Effects of maternal diet-induced obesity on metabolic disorders and age-associated miRNA expression in the liver of male mouse offspring

Objective: This study investigated the effect of maternal obesity on aged-male offspring liver phenotype and hepatic expression of a programmed miRNA. Methods: A mouse model (C57BL/6 J) of maternal diet-induced obesity was used to investigate fasting-serum metabolites, hepatic lipid content, steatosis, and relative mRNA levels (RT-PCR) and protein expression (Western blotting) of key components involved in hepatic and mitochondrial metabolism in 12-month-old offspring. We also measured hepatic lipid peroxidation, mitochondrial content, fibrosis stage, and apoptosis in the offspring. To investigate potential mechanisms leading to the observed phenotype, we also measured the expression of miR-582 (a miRNA previously implicated in liver cirrhosis) in 8-week-old and 12-month-old offspring. Results: Body weight and composition was similar between 8-week-old offspring, however, 12-month-old offspring from obese mothers had increased body weight and fat mass (19.5 ± 0.8 g versus 10.4 ± 0.9 g, p < 0.001), as well as elevated serum levels of LDL and leptin and hepatic lipid content (21.4 ± 2.1 g versus 12.9 ± 1.8 g, p < 0.01). This was accompanied by steatosis, increased Bax/Bcl-2 ratio, and overexpression of p-SAPK/JNK, Tgfβ1, Map3k14, and Col1a1 in the liver. Decreased levels of Bcl-2, p-AMPKα, total AMPKα and mitochondrial complexes were also observed. Maternal obesity was associated with increased hepatic miR-582-3p (p < 0.001) and miR-582-5p (p < 0.05). Age was also associated with an increase in both miR-582-3p and miR-582-5p, however, this was more pronounced in the offspring of obese dams, such that differences were greater in 12-month-old animals (−3p: 7.34 ± 1.35 versus 1.39 ± 0.50, p < 0.0001 and −5p: 4.66 ± 1.16 versus 1.63 ± 0.65, p < 0.05). Conclusion: Our findings demonstrate that maternal diet-induced obesity has detrimental effects on offspring body composition as well as hepatic phenotype that may be indicative of accelerated-ageing phenotype. These whole-body and cellular phenotypes were associated with age-dependent changes in expression of miRNA-582 that might contribute mechanistically to the development of metabolic disorders in the older progeny

Insights into the Complex Formed by Matrix Metalloproteinase-2 and Alloxan Inhibitors: Molecular Dynamics Simulations and Free Energy Calculations

Matrix metalloproteinases (MMP) are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of pro-apoptotic ligands, and the release and cleavage of cell-surface receptors. Hence, the development of potent and selective inhibitors targeting these enzymes continues to be eagerly sought. In this paper, a number of alloxan-based compounds, initially conceived to bias other therapeutically relevant enzymes, were rationally modified and successfully repurposed to inhibit MMP-2 (also named gelatinase A) in the nanomolar range. Importantly, the alloxan core makes its debut as zinc binding group since it ensures a stable tetrahedral coordination of the catalytic zinc ion in concert with the three histidines of the HExxHxxGxxH metzincin signature motif, further stabilized by a hydrogen bond with the glutamate residue belonging to the same motif. The molecular decoration of the alloxan core with a biphenyl privileged structure allowed to sample the deep S1′ specificity pocket of MMP-2 and to relate the high affinity towards this enzyme with the chance of forming a hydrogen bond network with the backbone of Leu116 and Asn147 and the side chains of Tyr144, Thr145 and Arg149 at the bottom of the pocket. The effect of even slight structural changes in determining the interaction at the S1′ subsite of MMP-2 as well as the nature and strength of the binding is elucidated via molecular dynamics simulations and free energy calculations. Among the herein presented compounds, the highest affinity (pIC50 = 7.06) is found for BAM, a compound exhibiting also selectivity (>20) towards MMP-2, as compared to MMP-9, the other member of the gelatinases

Forty years literature review of primary lung lymphoma

There are several unresolved issues through out the literature regarding the entity of primary lung lymphoma. Extensive literature review of this uncommon pathology is carried out

Financial Satisfaction and (in)formal Sector in a Transition Country

This paper examines the relationship between working in the formal or informal sector and self-reported individual financial satisfaction in a country in transition. It does so by allowing for individual heterogeneity in terms of perceived financial insecurity and tax morale. The empirical analysis uses a dataset for Albania, a country in transition. The method applied is the ‘self-administered questionnaire’, which combines personal contacts with written questionnaire. The results indicate that, for most individuals, working in the informal sector has negative effects on their self reported financial satisfaction. For some individuals, however, this effect is positive. The characteristic defining these two groups of individuals is their attitude towards the perceived financial insecurity related to not paying taxes. These findings have important implications, in particular for transition countries with large informal sectors. Given the involuntary participation in the informal sector in these countries, the majority of individuals working in this sector will remain financially dissatisfied as long as they have no other social safety net

Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary

There has been considerable investigation of the potential for soyfoods to reduce risk of cancer, and in particular cancer of the breast. Most interest in this relationship is because soyfoods are essentially a unique dietary source of isoflavones, compounds which bind to estrogen receptors and exhibit weak estrogen-like effects under certain experimental conditions. In recent years the relationship between soyfoods and breast cancer has become controversial because of concerns – based mostly on in vitro and rodent data – that isoflavones may stimulate the growth of existing estrogen-sensitive breast tumors. This controversy carries considerable public health significance because of the increasing popularity of soyfoods and the commercial availability of isoflavone supplements. In this analysis and commentary we attempt to outline current concerns regarding the estrogen-like effects of isoflavones in the breast focusing primarily on the clinical trial data and place these concerns in the context of recent evidence regarding estrogen therapy use in postmenopausal women. Overall, there is little clinical evidence to suggest that isoflavones will increase breast cancer risk in healthy women or worsen the prognosis of breast cancer patients. Although relatively limited research has been conducted, and the clinical trials often involved small numbers of subjects, there is no evidence that isoflavone intake increases breast tissue density in pre- or postmenopausal women or increases breast cell proliferation in postmenopausal women with or without a history of breast cancer. The epidemiologic data are generally consistent with the clinical data, showing no indication of increased risk. Furthermore, these clinical and epidemiologic data are consistent with what appears to be a low overall breast cancer risk associated with pharmacologic unopposed estrogen exposure in postmenopausal women. While more research is required to definitively allay concerns, the existing data should provide some degree of assurance that isoflavone exposure at levels consistent with historical Asian soyfood intake does not result in adverse stimulatory effects on breast tissue

Early exposure to distinct sources of lipids affects differently the development and hepatic inflammatory profiles of 21-day-old rat offspring

La&iacute;s Vales Mennitti,1&nbsp;Lila Missae Oyama,2 Aline Boveto Santamarina,1 Claudia Maria da Penha Oller do Nascimento,2 Luciana Pellegrini Pisani3 1PhD Program &lsquo;Interdisciplinar in Health Sciences&rsquo;, Federal University of S&atilde;o Paulo (UNIFESP), Santos, SP, Brazil; 2Department of Physiology, Discipline of Nutrition Physiology, Federal University of S&atilde;o Paulo (UNIFESP), S&atilde;o Paulo, SP, Brazil; 3Department of Biosciences, Institute of Health and Society, Federal University of S&atilde;o Paulo (UNIFESP), Santos, SP, Brazil Introduction: Maternal diet composition of fatty acids during pregnancy and lactation seems to modify the fetal programming, epigenetic pattern and offspring phenotype. Aim: Herein, we investigated the effects of maternal consumption of normal-fat diets with distinct lipid sources during pregnancy and lactation on the somatic development and proinflammatory status of 21-day-old rat offspring. Materials and Methods: On the first day of pregnancy, female Wistar rats were divided into four groups as follows: soybean oil (M-SO), lard (M-L), hydrogenated vegetable fat (M-HVF) and fish oil (M-FO). Diets were maintained during pregnancy and lactation. Male offspring constituted the SO, L, HVF and FO groups. Pups were weighed and measured weekly. Lipopolysaccharide serum concentration was determined. Tumor necrosis factor alpha, interleukin (IL)-6 and IL-10 in the liver were evaluated by enzyme-linked immunosorbent assay. Liver gene expressions were determined by real-time polymerase chain reaction. Protein expressions in the liver were analyzed by Western blotting. Results: We observed an increase in body weight and adiposity in L and HVF groups. Moreover, HVF group showed an increase in the toll-like receptor 4 mRNA levels, IL10R&alpha; and phosphorylated form of I&kappa;B kinase (IKK; p-IKK&alpha;+&beta;) protein expression. The FO group presented a decrease in body weight, relative weight of retroperitoneal adipose tissue, ADIPOR2 gene expression, lipopolysaccharide and p-IKK&alpha;+&beta; and phosphorylated form of nuclear transcription factor kappa B (NF&kappa;B) p50 (p-NF&kappa;B p50) protein expression. Conclusion: Summarily, whereas maternal intake of normal-fat diets based on L and HVF appear to affect the somatic development negatively, only early exposure to HVF impairs the pups&rsquo; proinflammatory status. In contrast, maternal diets based on FO during pregnancy and lactation have been more beneficial to the adiposity and toll-like receptor 4 signaling pathway of the 21-day-old rat offspring, particularly when compared to L or HVF diets. Keywords: fatty acids, pregnancy and lactation, adiposity, proinflammatory status, pup