Antitumor Activity of Alloy and Core-Shell-Type Bimetallic AgAu Nanoparticles.

Nanoparticles (NPs) of noble metals, namely gold and silver, remain promising anticancer agents capable of enhancing current surgery- and chemotherapeutic-based approaches in cancer treatment. Bimetallic AgAu composition can be used as a more effective agent due to the synergetic effect. Among the physicochemical parameters affecting gold and silver nanoparticle biological activity, a primary concern relates to their size, shape, composition, charge, etc. However, the impact of metal components/composition as well as metal topological distribution within NPs is incompletely characterized and remains to be further elucidated and clarified. In the present work, we tested a series of colloidal solutions of AgAu NPs of alloy and core-shell type for an antitumor activity depending on metal molar ratios (Ag:Au = 1:1; 1:3; 3:1) and topological distribution of gold and silver within NPs (AucoreAgshell; AgcoreAushell). The efficacy at which an administration of the gold and silver NPs inhibits mouse Lewis lung carcinoma (LLC) growth in vivo was compared. The data suggest that in vivo antitumor activity of the studied NPs strongly depends on gold and silver interaction arising from their ordered topological distribution. NPs with Ag core covered by Au shell were the most effective among the NPs tested towards LLC tumor growth and metastasizing inhibition. Our data show that among the NPs tested in this study, AgcoreAushell NPs may serve as a suitable anticancerous prototype.

Hepatic Detoxification of Bisphenol A is Retinoid-Dependent.

Bisphenol A (BPA, 2,2-bis(4-hydroxyphenyl) propane) is a widely used industrial chemical. The extensive distribution of BPA in the environment poses risks to humans. However, the molecular mechanisms underlying BPA toxicity as well as its effective detoxification and elimination are not well understood. We have investigated specifically for BPA the notion raised in the literature that the optimal sensing, detoxification, and elimination of xenobiotics requires retinoid (natural derivatives and synthetic analogs of vitamin A) actions. The objective of the study was to explore how retinoids, both those stored in the liver and those originating from recent oral intake, help maintain an optimal xenobiotic detoxification response, affecting mRNA expression and activities of elements of xenobiotic detoxification system upon BPA administration to mice. Wild-type and mice lacking hepatic retinoid stores (Lrat-/-) were acutely treated with BPA (50 mg/kg body weight), with or without oral supplementation with retinyl acetate. Hepatic mRNA expression levels of the genes encoding nuclear receptors and their downstream targets involved in xenobiotic biotransformation, phase I and phase II enzyme activities, and levels of oxidative damage to cellular proteins and lipids in hepatic microsomes, mitochondria and cytosol, were assessed. BPA treatment induced hepatic activities needed for its detoxification and elimination in wild-type mice. However, BPA failed to induce these activities in the livers of Lrat-/- mice. Oral supplementation with retinyl acetate restored phase I and phase II enzyme activities, but accelerated BPA-induced oxidative damage through enhancement of non-mitochondrial ROS production. Thus, the activities of the enzymes involved in the hepatic elimination of BPA require hepatic retinoid stores. The extent of hepatic damage that arises from acute BPA intoxication is directly affected by retinoid administration during the period of BPA exposure and hepatic retinoid stores that have accumulated over the lifetime of the organism.

Retinoids modulate thioacetamide-induced acute hepatotoxicity.

The literature indicates that retinoids can influence the metabolism and actions of xenobiotics and conversely that xenobiotics can influence the metabolism and actions of retinoids. We were interested in understanding the degree to which hepatic retinoid stores, accumulated over a lifetime, affect xenobiotic metabolism, and actions. To investigate this, we induced liver injury through administration of the hepatotoxin thioacetamide (TAA) to chow fed wild type (WT) mice and lecithin:retinol acyltransferase-deficient (Lrat(-/-)) mice that are genetically unable to accumulate hepatic retinoid stores. Within 48 h of TAA-treatment, WT mice develop liver injury as evidenced by focal necrotic areas and increases in serum ALT activity and myeloperoxidase activity in hepatic parenchyma. Simultaneously, features of hepatic encephalopathy develop, as evidenced by a 25% increase in blood ammonia and a threefold reduction of blood glucose levels. This is accompanied by reduced hepatic glutathione, and increased thiobarbituric acid reactive substances, protein carbonyl and sulfhydryl groups, and increased cytochrome P450-catalyzed hydroxylation activity and flavin-containing monooxygenase activity in microsomes prepared from WT liver. Strikingly, none of these TAA-induced effects were observed for matched Lrat(-/-) mice. To confirm that TAA hepatotoxicity depends on retinoid availability, we administered, over 48 h, four oral doses of 3000 IU retinyl acetate each to the mice. This led to the development of hepatotoxicity in Lrat(-/-) mice that was similar in extent to that observed in WT mice. Our findings establish that endogenous hepatic retinoid stores can modulate the toxicity of TAA in mice.