Oxidative stress and antioxidant parameters in dogs with lymphoma during chemotherapy

Main Article Content

Peter Vajdovich Bernadett Szabó Noémi Tarpataki Judit Jakus

Abstract

Purpose: Oxidative stress is a contributor in the development of neoplasms. OS is involved in multidrug resistance, adverse events, and outcome.


Methods: Forty- two dogs with lymphoma have been included in the study, 30 of which were treated by Cyclophosphamide - Hydroxyldaunorubicin® (doxorubicin) - Oncovin® (vincristine) - Prednisolone (CHOP)-based protocol. Tumor samples were excised for histopatholgy, immunophenotyping, Ki67%, and biochemical analyses. Thiobarbituric acid reactive substances (TBARS), reduced and oxidized glutathione (GSH, GSSG), glutathione peroxidase (GSH-Px), Cu-Zn-superoxide dismutase (SOD), ferric reducing ability (FRAP), vitamin-C, -E, retinyl palmitate and trans-retinol in red blood cell hemolysates, lymph node homogenates, and blood plasma have been measured. The results were correlated with the outcome of the chemotherapy.


Results: Median overall survival time (OST), relapse-free period (RFP) were 862 and 280 days, respectively, with adverse effects in 18 cases.


Plasma GSH levels increased with age (dogs from 1 to 6 years vs 9 to 13 years, p = 0.0385). Lymph node FRAP levels were higher in samples with higher Ki67%, and plasma GSH/GSSG ratio was lower in dogs with increased OST and RFP. Plasma retinyl palmitate levels were lower in dogs with increased RFP. Overall survival time was increased with lower lymph node TBARS (cut off: 53 nmol/mg protein), GHS-Px (cut off: 16 U/mg protein), and higher plasma all-trans-retinol (cut off: 4 mg/ml). Relapse-free period was increased with lower lymph node TBARS (cut off: 53 nmol/mg protein), lower FRAP (cut off: 6 µmol/mg) and higher SOD (cut off: 70 U/mg protein). During chemotherapy a gradual increase in plasma vitamin E and C concentrations was detected, while GSH and GSSG showed a decrease before adverse events.


Conclusion: Although oxidative stress parameters varied, some parameters, i.e. TBARS, GSH-Px, SOD, FRAP measured in lymph node samples, and plasma all-trans retinol might be used as prognostic indices.

Article Details

How to Cite
VAJDOVICH, Peter et al. Oxidative stress and antioxidant parameters in dogs with lymphoma during chemotherapy. Medical Research Archives, [S.l.], v. 12, n. 8, aug. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/5564>. Date accessed: 04 dec. 2024. doi: https://doi.org/10.18103/mra.v12i8.5564.
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Research Articles

References

1. Mandelker L, Fellow, D. Mitochondrial Dysfunction and Chronic Disease. AHVMA J. 2016;43:35-38.
2. Wang J, Schipper HM, Velly AM, Mohit S, et al. Salivary biomarkers of oxidative stress: A critical review. Free Radic Biol Med. 2015;85:95-104. doi: 10.1016/j.freeradbiomed.2015.04.005. Epub 2015 PMID: 25889823.
3. Karihtala P, Soini Y. Reactive oxygen species and antioxidant mechanisms in human tissues and their relation to malignancies. APMIS. 2007;115(2):81-103. doi: 10.1111/j.1600-0463.2007.apm_514.x. PMID: 17295675.
4. Ishikawa T, Shigeoka S. Recent advances in ascorbate biosynthesis and the physiological significance of ascorbate peroxidase in photosynthesizing organisms. Biosci Biotechnol Biochem. 2008;72(5):1143-54. doi: 10.1271/bbb.80062. Epub 2008 PMID: 18460785.
5. Klaunig JE, Kamendulis LM, Hocevar BA. Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol. 2010;38(1):96-109. doi: 10.1177/0192623309356453. Epub 2009 PMID: 20019356.
6. Maulik N, Das DK. Redox signaling in vascular angiogenesis. Free Radic Biol Med. 2002;33(8):1047-60. doi: 10.1016/s0891-5849(02)01005-5. PMID: 12374616.
7. Mantovani G, Macciò A, Madeddu C, et al. Quantitative evaluation of oxidative stress, chronic inflammatory indices and leptin in cancer patients: correlation with stage and performance status. Int J Cancer. 2002;98(1):84-91. doi: 10.1002/ijc.10143. PMID: 11857390.
8. Ceriello A. Oxidative stress and glycemic regulation. Metabolism. 2000;49 (Suppl 1):27-9. doi: 10.1016/s0026-0495(00)80082-7. PMID: 10693917.
9. Weijl NI, Hopman GD, Wipkink-Bakker A, et al. Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients. Ann Oncol. 1998;9(12):1331-7. doi: 10.1023/a:1008407014084. PMID: 9932164.c
10. Valko M, Rhodes CJ, Moncol J, et al. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160(1):1-40. doi: 10.1016/j.cbi.2005.12.009. Epub 2006 PMID: 16430879.
11. Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44-84. doi: 10.1016/j.biocel.2006.07.001. Epub 2006 PMID: 16978905.
12. Peroja P, Pasinen AK, Haapasaan KM, et al. Oxidative stress and redox state-regulating enzymes have prognostic relevance in diffuse large B-cell lymphoma. Exp Hematol Oncol. 2012;1:2 doi: 10.1186/2162-3619-1-2 DOI:10.1186 %2 F2162-3619-1-2#pmc_ext.
13. Vajdovich P, Kriska T, Mézes M, et al. Redox status of dogs with non-hodgkin lymphomas. An ESR study. Cancer Lett. 2005;224(2):339-46. doi: 10.1016/j.canlet.2004.11.037. Epub 2004 PMID: 15914284.
14. Finotello R, Pasquini A, Meucci V, et al. Redox status evaluation in dogs affected by mast cell tumour. Vet Comp Oncol. 2014;12(2):120-9. doi: 10.1111/j.1476-5829.2012.00343.x. Epub 2012 PMID: 22823560.
15. Cucchi A, Ramoni, R Basini G, et al. Oxidant–Antioxidant Status in Canine Multicentric Lymphoma and Primary Cutaneous Mastocytoma. Processes 2020;8:802. doi:10.3390/pr8070802
16. Winter JL, Barber LG, Freeman L, et al. Antioxidant status and biomarkers of oxidative stress in dogs with lymphoma. J Vet Intern Med. 2009;23(2):311-6. doi: 10.1111/j.1939-1676.2009.0273.x. Epub 2009 PMID: 19210312.
17. Alberti, A., Bolognini, L., Macciantelli, D. et al. The radical cation of N,N-diethyl-para-phenylendiamine: A possible indicator of oxidative stress in biological samples. Res Chem Intermed . 2000;26:253–267. https://doi.org/10.1163/156856700X00769
18. Pasquini A, Luchetti E, Marchetti V, et al. Analytical performances of d-ROMs test and BAP test in canine plasma. Definition of the normal range in healthy Labrador dogs. Vet Res Commun. 2008;32(2):137-43. doi: 10.1007/s11259-007-9014-x. Epub 2007 PMID: 17846911.
19. Ray G, Batra S, Shukla NK, et al. Lipid peroxidation, free radical production and antioxidant status in breast cancer. Breast Cancer Res Treat. 2000;59(2):163-70. doi: 10.1023/a:1006357330486. PMID: 10817351.
20. Tome ME, Johnson DB, Rimsza LM, et al. A redox signature score identifies diffuse large B-cell lymphoma patients with a poor prognosis. Blood. 2005;106(10):3594-601. doi: 10.1182/blood-2005-02-0487. Epub 2005 PMID: 16081686; PMCID: PMC1895056.
21. Andreadis C, Gimotty PA, Wahl P, et al. Members of the glutathione and ABC-transporter families are associated with clinical outcome in patients with diffuse large B-cell lymphoma. Blood. 2007;109(8):3409-16. doi: 10.1182/blood-2006-09-047621. Epub 2006 PMID: 17179223; PMCID: PMC1852238.
22. Bottari NB, Munhoz TD, Torbitz VD, et al. Oxidative stress in dogs with multicentric lymphoma: Effect of chemotherapy on oxidative and antioxidant biomarkers. Redox Rep. 2015;20(6):267-74. doi: 10.1179/1351000215Y.0000000037. Epub 2015 PMID: 26274787; PMCID: PMC6837369.
23. Tsai SY, Sun NK, Lu HP, Cheng ML, et al. Involvement of reactive oxygen species in multidrug resistance of a vincristine-selected lymphoblastoma. Cancer Sci. 2007;98(8):1206-14. doi: 10.1111/j.1349-7006.2007.00513.x. Epub 2007 PMID: 17517054; PMCID: PMC11158752.
24. Asano T, Tsutsuda-Asano A, Fukunaga Y. Indomethacin overcomes doxorubicin resistance by decreasing intracellular content of glutathione and its conjugates with decreasing expression of gamma-glutamylcysteine synthetase via promoter activity in doxorubicin-resistant leukemia cells. Cancer Chemother Pharmacol. 2009;64(4):715-21. doi: 10.1007/s00280-008-0920-6. Epub 2009 PMID: 19153736.
25. Il'yasova D, Mixon G, Wang F, et al. Markers of oxidative status in a clinical model of oxidative assault: a pilot study in human blood following doxorubicin administration. Biomarkers. 2009;14(5):321-5.
doi: 10.1080/13547500902946757.
PMID: 19476408; PMCID: PMC2716435.
26. Kretzschmar M, Pfeiffer L, Schmidt C, et al. Plasma levels of glutathione, alpha-tocopherol and lipid peroxides in polytraumatized patients; evidence for a stimulating effect of TNF alpha on glutathione synthesis. Exp Toxicol Pathol. 1998;50(4-6):477-83. doi: 10.1016/s0940-2993(98)80037-7 PMID: 9784026.
27. Valli VE, San Myint M, Barthel A, et al. Classification of canine malignant lymphomas according to the World Health Organization criteria. Vet Pathol. 2011;48(1):198-211.
doi: 10.1177/0300985810379428. Epub 2010 PMID: 20861499.
28. Owen LN. Lymphoid and haemopoietic tissues (including lymphosarcoma of skin). TNM Classification of Tumours in Domestic Animals, ed 9. Published: Geneva, World Health Organization, VPH/CMO/~O.20. 1980: 46–47.
29. Cotter SM, Goldstein MA. Comparison of two protocols for maintenance of remission in dogs with lymphoma. J Am Anim Hosp Assoc. 1987;23( 5): 495-499. ISSN Print: 0587-2871, CABI Record Number: 19872203485
30. Rassnick KM, McEntee MC, Erb HN, Burke BP, Balkman CE, Flory AB, Kiselow MA, Autio K, Gieger TL. Comparison of 3 protocols for treatment after induction of remission in dogs with lymphoma. J Vet Intern Med. 2007 Nov-Dec;21(6):1364-73. doi: 10.1892/07-057.1. PMID: 18196748.
31. LeBlanc AK, Atherton M, Bentley RT, et al. Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) following investigational therapy in dogs and cats. Vet Comp Oncol. 2021;19(2):311-352. doi: 10.1111/vco.12677. Epub 2021 PMID: 33427378; PMCID: PMC8248125.
32. Flatland B, Freeman KP, Friedrichs KR, Vap LM, Getzy KM, Evans EW, Harr KE. ASVCP quality assurance guidelines: control of general analytical factors in veterinary laboratories. Vet Clin Pathol. 2010 Sep;39(3):264-77. doi: 10.1111/j.1939-165X.2010.00251.x. PMID: 21054473.
33. Valli VE, Kass PH, San Myint M, et al. Canine lymphomas: association of classification type, disease stage, tumor subtype, mitotic rate, and treatment with survival. Vet Pathol. 2013;50(5):738-48. doi: 10.1177/0300985813478210. Epub 2013 PMID: 23444036.
34. Carter RF, Valli VE, Lumsden JH. The cytology, histology and prevalence of cell types in canine lymphoma classified according to the National Cancer Institute Working Formulation. Can J Vet Res. 1986;50(2):154-64. PMID: 3756669; PMCID: PMC1255183.
35. Matkovics, B., Szabó, L. és Sz Varga, I. Determination of activity of lipid peroxidation and reduced glutathione metabolic enzymes in biological samples (in Hungarian). Lab Diagnoszt. 1988;15 (4): 248-250.
36. Czakó L, Takács T, Varga IS, et al. Involvement of oxygen-derived free radicals in L-arginine-induced acute pancreatitis. Dig Dis Sci. 1998;43(8):1770-7. doi: 10.1023/a:1018839821176. PMID: 9724167.
37. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968;25(1):192-205. doi: 10.1016/0003-2697(68)90092-4. PMID: 4973948.
38. Kosower NS, Song KR, Kosower EM, et al. Glutathione. II. Chemical aspects of azoester procedure for oxidation to disulfide. Biochim Biophys Acta. 1969;192(1):8-14. doi: 10.1016/0304-4165(69)90003-8. PMID: 5347974.
39. Benzie IFF, Strain JJ. The ferric reducing ability of plasma [FRAP] as a measure of „antioxidant power”: the FRAP assay. Anal Biochem. 1996;239(1):70-76, ISSN 0003-2697, doi.org:10.1006/abio.1996.0292.
40. Harapanhalli RS, Howell RW, Rao DV. Testicular and plasma ascorbic acid levels in mice following dietary intake: a high-performance liquid chromatographic analysis. J Chromatogr. 1993;614(2):233-43. doi: 10.1016/0378-4347(93)80314-t. PMID: 8314935.
41. Barbas C, Castro M, Bonet B, et al. Simultaneous determination of vitamins A and E in rat tissues by high-performance liquid chromatography. J Chromatogr A. 1997;778(1-2):415-20. doi: 10.1016/s0021-9673(97)00416-0. PMID: 9299749.
42. Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967;70(1):158-69. PMID: 6066618.
43. Kraus RJ, Ganther HE. Reaction of cyanide with glutathione peroxidase. Biochem Biophys Res Commun. 1980;96(3):1116-22. doi: 10.1016/0006-291x(80)90067-4. PMID: 7437
44. Woolliams JA, Wiener G, Anderson PH, et al. Variation in the activities of glutathione peroxidase and superoxide dismutase and in the concentration of copper in the blood in various breed crosses of sheep. Res Vet Sci. 1983;34(3):253-6. PMID: 6878874.
45. Lee JJ, Liao AT, Wang SL. L-Asparaginase, Doxorubicin, Vincristine, and Prednisolone (LHOP) Chemotherapy as a First-Line Treatment for Dogs with Multicentric Lymphoma. Animals (Basel). 2021;11(8):2199. doi: 10.3390/ani11082199. PMID: 34438662; PMCID: PMC8388373.
46. Withrow SJ, Vail DM, Page R. Withrow and MacEwen’s Small Animal Clinical Oncology - 5th Edition. Philadelphia: Elsevier; 2013. ISBN: 9781437723625. 608-678.
47. Zandvliet M. Canine lymphoma: a review. Vet Q. 2016;36(2):76-104. doi: 10.1080/01652176.2016.1152633. Epub 2016 Mar 8. PMID: 26953614.
48. Vail DM, Thamm LH, Liptak JM. Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition. Section 4: SPECIFIC MALIGNANCIES IN THE SMALL ANIMAL PATIENT. Hematopoietic Tumors 34. Philadelphia; Elsevier Health Sciences, 2019. ISBN: 0323594972, 97803235949742013. 688-715.
49. Merlo DF, Rossi L, Pellegrino C, et al. Cancer incidence in pet dogs: findings of the Animal Tumor Registry of Genoa, Italy. J Vet Intern Med. 2008;22(4):976-84. doi: 10.1111/j.1939-1676.2008.0133.x. PMID: 18564221.
50. Kiupel M, Teske E, Bostock D. Prognostic factors for treated canine malignant lymphoma. Vet Pathol. 1999;36(4):292-300. doi: 10.1354/vp.36-4-292. PMID: 10421095.
51. Poggi A, Miniscalco B, Morello E, ett al. Prognostic significance of Ki67 evaluated by flow cytometry in dogs with high-grade B-cell lymphoma. Vet Comp Oncol. 2017;15(2):431-440. doi: 10.1111/vco.12184. Epub 2016. PMID: 26792094.
52. Rout ED, Labadie JD, Yoshimoto JA, et al. Clinical outcome and prognostic factors in dogs with B-cell chronic lymphocytic leukemia: A retrospective study. J Vet Intern Med. 2021;35(4):1918-1928. doi: 10.1111/jvim.16160. Epub 2021 May 17. PMID: 33998726; PMCID: PMC8295712.
53. Dhaliwal RS, Kitchell BE, Ehrhart E, et al. Clinicopathologic significance of histologic grade, pgp, and p53 expression in canine lymphoma. J Am Anim Hosp Assoc. 2013;49(3):175-84. doi: 10.5326/JAAHA-MS-5843. EPub 2013 PMID: 23535752.
54. Cunha SCS, Silva FBF, Corgozinho KB, et al. Adverse Effects of Chemotherapy in Dogs. World Vet. J. 20017;7(3): 74-82. pii:S232245681700010-7. DOI: http://dx.doi.org/10.5455/wvj.20170896
55. Bauer NB, Zervos D, Moritz A. Argyrophilic nucleolar organizing regions and Ki67 equally reflect proliferation in fine needle aspirates of normal, hyperplastic, inflamed, and neoplastic canine lymph nodes (n = 101). J Vet Intern Med. 2007;21(5):928-35. doi: 10.1892/0891-6640(2007)21[928:anorak]2.0.co;2. PMID: 17939545.
56. Viviano KR, Lavergne SN, Goodman L, et al. Glutathione, cysteine, and ascorbate concentrations in clinically ill dogs and cats. J Vet Intern Med. 2009r;23(2):250-7. doi: 10.1111/j.1939-1676.2008.0238.x. Epub 2008 Dec 16. PMID: 19143933.
57. Center SA, Warner KL, Erb HN. Liver glutathione concentrations in dogs and cats with naturally occurring liver disease. Am J Vet Res. 2002;63(8):1187-97. doi: 10.2460/ajvr.2002.63.1187. PMID: 12171175.
58. Spee B, Mandigers PJ, Arends B, et al. Differential expression of copper-associated and oxidative stress related proteins in a new variant of copper toxicosis in Doberman pinschers. Comp Hepatol. 2005;4(1):3. doi: 10.1186/1476-5926-4-3. PMID: 15790412; PMCID: PMC1079907.
59. Dragin N, Smani M, Arnaud-Dabernat S, et al. Acute oxidative stress is associated with cell proliferation in the mouse liver. FEBS Lett. 2006;580(16):3845-52. doi: 10.1016/j.febslet.2006.06.006. Epub 2006 PMID: 16797015.
60. Jiang H, Zuo J, Li B, Chen R, Luo K, Xiang X, et al. Drug-induced oxidative stress in cancer treatments: Angel or devil? Redox Biol. 2023;63:102754. doi: 10.1016/j.redox.2023.102754. Epub 2023 May 18. PMID: 37224697; PMCID: PMC10220276.
61. D’Ambrosio D.N., Clugston R.D., Blaner W.S. Vitamin A metabolism: An update. Nutrients. 2011;3:63–103. doi: 10.3390/nu3010063
62. Fritz H, Kennedy D, Fergusson D, et al. Vitamin A and retinoid derivatives for lung cancer: a systematic review and meta analysis. PLoS One. 2011;6(6):e21107. doi: 10.1371/journal.pone.0021107. Epub 2011 Jun 27. PMID: 21738614; PMCID: PMC3124481.
63. Ollberding NJ, Maskarinec G, Conroy SM, et al. Prediagnostic circulating carotenoid levels and the risk of non-Hodgkin lymphoma: the Multiethnic Cohort. Blood. 2012;119(24):5817-23. doi: 10.1182/blood-2012-02-413609. Epub 2012. PMID: 22550343; PMCID: PMC3382940.
64. Hada M, Mondul AM, Weinstein SJ, et al. Serum Retinol and Risk of Overall and Site-Specific Cancer in the ATBC Study. Am J Epidemiol. 2020;189(6):532-542. doi: 10.1093/aje/kwz226. PMID: 31612201; PMCID: PMC7443202
65. Hawk MA, McCallister C, Schafer ZT. Antioxidant Activity during Tumor Progression: A Necessity for the Survival of Cancer Cells? Cancers (Basel). 2016;8(10):92. doi: 10.3390/cancers8100092. PMID: 27754368; PMCID: PMC5082382.
66. Hohaus S, Massini G, D'Alo' F, et al. Association between glutathione S-transferase genotypes and Hodgkin's lymphoma risk and prognosis. Clin Cancer Res. 2003;9(9):3435-40. PMID: 12960134.
67. Ginn J, Sacco J, Wong YY, et al. Positive association between a glutathione-S-transferase polymorphism and lymphoma in dogs. Vet Comp Oncol. 2014;12(3):227-36. doi: 10.1111/vco.12000. Epub 2012 PMID: 23020265.
68. Kinowaki Y, Kurata M, Ishibashi S, et al. Glutathione peroxidase 4 overexpression inhibits ROS-induced cell death in diffuse large B-cell lymphoma. Lab Invest. 2018;98(5):609-619. doi: 10.1038/s41374-017-0008-1. Epub 2018 PMID: 29463878.
69. Iqbal MJ, Kabeer A, Abbas Z, et al. Interplay of oxidative stress, cellular communication and signaling pathways in cancer. Cell Commun Signal. 2024;22(1):7. doi: 10.1186/s12964-023-01398-5. PMID: 38167159; PMCID: PMC10763046.
70. Arfin S, Jha NK, Jha SK, et al. Oxidative Stress in Cancer Cell Metabolism. Antioxidants (Basel). 2021;10(5):642. doi: 10.3390/antiox10050642. PMID: 33922139; PMCID: PMC8143540.
71. Kinnula VL, Crapo JD. Superoxide dismutases in malignant cells and human tumors. Free Radic Biol Med. 2004;36(6):718-44. doi: 10.1016/j.freeradbiomed.2003.12.010. PMID: 14990352.
72. Sun Y. Free radicals, antioxidant enzymes, and carcinogenesis. Free Radic Biol Med. 1990;8(6):583-99. doi: 10.1016/0891-5849(90)90156-d. PMID: 2193855.
73. Bae I, Fan S, Meng Q, Rih JK, et al. BRCA1 induces antioxidant gene expression and resistance to oxidative stress. Cancer Res. 2004;64(21):7893-909. doi: 10.1158/0008-5472.CAN-04-1119. PMID: 15520196.
74. White R, Nonis M, Pearson JF, Burgess E, et al. Low Vitamin C Status in Patients with Cancer Is Associated with Patient and Tumor Characteristics. Nutrients. 2020;12(8):2338. doi: 10.3390/nu12082338. PMID: 32764253; PMCID: PMC7468872.
75. Dawson M.I. The importance of vitamin a in nutrition. Curr. Pharm. Des. 2000;6:311–325. doi: 10.2174/1381612003401190.
76. Kim JA, Jang JH, Lee SY. An Updated Comprehensive Review on Vitamin A and Carotenoids in Breast Cancer: Mechanisms, Genetics, Assessment, Current Evidence, and Future Clinical Implications. Nutrients. 2021;13(9):3162. doi: 10.3390/nu13093162. PMID: 34579037; PMCID: PMC8465379
77. Lubos E, Loscalzo J, Handy DE. Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2011;15(7):1957-97. doi: 10.1089/ars.2010.3586. Epub 2011. PMID: 21087145; PMCID: PMC3159114.
78. Yi L, Shen H, Zhao M, et al. Inflammation-mediated SOD-2 upregulation contributes to epithelial-mesenchymal transition and migration of tumor cells in aflatoxin G1-induced lung adenocarcinoma. Sci Rep. 2017;7(1):7953. doi: 10.1038/s41598-017-08537-2. PMID: 28801561; PMCID: PMC5554181.
79. Mahoney DJ, Kaczor JJ, Bourgeois J, et al. Oxidative stress and antioxidant enzyme upregulation in SOD1-G93A mouse skeletal muscle. Musc. Nerve. 2006;33(6):809-16. doi: 10.1002/mus.20542. PMID: 16583367.
80. Haddad JJ. L-Buthionine-(S,R)-sulfoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, augments LPS-mediated pro-inflammatory cytokine biosynthesis: evidence for the implication of an IkappaB-alpha/NF-kappaB insensitive pathway. Eur Cytokine Netw. 2001;12(4):614-24. Erratum in: Eur Cytokine Netw 2002;13(1):134. PMID: 11781188.
81. Plato. Plato in Twelve Volumes, Vol. 12 translated by Harold N. Fowler. Cambridge, MA, Harvard University Press; London, William Heinemann Ltd. 1921. 169-170
82. Appendix
83. Reference intervals
84. Method: Box-Cox transformed data, Standard