoodmicro.2013.11.020
Sorenson WG, Simpson J, Castranova V (1985) Toxicity of the mycotoxin patulin for rat alveolar macrophages. Environ Res 38:407–416. https://doi.org/10.1016/0013-9351(85)90102-1
Sorenson WG, Gerberick GF, Lewis DM, Castranova V (1986) Toxicity of mycotoxins for the rat pulmonary macrophage in vitro. Environ Health Perspect 66:45–53. https://doi.org/10.1289/ehp.866645
Sorokin A (2016) Nitric oxide synthase and cyclooxygenase pathways: a complex interplay in cellular signaling. Curr Med Chem 23:2559–2578. https://doi.org/10.2174/0929867323666160729105312
Steyn PS (1980) The biosynthesis of polyketide-derived mycotoxins. Pure Appl Chem 52:189–204. https://doi.org/10.1351/pac198052010189
Steyn PS (1992) The biosynthesis of polyketide-derived mycotoxins. J Environ Pathol Toxicol Oncol 11:47–59
Strober W, Fuss I, Mannon P (2007) The fundamental basis of inflammatory bowel disease. J Clin Invest 117:514–521. https://doi.org/10.1172/JCI30587
Sugiyama K, Muroi M, Tanamoto K, Nishijima M, Sugita-Konishi Y (2010) Deoxynivalenol and Nivalenol inhibit lipopolysaccharide-induced nitric oxide production by mouse macrophage cells. Toxicol Lett 192:150–154. https://doi.org/10.1016/j.toxlet.2009.10.020
Sun Y, Huang K, Long M, Yang S, Zhang Y (2022) An update on immunotoxicity and mechanisms of action of six environmental mycotoxins. Food Chem Toxicol 163:112895. https://doi.org/10.1016/j.fct.2022.112895
Takeda K, Akira S (2015) Toll-like receptors. Curr Protoc Immunol 109:141211–141210. https://doi.org/10.1002/0471142735.im1412s109
Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820. https://doi.org/10.1016/j.cell.2010.01.022
Tanaka T, Narazaki M, Kishimoto T (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6:a016295. https://doi.org/10.1101/cshperspect.a016295
Tommasi S, Zheng A, Weninger A, Bates SE, Li XA, Wu X, Hollstein M, Besaratinia A (2013) Mammalian cells acquire epigenetic hallmarks of human cancer during immortalization. Nucleic Acids Res 41:182–195. https://doi.org/10.1093/nar/gks1051
Tsai WT, Lo YC, Wu MS, Li CY, Kuo YP, Lai YH, Tsai Y, Chen KC, Chuang TH, Yao CH, Lee JC, Hsu LC, Hsu JT, Yu GY (2016) Mycotoxin patulin suppresses innate immune responses by mitochondrial dysfunction and p62/sequestosome-1-dependent mitophagy. J Biol Chem 291:19299–19311. https://doi.org/10.1074/jbc.M115.686683
Turner WB (1976) Polyketides and related metabolites. In: Smith JE, Berry DR (eds) The filamentous fungi. Edward Arnold, London
Unanue ER (1984) Antigen-presenting function of the macrophage. Annu Rev Immunol 2:395–428. https://doi.org/10.1146/annurev.iy.02.040184.002143
Unanue ER (2002) Perspective on antigen processing and presentation. Immunol Rev 185:86–102. https://doi.org/10.1034/j.1600-065x.2002.18510.x
Varela ML, Mogildea M, Moreno I, Lopes A (2018) Acute inflammation and metabolism. Inflammation 41:1115–1127. https://doi.org/10.1007/s10753-018-0739-1
Vidal A, Ouhibi S, Ghali R, Hedhili A, De Saeger S, De Boevre M (2019) The mycotoxin patulin: an updated short review on occurrence, toxicity and analytical challenges. Food Chem Toxicol 129:249–256. https://doi.org/10.1016/j.fct.2019.04.048
Vodovotz Y, Russell D, Xie QW, Bogdan C, Nathan C (1995) Vesicle membrane association of nitric oxide synthase in primary mouse macrophages. J Immunol 154:2914–2925
Wang IK, Reeves C, Gaucher GM (1991) Isolation and sequencing of a genomic DNA clone containing the 3’ terminus of the 6-methylsalicylic acid polyketide synthetase gene of Penicillium Urticae. Can J Microbiol 37:86–95. https://doi.org/10.1139/m91-013
Westman J, Grinstein S, Marques PE (2019) Phagocytosis of necrotic debris at sites of injury and inflammation. Front Immunol 10:3030. https://doi.org/10.3389/fimmu.2019.03030
Yang S, Zhao M, Jia S (2023) Macrophage: key player in the pathogenesis of autoimmune diseases. Front Immunol 14:1080310. https://doi.org/10.3389/fimmu.2023.1080310
Yazdi AS, Ghoreschi K (2016) The interleukin-1 family. Adv Exp Med Biol 941:21–29. https://doi.org/10.1007/978-94-024-0921-5_2
Yoneyama M, Onomoto K, Jogi M, Akaboshi T, Fujita T (2015) Viral RNA detection by RIG-I-like receptors. Curr Opin Immunol 32:48–53. https://doi.org/10.1016/j.coi.2014.12.012
Zhang JM, An J (2007) Cytokines, inflammation, and pain. Int Anesthesiol Clin 45:27–37. https://doi.org/10.1097/AIA.0b013e318034194e
Zhong L, Carere J, Lu Z, Lu F, Zhou T (2018) Patulin in apples and apple-based food products: the burdens and the mitigation strategies. Toxins (Basel) 10. https://doi.org/10.3390/toxins10110475
Zhu Y, Chen L (2009) Turning the tide of lymphocyte costimulation. J Immunol 182:2557–2558. https://doi.org/10.4049/jimmunol.0990006
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This work was supported by Coordination for the Improvement of Higher Education Personnel (CAPES) and National Council for Scientific and Technological Development (CNPq) for financial support of this project (Universal Project – MCTI/CNPq; number: 14/2013).
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Conceptualization and writing - review & editing: Sandra Rodrigues-Mascarenhas and José Marreiro de Sales-Neto; Investigation and Writing - original draft: José Marreiro de Sales-Neto; Supervision: Sandra Rodrigues-Mascarenhas.
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de Sales-Neto, J.M., Rodrigues-Mascarenhas, S. Immunosuppressive effects of the mycotoxin patulin in macrophages. Arch Microbiol 206, 166 (2024). https://doi.org/10.1007/s00203-024-03928-2
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DOI: https://doi.org/10.1007/s00203-024-03928-2