Rev Med UAS
Rev Med UAS; Vol. 15 No. 4. Octubre-Diciembre 2025
ISSN 2007-8013

Inhibición de la enzima prooxidante NADPH oxidasa: un nuevo enfoque para la resolución del absceso hepático amibiano experimental

Inhibition of the pro-oxidant enzyme NADPH oxidase. A new approach to resolving experimental amoebic liver abscesses

David Levaro-Loquio1,#, Aldo Arturo Reséndiz-Albor1,#, Rosa Adriana Jarillo-Luna 1,2, Germán Higuera-Martínez1, Munich Guevara-Rubio1, Maritza Tatiana Velásquez-Torres1, Judith Pacheco-Yépez1*

  1. Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México
  2. Coordinación de Ciencias Morfológicas, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México

*Autor de correspondencia: Dr. Judith Pacheco Yépez
Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis S/N,
Casco de Santo Tomas, CP 11340, CDMX, México.
Email: jpachecoy@ipn.mx; Tel. +52 5557296300 ext 62743
#Estos autores han contribuido de igual forma en este trabajo

DOI http://dx.doi.org/10.28960/revmeduas.2007-8013.v15.n4.007

Texto Completo PDF

Recibido 24 de junio 2025, aceptado 22 de octubre 2025

RESUMEN
El absceso hepático amibiano (AHA) ocasionado por Entamoeba histolytica (E. histolytica) ocurre debido a la liberación exacerbada de especies reactivas de oxígeno (EROs). Enzimas prooxidantes como la NADPH oxidasa (NOX) participa en la producción de EROs producidas por las células inmunitarias, como mecanismo de defensa, pero estas EROs también dañan a las células del hospedero. Trabajos in vitro han mostrado que el tratamiento con diversos inhibidores de la NOX, entre ellos la apocinina, han demostrado la disminución del daño celular inducido por E. histolytica. El objetivo de la presente revisión es explorar la modulación de enzimas prooxidantes como la NOX como una nueva estrategia en el tratamiento del AHA disminuyendo así el daño oxidativo y favoreciendo la resolución de la infección causada por E. histolytica.
Palabras clave: Entamoeba histolytica, Absceso Hepático Amibiano, Enzima NADPH oxidasa, modelo animal

ABSTRACT
The amebic liver abscess (ALA) caused by E. histolytica occurs due to the exacerbated release of reactive oxygen species (ROS). Pro-oxidant enzymes, such as NADPH oxidase (NOX) participates in the production of ROS produced by immune cells as a defense mechanism, but these ROS also damage host cells. In vitro work has shown that treatment with various NOX inhibitors, including apocynin, have demonstrated the decrease in cell damage induced by E. histolytica. This review aims to explore the modulation of pro-oxidant enzyme, such as NOX, as a new strategy for treating ALA. This plan would reduce oxidative damage and promote the resolution of E. histolytica caused infections.
Keywords: Entamoeba histolytica, Amebic Liver Abscess, NADPH oxidase enzyme, animal model

Referencias

  1. Ortega YR. Protozoan diseases Cryptosporidiosis, giardiasis and other instestinal protozoan diseases. Int Encycl Public Heal. Published online 2005:354-366.
  2. Woolhouse M, Waugh C, Perry MR, Nair H. Global disease burden due to antibiotic resistance - State of the evidence. J Glob Health. 2016;6(1):1-5.
  3. Stark D, Barratt JLN, Van Hal S, Marriott D, Harkness J, Ellis JT. Clinical significance of enteric protozoa in the immunosuppressed human population. Clin Microbiol Rev. 2009;22(4):634-650.
  4. The Institut Pasteur. Amebiasis. March 2024. Accessed August 15, 2025. https://www.pasteur.fr/en/medical-center/disease-sheets/Amebiasis
  5. SINAVE. Secretaría de Salud. (2024). Reporte Anual de Morbilidad 2023. https://www.gob.mx/salud/acciones-y-programas/direccion-general-de-epidemiologia-boletin-epidemiologico
  6. Mitchell GF. Co-evolution of parasites and adaptive immune responses. Immunol Today. 1991;12(3):2-5.
  7. Tsutsumi V, Mena-Lopez R, Anaya-Velazquez F, Martinez-Palomo A. Cellular bases of experimental amebic liver abscess formation. Am J Pathol. 1984;117(1):81-91.
  8. Tsutsumi V, Shibayama M. Experimental amebiasis: A selected review of some in vivo models. Arch Med Res. 2006;37(2):210-220.
  9. Pacheco J, Shibayama M, Campos R, et al. In vitro and in vivo interaction of Entamoeba histolytica Gal/GalNAc lectin with various target cells: An immunocytochemical analysis. Parasitol Int. 2004;53(1):35-47.
  10. Higuera-Martínez G, Arciniega-Martínez IM, Jarillo-Luna RA, Cárdenas-Jaramillo LM, Levaro-Loquio D, Velásquez-Torres M, Abarca-Rojano E, Reséndiz-Albor AA PYJ. Apocynin, an NADPH Oxidase Enzyme Inhibitor, Prevents Amebic Liver Abscess in Hamster. Biomedicines. Published online 2023:1-16.
  11. Cortes A, Nequiz M, Sandoval J, et al. Mechanisms of natural resistance of Balb/c mice to experimental liver amoebiasis. Biosci Rep. 2019;39(5):1-13.
  12. Tanyuksel, M. P. Laboratory diagnosis of amebiasis. Clin Microbiol Rev. 2003;22(4):713-929.
  13. Haque R, Huston CD, Hughes M, Houpt E PWJ. Amebiasis. N Engl J Med. 2003;(3):1565-1573.
  14. Cruz-Baquero A, Jaramillo LMC, Gutiérrez-Meza M, et al. Different behavior of myeloperoxidase in two rodent amoebic liver abscess models. PLoS One. 2017;12(8):1-23.
  15. Pacheco-Yépez J, Rivera-Aguilar V, Barbosa-Cabrera E, Rojas Hernández S, Jarillo-Luna RA, Campos-Rodríguez R. Myeloperoxidase binds to and kills Entamoeba histolytica trophozoites. Parasite Immunol. 2011;33(5):255-264.
  16. Santi-Rocca J, Rigothier MC, Guillén N. Host-microbe interactions and defense mechanisms in the development of amoebic liver abscesses. Clin Microbiol Rev. 2009;22(1):65-75.
  17. Campos-Rodríguez R, Gutiérrez-Meza M, Jarillo-Luna RA, et al. A review of the proposed role of neutrophils in rodent amebic liver abscess models. Parasite. 2016;23.
  18. Klaunig JE, Kamendulis LM. The Role of Oxidative Stress in Carcinogenesis. Annu Rev Pharmacol Toxicol. 2004;44:239-267.
  19. Rochael NC, Guimarães-Costa AB, Nascimento MTC, et al. Classical ROS-dependent and early/rapid ROS-independent release of Neutrophil Extracellular Traps triggered by Leishmania parasites. Sci Rep. 2015;5(December):1-11.
  20. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol. 2004;4(3):181-189.
  21. Aldaba-Muruato LR, Muñoz-Ortega MH, Campos-Esparza MDR, et al. Antioxidant defense of Nrf2 vs pro-inflammatory system of NF-κB during the amoebic liver infection in hamster. Parasitology. 2017;144(4):384-393.
  22. Arias DG, Regner EL, Iglesias AA, Guerrero SA. Entamoeba histolytica thioredoxin reductase: Molecular and functional characterization of its atypical properties. Biochim Biophys Acta - Gen Subj. 2012;1820(12):1859-1866.
  23. Lacy P. Mechanisms of degranulation in neutrophils. Allergy, Asthma Clin Immunol. 2006;2(3):98-108.
  24. Nguyen GT, Green ER, Mecsas J. Neutrophils to the ROScue: Mechanisms of NADPH oxidase activation and bacterial resistance. Front Cell Infect Microbiol. 2017;7(AUG).
  25. Hampton. Inside the Neutrophil Phagosome: Oxidants, Myeloperoxidase, and Bacterial Killing. Blood. 2008;94(4):1043-1052.
  26. Klebanoff SJ. Myeloperoxidase. Proc Assoc Am Physicians 1999. 1999;111:383-389.
  27. Aratani Y. Myeloperoxidase: Its role for host defense, inflammation, and neutrophil function. Arch Biochem Biophys. 2018;640:47-52.
  28. Bannister J V, Bannister WH, Rotilio G. Aspects of the structure, function, and applications of Superoxide Dismutase. CRC Crit Rev Biochem. 1987;22(2):111-180.
  29. Vermot A, Petit-Härtlein I, Smith SME, Fieschi F. Nadph oxidases (Nox): An overview from discovery, molecular mechanisms to physiology and pathology. Antioxidants. 2021;10(6).
  30. Brandes RP, Weissmann N, Schröder K. Nox family NADPH oxidases: Molecular mechanisms of activation. Free Radic Biol Med. 2014;76:208-226.
  31. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev. 2007;87(1):245-313.
  32. DeCoursey TE, Ligeti E. Regulation and termination of NADPH oxidase activity. Cell Mol Life Sci. 2005;62(19-20):2173-2193.
  33. Andrés CMC, Pérez de la Lastra JM, Juan CA, Plou FJ, Pérez-Lebeña E. The Role of Reactive Species on Innate Immunity. Vaccines. 2022;10(10):1-24.
  34. Nauseef WM. Biological roles for the NOX family NADPH oxidases. J Biol Chem. 2008;283(25):16961-16965.
  35. Segal AW, West I, Wientjes F, et al. Cytochrome b-245 is a flavocytochrome containing FAD and the NADPH-binding site of the microbicidal oxidase of phagocytes. Biochem J. 1992;284(3):781-788.
  36. Winterbourn CC, Kettle AJ, Hampton MB. Reactive Oxygen Species and Neutrophil Function. Annu Rev Biochem. 2016;85:765-792.
  37. Carneiro MBH, Roma EH, Ranson AJ, et al. NOX2-Derived Reactive Oxygen Species Control Inflammation during Leishmania amazonensis Infection by Mediating Infection-Induced Neutrophil Apoptosis . J Immunol. 2018;200(1):196-208.
  38. Cross AR, Jones OTG. The effect of the inhibitor diphenylene iodonium on the superoxide-generating system of neutrophils. Specific labelling of a component polypeptide of the oxidase. Biochem J. 1986;237(1):111-116.
  39. O’Donnell VB, Tew DG, Jones OTG, England PJ. Studies on the inhibitory mechanism of iodonium compounds with special reference to neutrophil NADPH oxidase. Biochem J. 1993;290(1):41-49.
  40. Wang Q, Qian L, Chen SH, et al. Post-treatment with an ultra-low dose of NADPH oxidase inhibitor diphenyleneiodonium attenuates disease progression in multiple Parkinson’s disease models. Brain. 2015;138(5):1247-1262.
  41. Kuai Y, Liu H, Liu D, et al. An ultralow dose of the NADPH oxidase inhibitor diphenyleneiodonium (DPI) is an economical and effective therapeutic agent for the treatment of colitis-associated colorectal cancer. Theranostics. 2020;10(15):6743-6757.
  42. Diatchuk V, Lotan O, Koshkin V, Wikstroem P, Pick E. Inhibition of NADPH oxidase activation by 4-(2-aminoethyl)- benzenesulfonyl fluoride and related compounds. J Biol Chem. 1997;272(20):13292-13301.
  43. Shi J, Ross CR, Leto TL, Blecha F, Klebanoff SJ. PR-39, a proline-rich antibacterial peptide that inhibits phagocyte NADPH oxidase activity by binding to Src homology 3 domains of p47phox (neutrophil/superoxide anion/cytochrome bsss/p22Pbox). Proc Natl Acad Sci USA. 1996;93(June):6014-6018.
  44. Hancock REW, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol. 2006;24(12):1551-1557.
  45. Wang S Bin, Jang JY, Chae YH, et al. Kaempferol suppresses collagen-induced platelet activation by inhibiting NADPH oxidase and protecting SHP-2 from oxidative inactivation. Free Radic Biol Med. 2015;83:41-53.
  46. Tauber AI, Fay JR, Marletta MA. Flavonoid inhibition of the human neutrophil NADPH-oxidase. Biochem Pharmacol. 1984;33(8):1367-1369.
  47. Levaro-Loquio D, Serrano-Luna J, Velásquez-Torres M, et al. In Vitro Evaluation of the Antiamoebic Activity of Kaempferol against Trophozoites of Entamoeba histolytica and in the Interactions of Amoebae with Hamster Neutrophils. Int J Mol Sci. 2023;24(13).
  48. Calderón-Montaño JM, Burgos-Morón E, Pérez-Guerrero C, López-Lázaro M. A Review on the Dietary Flavonoid Kaempferol | BenthamScience. Mini Rev Med Chem. 2011;11(4):298-344.
  49. Deng SP, Yang YL, Cheng XX, Li WR, Cai JY. Synthesis, spectroscopic study and radical scavenging activity of Kaempferol derivatives: Enhanced water solubility and antioxidant activity. Int J Mol Sci. 2019;20(4).
  50. Luo M, Tian R, Yang Z, Peng YY, Lu N. Quercetin suppressed NADPH oxidase-derived oxidative stress via heme oxygenase-1 induction in macrophages. Arch Biochem Biophys. 2019;671(June):69-76.
  51. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol. 2007;45(11):2179-2205.
  52. Stefanska J, Pawliczak R. Apocynin: Molecular aptitudes. Mediators Inflamm. 2008;2008.
  53. Kanegae MPP, da Fonseca LM, Brunetti IL, de Oliveira Silva S, Ximenes VF. The reactivity of ortho-methoxy-substituted catechol radicals with sulfhydryl groups: Contribution for the comprehension of the mechanism of inhibition of NADPH oxidase by apocynin. Biochem Pharmacol. 2007;74(3):457-464.
  54. Oostwoud LC, Gunasinghe P, Seow HJ, et al. Apocynin and ebselen reduce influenza A virus-induced lung inflammation in cigarette smoke-exposed mice. Sci Rep. 2016;6(January):1-16.
  55. Horemans T, Boulet G, Van Kerckhoven M, et al. In-vivo evaluation of apocynin for prevention of Helicobacter pylori-induced gastric carcinogenesis. Eur J Cancer Prev. 2017;26(1):10-16.
  56. El-Sawalhi MM, Ahmed LA. Exploring the protective role of apocynin, a specific NADPH oxidase inhibitor, in cisplatin-induced cardiotoxicity in rats. Chem Biol Interact. 2014;207(1):58-66.
  57. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents. Incidence, treatment and prevention. Drug Saf. 2000;22(4):263-302.
  58. Lee YA, Kim KA, Min A, Shin MH. NOX4 activation is involved in ROS-dependent Jurkat T-cell death induced by Entamoeba histolytica. Parasite Immunol. 2019;41(11):1-7.
  59. Lee YA, Shin MH. Involvement of NOX2-derived ROS in human hepatoma HepG2 cell death induced by Entamoeba histolytica. Parasites, hosts Dis. 2023;61(4):388-396.