Proanthocyanidins Modulate MicroRNA Expression in Human HepG2 Cells

Mi(cro)RNAs are small non-coding RNAs of 18-25 nucleotides in length that modulate gene expression at the post-transcriptional level. These RNAs have been shown to be involved in a several biological processes, human diseases and metabolic disorders. Proanthocyanidins, which are the most abundant polyphenol class in the human diet, have positive health effects on a variety of metabolic disorders such as inflammation, obesity, diabetes and insulin resistance. The present study aimed to evaluate whether proanthocyanidin-rich natural extracts modulate miRNA expression. Using microarray analysis and Q-PCR, we investigated miRNA expression in HepG2 cells treated with proanthocyanidins. Our results showed that when HepG2 cells were treated with grape seed proanthocyanidin extract (GSPE), cocoa proanthocyanidin extract (CPE) or pure epigallocatechin gallate isolated from green tea (EGCG), fifteen, six and five differentially expressed miRNAs, respectively, were identified out of 904 mRNAs. Specifically, miR-30b* was downregulated by the three treatments, and treatment with GSPE or CPE upregulated miR-1224-3p, miR-197 and miR-532-3p. Therefore, these results provide evidence of the capacity of dietary proanthocyanidins to influence microRNA expression, suggesting a new mechanism of action of proanthocyanidins

Intake of an Obesogenic Cafeteria Diet Affects Body Weight, Feeding Behavior, and Glucose and Lipid Metabolism in a Photoperiod-Dependent Manner in F344 Rats

We previously demonstrated that chronic exposure to different photoperiods induced marked variations in several glucose and lipid metabolism-related parameters in normoweight Fischer 344 (F344) rats. Here, we examined the effects of the combination of an obesogenic cafeteria diet (CAF) and the chronic exposure to three different day lengths (L12, 12 h light/day; L18, 18 h light/day; and L6, 6 h light/day) in this rat strain. Although no changes were observed during the first 4 weeks of adaptation to the different photoperiods in which animals were fed a standard diet, the addition of the CAF for the subsequent 7 weeks triggered profound physiologic and metabolic alterations in a photoperiod-dependent manner. Compared with L12 rats, both L6 and L18 animals displayed lower body weight gain and cumulative food intake in addition to decreased energy expenditure and locomotor activity. These changes were accompanied by differences in food preferences and by a sharp upregulation of the orexigenic genes Npy and Ghsr in the hypothalamus, which could be understood as a homeostatic mechanism for increasing food consumption to restore body weight control. L18 rats also exhibited higher glycemia than the L6 group, which could be partly attributed to the decreased pAkt2 levels in the soleus muscle and the downregulation of Irs1 mRNA levels in the gastrocnemius muscle. Furthermore, L6 animals displayed lower whole-body lipid utilization than the L18 group, which could be related to the lower lipid intake and to the decreased mRNA levels of the fatty acid transporter gene Fatp1 observed in the soleus muscle. The profound differences observed between L6 and L18 rats could be related with hepatic and muscular changes in the expression of circadian rhythm-related genes Cry1, Bmal1, Per2, and Nr1d1. Although further research is needed to elucidate the pathophysiologic relevance of these findings, our study could contribute to emphasize the impact of the consumption of highly palatable and energy dense foods regularly consumed by humans on the physiological and metabolic adaptations that occur in response to seasonal variations of day length, especially in diseases associated with changes in food intake and preference such as obesity and seasonal affective disorder

Measurement report: Spatial variability of northern Iberian rainfall stable isotope values - investigating atmospheric controls on daily and monthly timescales

For the first time, this article presents a large dataset of precipitation isotopic measurements (δ18Op and δ2Hp) sampled every day or 2 d from seven sites on a west-to-east transect across northern Spain for 2010-2017. The main aim of this study is to (1) characterize the rainfall isotopic variability in northern Spain at daily and monthly timescales and (2) assess the principal factors influencing rainfall isotopic variability. The relative role of air temperature and rainfall in determining the stable isotope composition of precipitation changes along the west-to-east transect, with air temperature being highly correlated with δ18Op at daily and monthly timescales, while a few sites along the transect show a significant negative correlation with precipitation. The highest air temperature-δ18Op dependency is found for a station located in the Pyrenees. Frontal systems associated with North Atlantic cyclones are the dominant mechanism inducing precipitation in this region, particularly in winter. This study allows an exploration of the role of air mass source and trajectory in determining the isotopic composition of rainfall in northern Iberia by characterizing the moisture uptake for three of the seven stations. The importance of continental versus marine moisture sources is evident, with clear seasonal and spatial variations. In addition, the type of precipitation (convective versus frontal rainfall) plays a key role, with convective rainfall associated with higher δ18Op values. This comprehensive spatiotemporal approach to analyzing the rainfall isotopic composition represents another step forward towards developing a more detailed, mechanistic framework for interpreting stable isotopes in rainfall as a paleoclimate and hydrological tracer

Metabolomics Reveals Reduction of Metabolic Oxidation in Women with Polycystic Ovary Syndrome after Pioglitazone-Flutamide-Metformin Polytherapy

Polycystic ovary syndrome (PCOS) is a variable disorder characterized by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity, low-grade inflammation and increased cardiovascular disease risks. Recently, a new polytherapy consisting of low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen resulted in the regulation of endocrine clinical markers in young and non-obese PCOS women. However, the metabolic processes involved in this phenotypic amelioration remain unidentified. In this work, we used NMR and MS-based untargeted metabolomics to study serum samples of young non-obese PCOS women prior to and at the end of a 30 months polytherapy receiving low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen. Our results reveal that the treatment decreased the levels of oxidized LDL particles in serum, as well as downstream metabolic oxidation products of LDL particles such as 9- and 13-HODE, azelaic acid and glutaric acid. In contrast, the radiuses of small dense LDL and large HDL particles were substantially increased after the treatment. Clinical and endocrine-metabolic markers were also monitored, showing that the level of HDL cholesterol was increased after the treatment, whereas the level of androgens and the carotid intima-media thickness were reduced. Significantly, the abundance of azelaic acid and the carotid intima-media thickness resulted in a high degree of correlation. Altogether, our results reveal that this new polytherapy markedly reverts the oxidant status of untreated PCOS women, and potentially improves the pro-atherosclerosis condition in these patients

miRNAs differentially expressed in HepG2 cells after 5 hours of culture with grape seed proanthocyanidin extract.

<p>The fold change value and the standard deviations obtained by QRT-PCR is presented in parentheses.</p

Selection of validated target genes for miR-30b* grouped by pathway.

<p>(1): from the KEGG (<a href="http://www.genome.jp/kegg/" target="_blank">http://www.genome.jp/kegg/</a>) and BioCarta (<a href="http://www.biocarta.com/" target="_blank">http://www.biocarta.com/</a>) pathway databases.</p><p>(2): from the miRWalk database (<a href="http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/" target="_blank">http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/</a>).</p><p>(3): from the KEGG (<a href="http://www.genome.jp/kegg/" target="_blank">http://www.genome.jp/kegg/</a>) and NCBI-Gene (<a href="http://www.ncbi.nlm.nih.gov" target="_blank">http://www.ncbi.nlm.nih.gov</a>) databases.</p

Validated target genes for the miRNAs differentially expressed in response to both grape seed proanthocyanidin extract and epigallocatechin gallate.

<p>(1): from the miRWalk database (<a href="http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/" target="_blank">http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/</a>).</p><p>(2): from the KEGG (<a href="http://www.genome.jp/kegg/" target="_blank">http://www.genome.jp/kegg/</a>) and NCBI-Gene (<a href="http://www.ncbi.nlm.nih.gov" target="_blank">http://www.ncbi.nlm.nih.gov</a>) databases.</p

miRNAs differentially expressed in HepG2 cells after 5 hours of culture with epigallocatechin gallate.

<p>The fold change value and the standard deviations obtained by QRT-PCR is presented in parentheses.</p