We have found that N-acetylneuraminic acid (NANA) consumes toxic hydrogen peroxide (H 2 O 2 ) under physiological conditions. Close investigation of this ¢nding revealed that NANA was oxidized by an equimolar amount of H 2 O 2 to provide its decarboxylated product, 4-(acetylamino)-2,4-dideoxy-D-glycero-D-galacto-octonic acid (ADOA). To date, there have been little data on this reaction, and its physiological signi¢cance has not been discussed. Examining the detoxi¢cation of H 2 O 2 in cultured cells with NANA, we were able to con¢rm that the cell death caused by H 2 O 2 was suppressed by NANA in a dose-dependent manner. These results revealed a novel role for NANA as a reactive oxygen scavenger. It is known that terminal NANA residues are removed by neuraminidase and that free NANA molecules are recycled or degraded by enzymes. We propose that released monomeric NANA is the potent defense molecule against oxidative damage.

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Farnesol is well known as a quorum-sensing molecule of Candida albicans. To assess the pathological function of farnesol, its effects on macrophage viability and functions including growth inhibitory activities against C. albicans were examined in vitro. Murine macrophages, when cultured in the presence of 56-112 μM of farnesol for 1-2 hr, decreased their activity inhibiting the mycelial growth of C. albicans and lost their viability. This suppression of macrophage function by farnesol was neutralized by the coexistence of the anti-oxidants probucol and trolox. Macrophages cultured in the presence of farnesol for 2 hr displayed morphological change of nuclei and DNA fragmentation, which suggested apoptosis of the cells. Intracellular production of ROS in the farnesol-treated macrophages was shown by fluorescence of DCFH-DA and increase of peroxidized materials. These effects of farnesol were blocked by probucol or trolox. These results indicate that farnesol lowered viability of the murine macrophages and suppressed their anti-Candida activity, perhaps through induction of ROS.

BackgroundFood is known to affect drug absorption by delaying gastric emptying time, altering gastrointestinal pH, stimulating bile flow, increasing splanchnic blood flow, or physically interacting with drugs. Although food is known to affect the pharmacokinetics of oral antineoplastic drugs, the relationship between the effects of food and the physicochemical properties of drugs remains unclear.MethodsIn this study, we surveyed the literature on three kinds of pharmacokinetic changes, AUC ratio, Cmax ratio and Tmax ratio, in the fasted and fed state for 72 oral antineoplastic drugs that were listed on the drug price standard in May 2018 in Japan. We further predicted the physicochemical properties from the 2D chemical structure of the antineoplastic drugs using in silico predictions.ResultsAs a result of analyzing the relationship between the effects of food and physicochemical properties, we found that compounds that show increased absorption in the fed state had higher logP and lower solubility in fasted-state simulated intestinal fluid (FaSSIF). However, compounds with delayed absorption had higher solubility in FaSSIF. Furthermore, as a result of decision tree analysis, it was classified as AUC increase with logP ≥4.34. We found that an AUC increase in the fed state did not occur with compounds with low lipid solubilities (logP < 1.59). From these results, it is predicted that 7 compounds out of the 24 compounds for which the effects of food are unknown are at risk for increased absorption in the fed state and that no increase in absorption would occur in 13 compounds.ConclusionIn this study, we found that drugs that will show increased absorption in the fed state and drugs for which absorption is not dependent on food can generally be predicted by logP. These results suggest that logP can be a useful parameter for predicting the effects of food on drug absorption.

N-Acetylneuraminic acid (NANA) is a sialic acid, which occurs in mammals, certain mollusks, and microorganisms, and is found in the oligosaccharide chains of glycoproteins and glycolipids.1) Moreover, NANA exists as a capping sugar in the oligosaccharide chains. These facts suggest the important role of NANA as a surface recognition molecule. Thus, NANA-related factors such as sialyl Lewis X, selectin, and siglec family proteins are being studied. 2,3) In our previous paper, we reported the scavenger effect of NANA in which NANA reacts with hydrogen peroxide (H 2 O 2 ) as an antidote; in this reaction, water, carbon dioxide, and the decarboxylated product of NANA-4-(acetylamino)-2,4-dideoxy-Dglycero-D-galacto-octonic acid (ADOA)-were generated. 4)Such a reaction was known to occur between H 2 O 2 and a-ketocarboxylic acids such as pyruvic acid, 5) but in the case of NANA, which is the most complex kind of a-ketocarboxylic acid, this was not reported prior to our study. It is thought that due to the low reactivity of NANA and H 2 O 2 in low-pH solution, this reaction was not detected until very recently. Although the reactivity of pyruvic acid and H 2 O 2 is also strikingly pH-dependent and the reaction occurs under conditions of low pH, it is sufficiently detectable.5) In contrast, in the case of NANA, it was thought that the reaction velocity was extremely small at low pH, such as that in the NANA solution itself, hence rendering it difficult to detect a significant decrease in the amount of H 2 O 2 . If this reaction is occurred in the living bodies, it seemed that reaction velocity became fast under the physiology state. In this paper, we report the rate constant (k) of the NANA-H 2 O 2 reaction under different pH and temperature conditions. MATERIALS AND METHODSMaterials N-Acetylneuraminic acid (Cat. No. 00622-31; Nacalai Tesque, Inc., Japan) was dissolved in water, and the pH of the solution was adjusted to 7.0-7.5 with sodium hydroxide; a(2→8) homodimer of N-acetylneuraminic acid (DP2) sodium salt (Cat. No. 00640-0431; Nacalai Tesque, Inc.) was dissolved in water. The pH value of this 10-mM solution was 6.6; The H 2 O 2 solution for atomic absorption spectrophotometry (Cat. No. 085-04056), which did not contain any stabilizer agents, was obtained from Wako Pure Chemical Industries Ltd., Japan.Analysis of the Reaction Product The analysis of the compound was based on conventional methods: Mass spectra were measured using fast atom bombardment mass spectrometry (FAB-MS) and high-resolution (HR)-FAB-MS.1 H-NMR spectra was recorded at 600 MHz ( 1 H-NMR) with a pulse Fourier transform NMR spectrometer by using tetramethylsilane (TMS) as an internal standard. Chemical shifts are reported in ppm downfield from TMS. solution in a 96-well microtiter plate was incubated with nine volumes of aqueous peroxide color reagent for 30 min at room temperature, and the optical density at 550 nm was measured.2. Since 30 min of incubation is required for color development when using the PeroxiDetect TM KIT, this method is not ...

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