Glucose-6-phosphate-dehydrogenase deficiency as a risk factor in proliferative disorder development

Glucose-6-phosphate dehydrogenase (G6PD) is an important site of metabolic control in the pentose phosphate pathway (PPP) which provides reducing power (NADPH) and pentose phosphates. The former is mainly involved in the detoxification of chemical reactive species; the latter in the regulation of cell proliferation. G6PD deficiency is the most common enzymopathy in the human population, characterized by decreased G6PD activity, mainly in red blood cells, but actually also in nucleated cells. This decreased activity is not due to enzyme synthesis impairment, but rather to reduced enzyme stability, which leads to a shortening of its half-life. Therefore, a major problem is to understand the underlying mechanisms linking G6PD deficiency to oxidative stress and cell proliferation. In order to address this issue, in the present study we utilized, as an experimental model, fibroblasts isolated from pterygium, an ocular proliferative lesion, from G6PD normal and deficient (PFs+ and PFs-, respectively) patients. Our choice was determined by the fact that pterygium is believed to be caused by chronic oxidative stress induced by UV exposure, and that pterygium fibroblasts resemble a tumorigenic phenotype. As controls we utilized fibroblasts isolated from conjunctiva from G6PD normal and deficient patients (NCFs+ and NCFs-, respectively) who had undergone cataract surgery. 
Growth rate analysis revealed that PFs grow faster than NCFs, but while NCFs- grow more slowly than NCFs+, PFs- and PFs+ grow at the same rate. This was associated with significantly lower G6PD activity in NCFs+ compared to NCFs-, while no significant differences in the G6PD activity of PFs+ and PFs- were noted. This result was supported by the finding that in PFs-, G6PD mRNA levels were significantly higher than in PFs+. Another interesting finding of this study was increased green autofluorescence in both NCFs- and PFs- compared to corresponding positive cells, indicative of pronounced oxidative stress in deficient cells. Finally, abnormal accumulation of neutral lipids, mainly cholesterol esters was observed both in PFs- and PFs+ compared to NCFs- and NCFs+. Though further studies are necessary for better understanding the exact mechanism which links G6PD to oxidative stress and cell proliferation, our data allow to speculate on the role of G6PD on tumorigenesis, and to consider G6PD-deficient subjects at major risk to develop common and dreaded proliferative disorders, such as atherosclerosis and cancer. 
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1h nmr brain metabonomics of scrapie exposed sheep

While neurochemical metabolite modifications, determined by different techniques, have been diffusely reported in human and mice brains affected by transmissible spongiform encephalopathies (TSEs), this aspect has been little studied in the natural animal hosts with the same pathological conditions so far

Changes in cholesterol metabolism-related gene expression in peripheral blood mononuclear cells from Alzheimer patients

<p>Abstract</p> <p>Background</p> <p>Cholesterol homeostasis dysfunction has been reported to have role in the pathogenesis of Alzheimer disease (AD). Therefore, changes in cholesterol metabolism in blood components may help to develop new potential AD biomarkers. In this study changes in cholesterol metabolism-related gene expression genes were evaluated in peripheral blood mononuclear cells (PBMCs) from AD subjects, their first degree relatives (FDR) and two groups of age matched controls (C1 > 80 years, C2 < 60 years). The expression of three genes related to APP processing was also determined.</p> <p>Results</p> <p>Results showed significantly different behavior (P = 0.000) in the expression of all analyzed genes among the 4 groups. An inverse correlation emerged between the age of controls and the propensity of their PBMCs to express selected genes. Moreover, when gene expression was evaluated in PBMCs from AD patients and compared with that of PBMCs from healthy subjects of the same age, LDL-R and APP mRNAs were most abundant in AD as compared C1 whereas SREBP-2 and particularly nCEH were present at much lower mRNA levels in AD-PBMCs. This study describes for the first time a differential expression profile of cholesterol and APP related genes in PBMCs from AD patients and their FDR.</p> <p>Conclusions</p> <p>We suggest that the expressions of cholesterol homeostasis and APP processing related genes in PBMC could be proposed as possible biomarkers to evaluate AD risk. In addition, gene expression in PBMC could be also used for diagnosis and development of therapeutic strategies as well as for personalized prediction in clinical outcome of AD.</p

Nutrient intakes in an Italian population of infants during the complementary feeding period

Objective: To describe the nutrient intakes of an Italian cohort of infants at 6, 9 and 12 months of age. Design: Dietary data were collected using a food diary at three follow-ups (6, 9 and 12 months of age of infants). The infants' dietary data were used to estimate nutrient intakes using the Italian food composition database integrated with data from nutritional labels and the literature. The mean and standard deviation, median and interquartile range, minimum and maximum, and 5th, 25th, 75th and 95th percentiles were calculated for the daily intake of twenty-eight nutrients, with sex differences evaluated using parametric/non-parametric statistical methods. Setting: A prospective population-based birth cohort.SubjectInfants (n 400) living in the urban area of Trieste (Italy). Results: The sex distribution was fairly balanced at each follow-up. The mean daily intakes of energy and the other twenty-seven nutrients considered were greater in males at all follow-ups. In particular, a significant statistical difference was observed in higher male consumption of cholesterol at 9 months and in energy and carbohydrate intakes at 12 months (P < 0·05). The mean daily intake of proteins was greater than that recommended by the Italian Dietary Reference Values at all follow-ups. Conclusions: These preliminary results provide a useful basis for understanding the nutrient intake patterns of infants in this area of Italy during the first year of life

Accumulation and aberrant composition of cholesteryl esters in Scrapie-infected N2a cells and C57BL/6 mouse brains

<p>Abstract</p> <p>Objective</p> <p>Cholesterol changes have been described in prion-cell models and in experimental rodent scrapie; yet, the pattern of this association is still controversial.</p> <p>Methods</p> <p>To shed light on the matter, we analysed and compared cholesterol variations in ScN2a cells and in brains of Scrapie-infected C57Bl/6 mice, using two different methods: a fluorimetric-enzymatic cholesterol assay, and high performance liquid chromatography-mass spectroscopy (HPLC-MS).</p> <p>Results</p> <p>Compared to uninfected controls, similar cholesterol metabolism anomalies were observed in infected cells and brains by both methods; however, only HPLC-MS revealed statistically significant cholesterol variations, particularly in the cholesteryl esters (CE) fraction. HPLC-MS analyses also revealed different fatty acid composition of the CE fraction in cells and brains. In N2a cells, their profile reflected that of serum, while in normal brains cholesteryl-linoleate only was found at detectable levels. Following prion infection, most CE species were increased in the CE pool of ScN2a cells, whereas a conspicuous amount of cholesteryl-arachidonate only was found to contribute to the cerebral increase of CE. Of interest, oral pravastatin administration to Scrapie-infected mice, was associated with a significant reduction of cerebral free cholesterol (FC) along with a concomitant further increase of the CE pool, which included increased amounts of both cholesteryl-linoleate and cholesteryl-arachidonate.</p> <p>Conclusion</p> <p>Although mechanistic studies are needed to establish the pathophysiological relevance of changes in cerebral CE concentrations, to the best of our knowledge this is the first report to provide evidence of increased cholesterol esterification in brains of prion-infected mice, untreated and treated with pravastatin.</p

Synthesis and Evaluation of Cytostatic and Antiviral Activities of 3′ and 4′-Avarone Derivatives

A series of 3′ and 4′-substituted avarone derivatives were synthesized and tested in culture systems as antitumour and antiviral agents in comparison to avarol and avarone. 3′-alkylamino derivatives showed potent cytostatic activities against murine L1210 and human B (Raji) and T (C8166, H9) lymphoblast cells (ID50 range 1.7–3.7 μm). Avarol and avarone were six times less active. While none of the derivatives showed anti-human immunodeficiency virus (HIV) activity superior to that of the parent compounds, most of them, avarol and avarone included, were potent and selective inhibitors of poliovirus multiplication

Structure-activity relationship studies on new DABOS: effect of substitutions at pyrimidine C-5 and C-6 positions on anti-HIV-1 activity.

Several 5-alkyl, 5-alkenyl, 5-iso-alkyl, 5-halo, 5-aminomethyl and 5-carboxy derivatives of S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-benzyloxopyrimidines), DATNOs (dihydro-alkylthionaphthylmethyl-oxopyrimidines) and F2-S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-2,6-difluorobenzyl-oxopyrimidines) have been prepared and tested as anti-HIV-1 agents. S-DABO derivatives bearing at C-6 position monosubstituted phenylmethyl or heteroarylmethyl units have also been synthesized. 2-Alkylthio-3,4-dihydropyrimidin-4(3 H)-one derivatives of F2- S-DABO series bearing small alkyl groups at C-5 proved to be potent inhibitors of HIV-1 replication in vitro with selectivity indexes ranging from 250 to <2500