No abstract

trans-fatty acids (tfAs) are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. Epidemiological evidence has linked TFA consumption with various disorders, including cardiovascular diseases. However, the underlying pathological mechanisms are largely unknown. Here, we show a novel toxic mechanism of TFAs triggered by DNA damage. We found that elaidic acid (EA) and linoelaidic acid, major TFAs produced during industrial food manufacturing (so-called as industrial TFAs), but not their corresponding cis isomers, facilitated apoptosis induced by doxorubicin. Consistently, EA enhanced UV-induced embryonic lethality in C. elegans worms. The pro-apoptotic action of EA was blocked by knocking down Sab, a c-Jun N-terminal kinase (JNK)interacting protein localizing at mitochondrial outer membrane, which mediates mutual amplification of mitochondrial reactive oxygen species (ROS) generation and JNK activation. EA enhanced doxorubicin-induced mitochondrial ROS generation and JNK activation, both of which were suppressed by Sab knockdown and pharmacological inhibition of either mitochondrial ROS generation, JNK, or Src-homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) as a Sab-associated protein. These results demonstrate that in response to DNA damage, TFAs drive the mitochondrial JNK-Sab-ROS positive feedback loop and ultimately apoptosis, which may provide insight into the common pathogenetic mechanisms of diverse TFA-related disorders. trans-Fatty acids (TFAs) are defined as unsaturated fatty acids containing one or more carbon-carbon double bonds in trans configuration. TFAs, such as elaidic acid (EA, C18:1 t9) and linoelaidic acid (LEA, C18:2 t9,t12), so-called as industrial TFAs, are produced during the food manufacturing processes, mainly through partial hydrogenation of vegetable and fish oils that contain cis isomers of TFAs, hereafter referred to as cis-fatty acids (CFAs) 1. On the other hand, TFAs such as trans-vaccenic acid (TVA, C18:1 t11), so-called as ruminant TFAs, are produced via enzymatic isomerization of CFAs by ruminal microbes in cows and sheep, and are present in dairy products and meat 1. Compelling epidemiological evidence has shown that the intake of TFAs, particularly industrial TFAs, increases the risk of various disorders, such as systemic inflammation, metabolic syndrome, neurodegenerative disorders, and cardiovascular diseases (CVDs) 2-5. However, few studies have focused on the mechanisms of action of TFAs, and the molecular mechanisms underlying TFA-related disorders remain to be elucidated. Among TFA-related disorders, TFAs have been most highly linked with atherosclerosis, one of the major cause of CVDs, and the underlying mechanisms have been explained by their deleterious effects on vascular endothelial functions and lipoprotein regulation 3,6-10. Importantly, we have recently revealed a novel toxic function of TFAs as an enhancer of inflammatory signaling and cell death induced by extracellular ATP, one of the damage-assoc...

Valproic acid (VPA) is a multi-target drug and an inhibitor of histone deacetylase (HDAC). We have previously demonstrated that prenatal exposure to VPA at embryonic day 12.5 (E12.5), but not at E14.5, causes autism-like behavioral abnormalities in male mouse offspring. We have also found that prenatal VPA exposure causes transient histone hyperacetylation in the embryonic brain, followed by decreased neuronal cell numbers in the prefrontal and somatosensory cortices after birth. In the present study, we examined whether prenatal HDAC inhibition affects neuronal maturation in primary mouse cortical neurons. Pregnant mice were injected intraperitoneally with VPA (500 mg/kg) and the more selective HDAC inhibitor trichostatin A (TSA; 500 µg/kg) at E12.5 or E14.5, and primary neuronal cultures were prepared from the cerebral cortices of their embryos. Prenatal exposure to VPA at E12.5, but not at E14.5, decreased total number, total length, and complexity of neuronal dendrites at 14 days in vitro (DIV). The effects of VPA weakened at 21 DIV. Exposure to TSA at E12.5, but not at E14.5, also delayed maturation of cortical neurons. In addition, real-time quantitative PCR revealed that the prenatal exposure to TSA decreased neuroligin-1 (Nlgn1), Shank2, and Shank3 mRNA levels and increased contactin-associated protein-like 2 mRNA level. The delay in neuronal maturation was also observed in Nlgn1-knockdown cells, which were transfected with Nlgn1 siRNA. These findings suggest that prenatal HDAC inhibition causes changes in gene expression of autism-related molecules linked to a delay of neuronal maturation.

Antimicrobial activities of tea extracts on the cariogenic bacterium, Streptococcus mutans, were studied. Extracts of green and black tea leaves effectively suppressed the growth of S. mutans as compared with those of oolong and Pu-erh tea leaves. Ethyl acetate and n-butanol extracts of both green and black tea leaves and the non-dialyzable fraction of the water-soluble fraction of black tea leaves showed strong antimicrobial activities on S. mutans. Catechins were found in the ethyl acetate and n-butanol extracts of green tea leaves, while catechins, theaflavins, and gallic acid were found in these extracts of black tea leaves. Polyphenols and esterified gallic acid were found in the nondialyzable fraction of black tea leaves.

Samples of liver and perirenal, mesenteric and subcutaneous fat were collected from 16 sick necropsied dairy cows to evaluate the fatty acid profiles in the hepatic and adipose tissues associated with advanced fatty liver or hepatic lipidosis. Hepatic triglyceride and eight fatty acids were measured in the hepatic and adipose tissues. Six cows had more than 3% triglyceride on fresh weight in their livers and were classified as having fatty liver. Stearic and linoleic acid proportions in the liver decreased markedly with increased hepatic triglyceride levels, while the proportion of palmitic and oleic acids increased. The most striking fluctuations in hepatic lipidosis were manifested as decreased stearic acid in the adipose tissues including subcutaneous fat with the trend of decreasing stearic acid. Palmitic acid was elevated in hepatic and perirenal fat in fatty liver cows. In instances of advanced hepatic lipidosis, palmitoleic acid increased in only subcutaneous fat and not in perirenal or mesenteric fat. In addition to the proportions of hepatic fatty acids in fatty liver, this study also clarified the fluctuations observed in the profiles of fatty acids of the adipose tissues in cows with advanced hepatic lipidosis, particularly the decline in the proportions of stearic acid.