Waranya Chatuphonprasert

Photodynamic therapy (PDT) is a selective tumor treatment that consists of a photosensitive compound—a photosensitizer (PS), oxygen, and visible light. Although each component has no cytotoxic properties, their simultaneous use initiates photodynamic reactions (PDRs) and sequentially generates reactive oxygen species (ROS) and/or free radicals as cytotoxic mediators, leading to PDT-induced cell death. Nevertheless, tumor cells develop various cytoprotective mechanisms against PDT, particularly the adaptive mechanism of antioxidant status. This review integrates an in-depth analysis of the cytoprotective mechanism of detoxifying ROS enzymes that interfere with PDT-induced cell death, including superoxide dismutase (SOD), catalase, glutathione redox cycle, and heme oxygenase-1 (HO-1). Furthermore, this review includes the use of antioxidant enzymes inhibitors as a strategy in order to diminish the antioxidant activities of tumor cells and to improve the effectiveness of PDT. Conclusively, PDT is an effective tumor treatment of which its effectiveness can be improved when combined with a specific antioxidant inhibitor.

Purpose: To determine the effect of the glutathione (GSH) suppressors styrene oxide (SO) and diethyl maleate (DEM) on the hepatic expression of cytochrome P450 family 1 (Cyp1) isoforms that are related to carcinogenesis including Cyp1a1, Cyp1a2, and Cyp1b1. Methods: Seven-week-old ICR mice were intraperitoneally injected with SO (150 and 300 mg/kg/day), DEM (175 and 350 mg/kg/day), or N-acetylcysteine (NAC; 300 and 600 mg/kg/day) for 7, 14, or 28 days. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic Cyp1 expression, total glutathione, reduced glutathione (GSH), and oxidized glutathione (GSSG) were determined. Results: ALT and AST levels were markedly increased by SO and DEM while GSH/GSSG ratio was decreased by SO in all treatments (p < 0.05), while high dose (350 mg/kg/day) DEM significantly suppressed GSH/GSSG ratio at 28 days (p < 0.05). The expressions of Cyp1a1, Cyp1a2, and Cyp1b1 were induced by SO and DEM, corresponding with induction of ethoxy/methoxy-resorufin O- dealkylase activities. Conclusion: The Cyp1 family metabolizes procarcinogens to carcinogenic DNA adducts; exposure to the industrial solvents, SO and DEM, raises the risk of carcinogenesis via GSH depletion coupled with Cyp1 induction.

Differential Impacts of Phenol Red on Benzo[a]pyrene and Dexamethasone-Modified Cytochrome P450s in Human Cancer Cells

Purpose: To evaluate the molecular impact of ethanol, sodium selenite, and tert-butyl hydroperoxide (TBHP) on oxidant-antioxidant balance in HepG2 cells to establish an optimized oxidative stress model of HepG2 cells. Methods: HepG2 cells were treated with ethanol (10 - 500 mM) and sodium selenite (1 - 10 µM) for 24 and 48 h and with TBHP (50 - 200 µM) for 3 and 24 h, respectively. Biomarkers for cellular injury, ie, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA), and for antioxidant system, i.e., superoxide dismutase (SOD), catalase (CAT), and total glutathione content, were determined. Results: All treatments increased the levels of LDH, AST, ALT, and MDA but decreased SOD and CAT activities and the total glutathione content in HepG2 cells. Oxidative stress was induced by these oxidative stressors in HepG2 cells via oxidant-antioxidant imbalance, with TBHP (100 µM, 3 h) acting as a powerful oxidant based on the minimal time to induce oxidative stress. The antioxidants, ascorbic acid and gallic acid, improved oxidant-antioxidant imbalance against xenobiotic-induced oxidative stress in HepG2 cells. Conclusion: These oxidative stress models are suitable for investigating the antioxidant and/or hepatoprotective potential of chemicals, including natural compounds.

Flavonoids have demonstrated beneficial effects in fatty liver disease (FLD). Consumption of flavonoids is associated with several health benefits via their antioxidant and anti-inflammatory activities. The current study aimed to investigate hesperidin and myricetin as new candidates for FLD therapy. Five-week-old female ICR mice were provided a high fat diet (HFD) 60 kcal % fat of total food and daily intragastrically administered ethanol (0.5 g/kg/day) in combination with fenofibrate (40 mg/kg/day) or flavonoids, hesperidin or myricetin (50 and 200 mg/kg/day), for 60 consecutive days. Hepatic histomorphology was observed with oil red O (ORO) staining along with hepatic triglyceride (TG) level, activity of antioxidative enzymes, and mRNA expression of metabolic, antioxidative, and inflammatory genes, including peroxisome proliferator activated receptor-alpha and -gamma 2 (Ppara and Pparg2), sterol regulatory element binding protein-1c (Srebp-1c), acetyl-CoA carboxylase (Acaca), fatty acid synthase (Fasn), CD36 molecules (Cd36), catalase (Cat), superoxide dismutase 1 and 2 (Sod1 and Sod2), glutathione peroxidase 1 (Gpx1), nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (Nfkb1), tumor necrosis factor-alpha (Tnf-a), chemokine (C-C motif) ligand 2 (Ccl2). Fenofibrate, hesperidin, and myricetin improved hepatic histomorphology, restored expression of metabolic genes, improved antioxidative system, and suppressed inflammatory pathways. Interestingly, hesperidin attenuated TG level and down-regulated Ccl2 expression at low dose and reinstated Cat expression better than myricetin. These findings confirm that hesperidin is a promising candidate for FLD therapy.

Bergenin is a C-glucoside derivative of gallic acid claimed to exhibit antioxidant and hepatoprotective activities. However, its effect on sodium selenite-induced oxidative damage has never been elucidated. We investigated the impact of bergenin on the oxidant-antioxidant balance in sodium selenite-induced oxidative stress in HepG2 cells and mouse livers. HepG2 cells were co-incubated with sodium selenite (10 μM) and either bergenin (75, 150, and 300 μM) or gallic acid (60 μM) for 24 h. Adult male ICR mice were orally administered sodium selenite (4 mg/kg/day) in combination with either bergenin (10, 50, and 250 mg/kg/day) or gallic acid (100 mg/kg/day) for 7 days. Sodium selenite injured HepG2 cells and mouse livers by disturbing the oxidant-antioxidant balance. Bergenin exerted protective effects against sodium selenite-induced oxidative stress in HepG2 cells. Moreover, bergenin attenuated sodium selenite-induced liver damage (nuclear pyknosis and necrotic areas) through a decrease in plasma aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels, and decreased production of reactive oxygen species, resulting in reduced lipid peroxidation in plasma and livers. Bergenin also restored hepatic antioxidant enzyme expression levels and activities (superoxide dismutase, catalase, and glutathione peroxidase) and reinstated hepatic glutathione homeostasis. Finally, bergenin returned cytochrome P450 2E1 mRNA expression to normal levels. In conclusion, bergenin reduced-sodium selenite induced liver damage by restoring the oxidant-antioxidant balance and reducing lipid peroxidation through multiple pathways.