Effect of obesity and metabolic syndrome on plasma oxysterols and fatty acids in human

BACKGROUND: Obesity and the related entity metabolic syndrome are characterized by altered lipid metabolism and associated with increased morbidity risk for cardiovascular disease and cancer. Oxysterols belong to a large family of cholesterol-derived molecules known to play crucial role in many signaling pathways underlying several diseases. Little is known on the potential effect of obesity and metabolic syndrome on oxysterols in human. OBJECTIVES: In this work, we questioned whether circulating oxysterols might be significantly altered in obese patients and in patients with metabolic syndrome. We also tested the potential correlation between circulating oxysterols and fatty acids. METHODS: 60 obese patients and 75 patients with metabolic syndrome were enrolled in the study along with 210 age- and sex-matched healthy subjects, used as control group. Plasma oxysterols were analyzed by isotope dilution GC/MS, and plasma fatty acids profiling was assessed by gas chromatography coupled with flame ionization detection. RESULTS: We found considerable differences in oxysterols profiling in the two disease groups that were gender-related. Compared to controls, males showed significant differences only in 4α- and 4β-hydroxycholesterol levels in obese and metabolic syndrome patients. In contrast, females showed consistent differences in 7-oxocholesterol, 4α-hydroxycholesterol, 25-hydroxycholesterol and triol. Concerning fatty acids, we found minor differences in the levels of these variables in males of the three groups. Significant changes were observed in plasma fatty acid profile of female patients with obesity or metabolic syndrome. We found significant correlations between various oxysterols and fatty acids. In particular, 4β-hydroxycholesterol, which is reduced in obesity and metabolic syndrome, correlated with a number of saturated and mono-unsaturated fatty acids that are end-products of de novo lipogenesis. CONCLUSIONS: Our data provide the first evidence that obesity and metabolic syndrome are associated with major, gender-specific, changes in circulating oxysterols and fatty acids. These findings suggest a metabolic link between oxysterols and fatty acids, and that oxysterols may contribute to the epidemic diseases associated with obesity and metabolic syndrome in female

The Dividing Line between Federal and State Promotion of Aeronautics

<p>The model xeno-estrogen bisphenol A (BPA) has been extensively studied over the past two decades, contributing to major advances in the field of endocrine disrupting chemicals research. Besides its well documented adverse effects on reproduction and development observed in rodents, latest studies strongly suggest that BPA disrupts several endogenous metabolic pathways, with suspected steatogenic and obesogenic effects. BPA's adverse effects on reproduction are attributed to its ability to activate estrogen receptors (ERs), but its effects on metabolism and its mechanism(s) of action at low doses are so far only marginally understood. Metabolomics based approaches are increasingly used in toxicology to investigate the biological changes induced by model toxicants and chemical mixtures, to identify markers of toxicity and biological effects. In this study, we used proton nuclear magnetic resonance (¹H-NMR) based untargeted metabolite profiling, followed by multivariate statistics and computational analysis of metabolic networks to examine the metabolic modulation induced in human hepatic cells (HepG2) by an exposure to low and very low doses of BPA (10⁻⁶M, 10⁻⁹M, and 10⁻¹²M), vs. the female reference hormone 17β-estradiol (E2, 10⁻⁹M, 10⁻¹²M, and 10⁻¹⁵M). Metabolomic analysis combined to metabolic network reconstruction highlighted different mechanisms at lower doses of exposure. At the highest dose, our results evidence that BPA shares with E2 the capability to modulate several major metabolic routes that ensure cellular functions and detoxification processes, although the effects of the model xeno-estrogen and of the natural hormone can still be distinguished.</p

Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss

The Src substrate associated in mitosis of 68 kDa (Sam68) is a KH-type RNA binding protein that has been shown to regulate several aspects of RNA metabolism; however, its physiologic role has remained elusive. Herein we report the generation of Sam68-null mice by homologous recombination. Aged Sam68(−/−) mice preserved their bone mass, in sharp contrast with 12-month-old wild-type littermates in which bone mass was decreased up to approximately 75%. In fact, the bone volume of the 12-month-old Sam68(−/−) mice was virtually indistinguishable from that of 4-month-old wild-type or Sam68(−/−) mice. Sam68(−/−) bone marrow stromal cells had a differentiation advantage for the osteogenic pathway. Moreover, the knockdown of Sam68 using short hairpin RNA in the embryonic mesenchymal multipotential progenitor C3H10T1/2 cells resulted in more pronounced expression of the mature osteoblast marker osteocalcin when differentiation was induced with bone morphogenetic protein-2. Cultures of mouse embryo fibroblasts generated from Sam68(+/+) and Sam68(−/−) littermates were induced to differentiate into adipocytes with culture medium containing pioglitazone and the Sam68(−/−) mouse embryo fibroblasts shown to have impaired adipocyte differentiation. Furthermore, in vivo it was shown that sections of bone from 12-month-old Sam68(−/−) mice had few marrow adipocytes compared with their age-matched wild-type littermate controls, which exhibited fatty bone marrow. Our findings identify endogenous Sam68 as a positive regulator of adipocyte differentiation and a negative regulator of osteoblast differentiation, which is consistent with Sam68 being a modulator of bone marrow mesenchymal cell differentiation, and hence bone metabolism, in aged mice

Intraarterial Injection of Muscle-Derived Cd34+Sca-1+ Stem Cells Restores Dystrophin in mdx Mice

Duchenne muscular dystrophy is a lethal recessive disease characterized by widespread muscle damage throughout the body. This increases the difficulty of cell or gene therapy based on direct injections into muscles. One way to circumvent this obstacle would be to use circulating cells capable of homing to the sites of lesions. Here, we showed that stem cell antigen 1 (Sca-1), CD34 double-positive cells purified from the muscle tissues of newborn mice are multipotent in vitro and can undergo both myogenic and multimyeloid differentiation. These muscle-derived stem cells were isolated from newborn mice expressing the LacZ gene under the control of the muscle-specific desmin or troponin I promoter and injected into arterial circulation of the hindlimb of mdx mice. The ability of these cells to interact and firmly adhere to endothelium in mdx muscles microcirculation was demonstrated by intravital microscopy after an intraarterial injection. Donor Sca-1, CD34 muscle-derived stem cells were able to migrate from the circulation into host muscle tissues. Histochemical analysis showed colocalization of LacZ and dystrophin expression in all muscles of the injected hindlimb in all of five out of five 8-wk-old treated mdx mice. Their participation in the formation of muscle fibers was significantly increased by muscle damage done 48 h after their intraarterial injection, as indicated by the presence of 12% β-galactosidase–positive fibers in muscle cross sections. Normal dystrophin transcripts detected enzymes in the muscles of the hind limb injected intraarterially by the mdx reverse transcription polymerase chain reaction method, which differentiates between normal and mdx message. Our results showed that the muscle-derived stem cells first attach to the capillaries of the muscles and then participate in regeneration after muscle damage

Early childhood development of visual texture segregation in full-term and preterm children

AbstractTo date, very little is known about the normal development trajectory of visual texture segregation, or how it is affected by preterm birth. The goal of this study was to characterize the development of visual texture segregation using texture segregation visual evoked potentials (tsVEPs) in children born full-term and children born preterm without major neurological impairment. Forty-five full-term and 43 preterm children were tested at either 12, 24 or 36months of age (corrected age for prematurity at 12 and 24months old). VEPs were obtained using two lower-level stimuli defined by orientation (oriVEP) and two higher-level stimuli defined by texture (texVEP). TsVEP was obtained by dividing by two the subtraction of oriVEP from texVEP. Results show a clear maturation of the processes underlying visual texture segregation in the full-term group, with a significant N2 latency reduction between 12 and 36months of age for all conditions. Significant N2 amplitude reduction was observed for oriVEP between 12 and 24months, as well as for texVEP between 12 and 24months, and 12 and 36months. Comparison between full-term and preterm children indicated significantly lower N2 amplitude for the preterm group at 12months for oriVEP and texVEP. These differences were no longer apparent at 24months of age, suggesting that children born preterm catch up with their full-term counterparts somewhere between 12 and 24months of age. Our results appear to reflect a maturational delay in preterm children in both lower-level and higher-level visual processing during, at least, early childhood

Specific Metabolic Fingerprint of a Dietary Exposure to a Very Low Dose of Endosulfan

Like other persistent organochlorine pesticides, endosulfan residues have been detected in foods including fruit, vegetables, and fish. The aim of our study was to assess the impact of a dietary exposure to low doses of endosulfan from foetal development until adult age on metabolic homeostasis in mice and to identify biomarkers of exposure using an 1H-NMR-based metabonomic approach in various tissues and biofluids. We report in both genders an increase in plasma glucose as well as changes in levels of factors involved in the regulation of liver oxidative stress, confirming the prooxidant activities of this compound. Some metabolic changes were distinct in males and females. For example in plasma, a decrease in lipid LDL and choline content was only observed in female. Lactate levels in males were significantly increased. In conclusion, our results show that metabolic changes in liver could be linked to the onset of pathologies like diabetes and insulin resistance. Moreover from our results it appears that the NMR-based metabonomic approach could be useful for the characterization in plasma of a dietary exposure to low dose of pesticide in human

Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals.

The liver is a key organ of metabolic homeostasis with functions that oscillate in response to food intake. Although liver and gut microbiome crosstalk has been reported, microbiome-mediated effects on peripheral circadian clocks and their output genes are less well known. Here, we report that germ-free (GF) mice display altered daily oscillation of clock gene expression with a concomitant change in the expression of clock output regulators. Mice exposed to microbes typically exhibit characterized activities of nuclear receptors, some of which (PPARα, LXRβ) regulate specific liver gene expression networks, but these activities are profoundly changed in GF mice. These alterations in microbiome-sensitive gene expression patterns are associated with daily alterations in lipid, glucose, and xenobiotic metabolism, protein turnover, and redox balance, as revealed by hepatic metabolome analyses. Moreover, at the systemic level, daily changes in the abundance of biomarkers such as HDL cholesterol, free fatty acids, FGF21, bilirubin, and lactate depend on the microbiome. Altogether, our results indicate that the microbiome is required for integration of liver clock oscillations that tune output activators and their effectors, thereby regulating metabolic gene expression for optimal liver function

CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

Several human disorders mutated in core components of the major DNA double-strand break (DSB) repair pathway, non-homologous end joining (NHEJ), have been described. Cell lines from these patients are characterized by sensitivity to DSB-inducing agents. DNA ligase IV syndrome (LIG4) patients specifically, for unknown reasons, respond particularly badly following treatment for malignancy or BMT. We report the first systematic evaluation of the response of LIG4 syndrome to compounds routinely employed for BMT conditioning. We found human pre-B lymphocytes, a key target population for BMT conditioning, when deficient for DNA ligase IV, unexpectedly exhibit significant sensitivity to CsA the principal prophylaxis for GVHD. Furthermore, we found that CsA treatment alone or in combination with BU and fludarabine resulted in increased levels of DSBs specifically in LIG4 syndrome cells compared to wild-type or Artemis-deficient cells. Our study shows that CsA can induce DSBs and that LIG4 syndrome patient's fail to adequately repair this damage. These DSBs likely arise as a consequence of DNA replication in the presence of CsA. This work has implications for BMT and GVHD management in general and specifically for LIG4 syndrome

Perturbation analysis of transient population dynamics using matrix projection models

Non‐stable populations exhibit short‐term transient dynamics: size, growth and structure that are unlike predicted long‐term asymptotic stable, stationary or equilibrium dynamics. Understanding transient dynamics of non‐stable populations is important for designing effective population management strategies, predicting the responses of populations to environmental change or disturbance, and understanding population processes and life‐history evolution in variable environments. Transient perturbation analyses are vital tools for achieving these aims. They assess how transient dynamics are affected by changes to vital rates, population structure, or underlying variables that affect these. These changes could be imposed deliberately by population managers, or driven by environmental variables. Methodological approaches to transient perturbation analysis are diverse, and different methods are suited to different applications: choosing a method to use may be challenging. Here, I review existing methods for prospective transient perturbation analysis, and identify a number of key considerations for ecologists when choosing a method. These include the approach taken in calculating the perturbation, the type of model being analysed, the perturbation structure, the population response of interest, nonlinear response to perturbation, standardization for asymptotic dynamics, the initial population structure, and the time frame of interest. I discuss these with reference to the application of transient perturbation analyses in both population management and comparative analysis. The diversity of transient perturbation analyses available means that existing approaches are applicable to a wide range of population management and comparative analysis scenarios. It is important, however, for ecologists using these methods to know exactly what is being measured. Despite a wealth of existing methods, I identify some areas that would benefit from further development

Decreased corticospinal excitability after the illusion of missing part of the arm

Previous studies on body ownership illusions have shown that under certain multimodal conditions, healthy people can experience artificial body-parts as if they were part of their own body, with direct physiological consequences for the real limb that gets ‘substituted.' In this study we wanted to assess (a) whether healthy people can experience ‘missing’ a body-part through illusory ownership of an amputated virtual body, and (b) whether this would cause corticospinal excitability changes in muscles associated with the ‘missing’ body-part. Forty right-handed participants saw a virtual body from a first person perspective but for half of them the virtual body was missing a part of its right arm. Single pulse transcranial magnetic stimulation was applied before and after the experiment to left and right motor cortices. Motor evoked potentials (MEPs) were recorded from the first dorsal interosseous (FDI) and the extensor digitorum communis (EDC) of each hand. We found that the stronger the illusion of amputation and arm ownership, the more the reduction of MEP amplitudes of the EDC muscle for the contralateral sensorimotor cortex. In contrast, no association was found for the EDC amplitudes in the ipsilateral cortex and for the FDI amplitudes in both contralateral and ipsilateral cortices. Our study provides evidence that a short-term illusory perception of missing a body-part can trigger inhibitory effects on corticospinal pathways and importantly in the absence of any limb deafferentation or disuse