Chemopreventive activities of farnesol (FOH) and geraniol (GOH) were evaluated during the initial phases of hepatocarcinogenesis. Rats received during eight consecutive weeks 25 mg/100 g body weight FOH (FOH group) or GOH (GOH group), or only corn oil (CO group, controls). Incidence (%) and mean number of visible hepatocyte nodules/animal were inhibited in FOH group (13% and 4 +/- 1; P < 0.05), but not in GOH group (42% and 18 +/- 17, P > 0.05), compared to CO group (100% and 42 +/- 17). Mean area (mm2) and % liver section area occupied by total hepatic placental glutathione S-transferase positive preneoplastic lesions (PNLs) were reduced in FOH group (0.09 +/- 0.06; 2.8 +/- 1.3; P < 0.05) compared to CO group (0.18 +/- 0.12; 10.0 +/- 2.8), while in GOH group only the mean area of these PNL was reduced (0.11 +/- 0.09; P < 0.05), but not the % liver section area occupied by them (5.1 +/- 1.1; P > 0.05). Compared to CO group, FOH and GOH groups showed reduced (P < 0.05) PNL cell proliferation and DNA damage, but only GOH group showed increased PNL apoptosis (P < 0.05). FOH group, but not GOH group, presented reduced (P < 0.05) total plasma cholesterol levels and increased (P < 0.05) hepatic levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase mRNA, compared to CO group. No differences (P > 0.05) were observed between CO, FOH and GOH regarding hepatic levels of farnesoid X activated receptor (FXR) protein. Results indicate that FOH and GOH could represent promising chemopreventive agents against hepatocarcinogenesis. Inhibition of cell proliferation and DNA damage relate to both isoprenoids' anticarcinogenic actions while induction of apoptosis specifically relates to GOH protective actions. Inhibition of HMGCoA reductase activity could be associated with FOH, but not GOH anticarcinogenic actions. FXR does not seem to be involved in the isoprenoids' chemopreventive activities.

Hepatocellular carcinoma (HCC) ranks in prevalence and mortality among top 10 cancers worldwide. Butyric acid (BA), a member of histone deacetylase inhibitors (HDACi) has been proposed as an anticarcinogenic agent. However, its short half-life is a therapeutical limitation. This problem could be circumvented with tributyrin (TB), a proposed BA prodrug. To investigate TB effectiveness for chemoprevention, rats were treated with the compound during initial phases of ''resistant hepatocyte'' model of hepatocarcinogenesis, and cellular and molecular parameters were evaluated. TB inhibited (p < 0.05) development of hepatic preneoplastic lesions (PNL) including persistent ones considered HCC progression sites. TB increased (p < 0.05) PNL remodeling, a process whereby they tend to disappear. TB did not inhibit cell proliferation in PNL, but induced (p < 0.05) apoptosis in remodeling ones. Compared to controls, rats treated with TB presented increased (p < 0.05) hepatic levels of BA indicating its effectiveness as a prodrug. Molecular mechanisms of TB-induced hepatocarcinogenesis chemoprevention were investigated. TB increased (p < 0.05) hepatic nuclear histone H3K9 hyperacetylation specifically in PNL and p21 protein expression, which could be associated with inhibitory HDAC effects. Moreover, it reduced (p < 0.05) the frequency of persistent PNL with aberrant cytoplasmic p53 accumulation, an alteration associated with increased malignancy. Original data observed in our study support the effectiveness of TB as a prodrug of BA and as an HDACi in hepatocarcinogenesis chemoprevention. Besides histone acetylation and p21 restored expression, molecular mechanisms involved with TB anticarcinogenic actions could also be related to modulation of p53 pathways.

The molecular pathogenesis of autism is complex and involves numerous genomic, epigenomic, proteomic, metabolic, and physiological alterations. Elucidating and understanding the molecular processes underlying the pathogenesis of autism is critical for effective clinical management and prevention of this disorder. The goal of this study is to investigate key molecular alterations postulated to play a role in autism and their role in the pathophysiology of autism. In this study we demonstrate that DNA isolated from the cerebellum of BTBR T+tf/J mice, a relevant mouse model of autism, and from human post-mortem cerebellum of individuals with autism, are both characterized by an increased levels of 8-oxo-7-hydrodeoxyguanosine (8-oxodG), 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC). The increase in 8-oxodG and 5mC content was associated with a markedly reduced expression of the 8-oxoguanine DNA-glycosylase 1 (Ogg1) and increased expression of de novo DNA methyltransferases 3a and 3b (Dnmt3a and Dnmt3b). Interestingly, a rise in the level of 5hmC occurred without changes in the expression of ten-eleven translocation expression 1 (Tet1) and Tet2 genes, but significantly correlated with the presence of 8-oxodG in DNA. This finding and similar elevation in 8-oxodG in cerebellum of individuals with autism and in the BTBR T+tf/J mouse model warrant future large-scale studies to specifically address the role of OGG1 alterations in pathogenesis of autism.

Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and developed countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD. The goals of this study were to compare the magnitude of interindividual differences in the severity of liver injury induced by methyl-donor deficiency among individual inbred strains of mice and to investigate the underlying mechanisms associated with the variability. Feeding mice a choline- and folate-deficient diet for 12 wk caused liver injury similar to NAFLD. The magnitude of liver injury varied among the strains, with the order of sensitivity being A/J ≈ C57BL/6J ≈ C3H/HeJ < 129S1/SvImJ ≈ CAST/EiJ < PWK/PhJ < WSB/EiJ. The interstrain variability in severity of NAFLD liver damage was associated with dysregulation of genes involved in lipid metabolism, primarily with a down-regulation of the peroxisome proliferator receptor α (PPARα)-regulated lipid catabolic pathway genes. Markers of oxidative stress and oxidative stress-induced DNA damage were also elevated in the livers but were not correlated with severity of liver damage. These findings suggest that the PPARα-regulated metabolism network is one of the key mechanisms determining interstrain susceptibility and severity of NAFLD in mice.

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Synopsis Ceramide 1 is the main repository of stratum corneum linoleic acid, and changes in the levels of ceramide 1 linoleate are associated with cutaneous abnormalities: essential fatty acid deficiency, atopic dermatitis and acne. We have previously reported seasonal variation in stratum corneum lipids where lipids, particularly ceramides, are very much reduced in winter which probably influences the appearance of skin xerosis in this season. However, investigations into the seasonal variation in ceramide 1 fatty acid levels and the effects of topical essential fatty acids on the composition of these lipid species have not been conducted in healthy subjects. We determined the composition of stratum corneum ceramide 1 esterified fatty acids in leg skin from Caucasian women in winter and summer and also investigated the effects of topical triglycerides rich in linoleic acid on stratum corneum ceramide 1 fatty acid levels in winter. A dramatic seasonal variation was observed. Whereas decreased levels of linoleic acid and some saturated fatty acids (C-15 and C-24) were observed in the winter months, increased levels of oleic acid were found. Nevertheless, it was possible to normalize the levels of stratum corneum ceramide 1 linoleate following topical application of formulations containing linoleic acid-rich triglycerides for 4 weeks. The reduction in ceramide 1 linoleate may lead to impaired stratum corneum function and increased susceptibility to skin xerosis in winter. However, by using formulations containing linoleic acid esters it is possible to correct these changes and possibly improve barrier resilience.

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