Intracellular GSH Depletion (intracellular + gsh_depletion)

Distribution by Scientific Domains

Selected Abstracts

Butterfat fatty acids differentially regulate growth and differentiation in Jurkat T-cells

Paolo Bergamo
Abstract Synthetic Conjugated Linoleic Acid mixture (CLA; c9,t11; t10,c12-18:2) has been previously shown to inhibit growth, and enhance apoptosis and IL-2 mRNA synthesis in human lymphoblastic Jurkat T-cells. In this study, two different butterfat types were evaluated and compared for their effects on Jurkat cell viability, oxidative stress, pro-apoptotic activity, and cytokine synthesis: the conventionally produced butterfat (CBF), and organic butterfat (OBF) containing significantly higher amounts of c9,t11 (Rumenic Acid, RA), trans-vaccenic acid (VA; t11-18:1), ,-linolenic acid (ALA), and lower levels of linoleic acid (LA). Results from cell treatment with both butterfat mixtures showed comparable oxidative stress (superoxide production, intracellular GSH depletion,and lipid peroxides yield), NADPH oxidase activation, cytotoxicity (LDH release), and IL-2 transcript level, whereas the effects of enhanced growth-inhibitory and pro-apoptotic activities were associated with OBF treatment. To then investigate each butterfat-induced effect caused by RA, VA, LA, and ALA, cells were exposed to synthetic FA concentrations similar to those from the different butterfats. Higher oxidative stress (superoxide production, intracellular GSH depletion) was induced by ,-linolenic (ALA) and linoleic (LA) incubation (P,<,0.01) and superoxide production was suppressed by specific PKC, inhibitor (G 6976) and linked to increased toxicity and IL-2 synthesis inhibition. By contrast, cell treatment with RA increased apoptosis and IL-2 synthesis. These results suggest that a supply of ALA and LA is responsible for BF-induced oxidative stress via PKC,-NADPH oxidase pathway, and that enhanced antiproliferative effects in OBF treated cells is essentially determined by RA-induced pro-apoptotic activity. 2005 Wiley-Liss, Inc. [source]

Nordihydroguaiaretic acid induces astroglial death via glutathione depletion

Joo-Young Im
Abstract Nordihydroguaiaretic acid (NDGA) is known to cause cell death in certain cell types that is independent of its activity as a lipoxygenase inhibitor; however, the underlying mechanisms are not fully understood. In the present study, we examined the cellular responses of cultured primary astroglia to NDGA treatment. Continuous treatment of primary astroglia with 30 ,M NDGA caused >85% cell death within 24 hr. Cotreatment with the lipoxygenase products 5-HETE, 12-HETE, and 15-HETE did not override the cytotoxic effects of NDGA. In assays employing the mitochondrial membrane potential-sensitive dye JC-1, NDGA was found to induce a rapid and almost complete loss of mitochondrial membrane potential. However, the mitochondrial permeability transition pore inhibitors cyclosporin A and bongkrekic acid did not block NDGA-induced astroglial death. We found that treatment with N-acetyl cysteine (NAC), glutathione (GSH), and GSH ethyl ester (GSH-EE) did inhibit NDGA-induced astroglial death. Consistently, NDGA-induced astroglial death proceeded in parallel with intracellular GSH depletion. Pretreatment with GSH-EE and NAC did not block NDGA-induced mitochondrial membrane potential loss, and there was no evidence that reactive oxygen species (ROS) production was involved in NDGA-induced astroglial death. Together, these results suggest that NDGA-induced astroglial death occurs via a mechanism that involves GSH depletion independent of lipoxygenase activity inhibition and ROS stress. 2007 Wiley-Liss, Inc. [source]

Azathioprine hepatotoxicity and the protective effect of liquorice and glycyrrhizic acid

Yue-Ting Wu
Abstract This study aimed to evaluate the responses of human hepatocytes to azathioprine hepatotoxicity in comparison with the well-studied azathioprine hepatotoxicity in rat hepatocytes and the effects of protective agents to suppress azathioprine hepatotoxicity. Azathioprine presented its hepatotoxicity at clinically relevant concentrations (lower than 10 m) in primary rat hepatocytes after 48 h of treatment as shown by a severe decrease in cell viability as well as intracellular GSH depletion. However, primary human hepatocytes exhibited only significant intracellular GSH depletion after treatment with azathioprine at these clinically relevant concentrations, while a reduction in cell viability by 29% was only evidenced after 48 h of treatment with azathioprine at the high concentration of 50 m. In addition, a monolayer culture of primary rat hepatocytes was used as an in vitro model to examine the protective effects of antihepatotoxic drugs including glutathione (GSH), N-acetylcysteine (NAC, a GSH precursor), liquorice and glycyrrhizic acid (GA), a major bioactive component of liquorice, against hepatotoxicity of 1 m azathioprine. It was found that both liquorice and GA showed substantial protection according to assays of cell viability and intracellular GSH, while neither GSH nor NAC had such a protective function. Similarly, GA protected human hepatocytes from intracellular GSH depletion on exposure to 1 m azathioprine. These results implied that GA or liquorice could be considered as potent protection agents against azathioprine hepatotoxicity. Copyright 2006 John Wiley & Sons, Ltd. [source]