Effects of acetyl-L-carnitine on the formation of fatty acid ethyl esters in brain and peripheral organs after short-term ethanol administration in rat

Increasing evidence suggests that Fatty acid ethyl esters (FAEE) play a central role in ethanol induced organ damage. In the current study we measured FAEE formation in rats after short-term oral administration of ethanol, in the presence and absence of pre-treatment with acetyl-L-carnitine. Ethanol treatment caused a significant increase in the levels of FAEE, particularly in the brain and heart, but also in the kidney and liver. Increases in FAEE were associated with a significant increase in FAEE synthase activity, GSH transferase activity, and lipid hydroperoxide levels. Pretreatment with acetyl-L-carnitine resulted in a significant reduction of FAEE accumulation, decrease in FAEE synthase and GSH transferase activities, and lipid hydroperoxide levels. Administration of acetyl-L-carnitine greatly reduced the metabolic abnormalities due to non-oxidative ethanol metabolism, through an increment in lipid metabolism/turnover and by the modulation of the activities of enzymes associated with FAEE synthesis. These results suggest a potentially important pharmacological role for acetyl-L-carnitine in the prevention of alcohol-induced cellular damage

Induction of heat shock protein synthesis in human skin fibroblasts in response to oxidative stress: regulation by a natural antioxidant from rosemary extract

Reactive oxygen species have been implicated in the pathogenesis of the severe connective tissue damage present in several photodermatologic disorders, including drug-induced phototoxicity, porphyrias and photoaging. Oxidative stress has been shown to alter the expression of mammalian antioxidant enzymes and to enhance numerous transcription factors, including nuclear factor-kappa B, stress-activated protein kinase and heat shock factor. The latter represents the transcription factor for the synthesis of cytoprotective proteins called heat shock proteins. In this study, we investigated the role of oxidative stress and sulfdryl (SH) groups in the induction of HSP70 in human skin fibroblasts and the effect of antioxidants. We found that significant HSP70 induction occurred after exposure to HOOH and this was associated with marked perturbation in protein and nonprotein SH groups and with a considerable increase in protein carbonyl levels. Treatment with a natural antioxidant from rosemary extract provided notable protection against stress-induced modifications of cellular SH and carbonyl content, maintaining functional levels of cytoprotective heat shock protein 70. Our results point to the possible involvement of redox mechanisms in the heat shock signal transduction pathway, which may play an important regulatory role in the genetic mechanisms of tolerance to oxidative stress. Exogenous supplementation of an antioxidant hydrophilic extract from rosemary could have cosmetic benefits and may represent an efficient tool to minimize free radical-induced skin damage

Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

We have recently shown that covalent attachment of the nitric oxide (NO) moiety to the HIV protease inhibitor Saquinavir (Saq) produced a qualitatively new chemical entity, named Saquinavir-NO (Saq-NO), with enhanced anticancer properties and reduced toxicity both in vitro and in vivo. The aim of this study was to address several unanswered questions both on the pharmacological profile of Saq-NO as well as on the in vivo role of NO in the oncogenesis of A375 human melanoma cells. To this end, we have evaluated here the impact of single and combined effects of Saq-NO, Saq, the NO-donor DETA NONOate and the iNOS inhibitor L-NAME on the in vitro as well as in vivo growth of the iNOS positive A375 cells. Our data confirm clear-cut evidence for a strong and powerful anti-melanoma action of Saq-NO that is not duplicable by the combined use of Saq and DETA NONOate. Surprisingly, but also in agreement with the complex and multifaceted role of endogenous NO in A375 cells, both DETA NONOate and L-NAME significantly suppressed the in vivo growth of xenotransplants.Ministry of Education and Science of the Republic of Serbia [173013

Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

We have recently shown that covalent attachment of the nitric oxide (NO) moiety to the HIV protease inhibitor Saquinavir (Saq) produced a qualitatively new chemical entity, named Saquinavir-NO (Saq-NO), with enhanced anticancer properties and reduced toxicity both in vitro and in vivo. The aim of this study was to address several unanswered questions both on the pharmacological profile of Saq-NO as well as on the in vivo role of NO in the oncogenesis of A375 human melanoma cells. To this end, we have evaluated here the impact of single and combined effects of Saq-NO, Saq, the NO-donor DETA NONOate and the iNOS inhibitor L-NAME on the in vitro as well as in vivo growth of the iNOS positive A375 cells. Our data confirm clear-cut evidence for a strong and powerful anti-melanoma action of Saq-NO that is not duplicable by the combined use of Saq and DETA NONOate. Surprisingly, but also in agreement with the complex and multifaceted role of endogenous NO in A375 cells, both DETA NONOate and L-NAME significantly suppressed the in vivo growth of xenotransplants.Ministry of Education and Science of the Republic of Serbia [173013