Regulation of oxidative stress and its modulation by natural health products
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Date
2010, 2012, 2013
Authors
Sarna, Lindsei
Journal Title
Journal ISSN
Volume Title
Publisher
NRC Research Press
NRC Research Press
NRC Research Press
NRC Research Press
NRC Research Press
Abstract
Oxidative stress is characterized by the cellular accumulation of reactive oxygen species (ROS). Increased production of ROS, such as the superoxide anion (O2.-), or a deficiency in their clearance by antioxidant defenses, mediates the cellular pathology. Non-alcoholic fatty liver disease (NAFLD) is a broad spectrum liver disorder commonly manifesting in milieu of the metabolic syndrome. Oxidative stress is an important pathogenic mediator in NAFLD, and in its associated morbidities like atherosclerosis. The objective of my research was to investigate the regulation of oxidative stress and the antioxidant actions of natural health products (NHPs) in the context of NAFLD and its associated disorders. The O2.- generating NADPH oxidase contributes to atherogenesis by facilitating macrophage induced vascular injury. In manuscript I, the plant alkaloid berberine effectively abolished NADPH oxidase mediated O2.- production in lipopolysaccharide stimulated macrophages. Real-time PCR analysis and siRNA transfection studies revealed that berberine mediated its effects through down-regulation of the oxidase’s catalytic subunit gp91phox. Berberine also restored the activity of the O2.- clearing enzyme superoxide dismutase (SOD). High fat diet (HFD) fed rodents are a popular model for investigating NAFLD pathogenesis. In manuscript II, folic acid supplementation significantly reduced HFD-induced hepatic oxidative stress and liver injury in mice. Folic acid decreased NF-kB/DNA binding, down-regulated NADPH oxidase gene expression, and inhibited the oxidase. The antioxidant activities of SOD and catalase were restored and the reduced to oxidized glutathione ratio (GSH:GSSG) was re-established with folic acid supplementation. Folic acid’s hepatoprotective antioxidant effects were associated with a marked improvement in liver histology. Homocysteine (Hcy) levels are perturbed in NAFLD, but the etiology is unclear. In manuscript III, HFD fed mice exhibited decreased Hcy levels. Real-time PCR and Western Immunoblotting analysis revealed that Hcy catabolising enzymes cystathionine-b-synthase (CBS) and cystathionine-g-lyase (CSE) were increased in the liver of these animals. The transsulfuration activities of these enzymes were elevated and coincided with enhanced hepatic hydrogen sulfide biosynthesis. Glutathione was maintained despite increased hepatic oxidative stress. Taken together, NHPs such as berberine and folate, and Hcy catabolising enzymes CBS and CSE, might have therapeutic potential for managing oxidative stress in NAFLD and its associated co-morbidities.
Description
Keywords
oxidative stress, natural health products, antioxidants, non-alcoholic fatty liver disease, berberine, folic acid
Citation
Lindsei K. Sarna, Nan Wu, Sun-Young Hwang, Yaw L. Siow and Karmin O. 2010. Berberine Inhibits NADPH Oxidase Mediated Superoxide Anion Production in Macrophages. Canadian Journal of Physiology and Pharmacology. 88: 369-378.
Lindsei K. Sarna, Nan Wu, Pengqi Wang, Sun-Young Hwang, Yaw L. Siow and Karmin O. 2012. Folic acid supplementation attenuates high fat diet induced hepatic oxidative stress via regulation of NADPH oxidase. Canadian Journal of Physiology and Pharmacology. 90: 155-165.
Sun-Young Hwang, Lindsei K. Sarna, Yaw L. Siow, Karmin O. High fat diet stimulates hepatic cystathionine b-synthase and cystathionine g-lyase expression. 2013. Canadian Journal of Physiology and Pharmacology. 91: 913-919.
Lindsei K. Sarna, Nan Wu, Pengqi Wang, Sun-Young Hwang, Yaw L. Siow and Karmin O. 2012. Folic acid supplementation attenuates high fat diet induced hepatic oxidative stress via regulation of NADPH oxidase. Canadian Journal of Physiology and Pharmacology. 90: 155-165.
Sun-Young Hwang, Lindsei K. Sarna, Yaw L. Siow, Karmin O. High fat diet stimulates hepatic cystathionine b-synthase and cystathionine g-lyase expression. 2013. Canadian Journal of Physiology and Pharmacology. 91: 913-919.