Jacques Carlos Eduardo Diaz, Lopes Franciele Fátima, Poletto Edina, Vera Luisa Natalia Pimentel, Vianna Priscila, Reinhardt Luiza Steffens, Baldo Guilherme, Vargas Carmen Regla
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Metab Brain Dis. 2023 Feb;38(2):519-529. doi: 10.1007/s11011-022-01062-w. Epub 2022 Aug 27.
Mucopolysaccharidosis type II (MPS II or Hunter Syndrome) is a lysosomal disease caused by deficient degradation of glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate due to the deficiency of the enzyme iduronate-2-sulfatase. The main treatment for MPS II is the administration of the recombinant form of the enzyme, in a process known as enzyme replacement therapy (ERT). Oxidative damage can contribute to the pathophysiology of MPS II and treatment with ERT can reduce the effects of oxidative stress. For a better understanding of pathophysiology of MPS II, we evaluated biomarkers of mitochondrial dysfunction, DNA (Deoxyribonucleic acid) damage, antioxidant defenses, reactive species production and lysosomal size in IDS-deficient HEK 293 cells and investigate the in vitro effect of genistein and coenzyme Q10 (CoQ) on these biomarkers. An increase in the production of reactive species was demonstrated, as well as an increase in the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Also, an increase in lysosomal volume and oxidative damage to DNA were verified. There was no evidence of a change in mitochondrial function in this cell model. In the HEK 293 (human embryonic kidney 293) knockout (KO) HP10 cell model we found that genistein at concentrations of 25 and 50 μm decreased in vitro the production of reactive species and the activity of the SOD enzyme, showing an antioxidant protective effect. Still, in these cells we verified that the coenzyme Q10 in the concentrations of 5 and 10 μm decreased in vitro the activity of the SOD enzyme and in the concentration of 10 μm decreased in vitro the DNA damage, also demonstrating antioxidant protection. In conclusion, MPS II knockout cells demonstrated oxidative stress and DNA damage and genistein, as well as coenzyme Q10, have been shown to have an important protective effect in vitro against these oxidative damages.
II型粘多糖贮积症（MPS II或亨特综合征）是一种溶酶体疾病，由于艾杜糖醛酸-2-硫酸酯酶缺乏，导致糖胺聚糖（GAGs）硫酸乙酰肝素和硫酸皮肤素降解不足。MPS II的主要治疗方法是给予重组形式的酶，这一过程称为酶替代疗法（ERT）。氧化损伤可能导致MPS II的病理生理过程，ERT治疗可以减轻氧化应激的影响。为了更好地理解MPS II的病理生理学，我们评估了IDS缺陷的HEK 293细胞中线粒体功能障碍、DNA（脱氧核糖核酸）损伤、抗氧化防御、活性物质产生和溶酶体大小的生物标志物，并研究了染料木黄酮和辅酶Q10（CoQ）对这些生物标志物的体外作用。结果表明，活性物质的产生增加，抗氧化酶超氧化物歧化酶（SOD）和过氧化氢酶（CAT）的活性也增加。此外，还证实了溶酶体体积增加和DNA氧化损伤。在这个细胞模型中没有线粒体功能改变的证据。在HEK 293（人胚肾293）基因敲除（KO）HP10细胞模型中，我们发现浓度为25和50μm的染料木黄酮在体外可降低活性物质的产生和SOD酶的活性，显示出抗氧化保护作用。此外，在这些细胞中我们还证实，浓度为5和10μm的辅酶Q10在体外可降低SOD酶的活性，浓度为10μm时可在体外降低DNA损伤，也显示出抗氧化保护作用。总之，MPS II基因敲除细胞表现出氧化应激和DNA损伤，染料木黄酮以及辅酶Q10在体外已被证明对这些氧化损伤具有重要的保护作用。
