Lipoxygenases and Poly(ADP-Ribose) Polymerase in Amyloid Beta Cytotoxicity

The 12/15-lipoxygenase(s) (LOX), poly(ADP-ribose) polymerase (PARP-1) activity and mitochondrial apoptosis inducing factor (AIF) protein in the amyloid β (Aβ) toxicity were investigated in PC12 cells that express either wild-type (APPwt) or double Swedish mutation (APPsw) forms of human Aβ precursor protein. Different levels of Aβ secretion and free radicals formation characterize these cells. The results demonstrated a relationship between the Aβ levels and LOX protein expression and activity. High Aβ concentration in APPsw cells correlated with a significant increase in free radicals and LOX activation, which leads to translocation of p65/NF-κB into the nucleus. An increase in AIF expression in mitochondria was observed concurrently with inhibition of PARP-1 activity in the nuclear fraction of APPsw cells. We suggested that AIF accumulation in mitochondria may be involved in adaptive/protective processes. However, inhibition of PARP-1 may be responsible for the disturbances in transcription and DNA repair as well as the degeneration of APP cells. Under conditions of increased nitrosative stress, evoked by the nitric oxide donor, sodium nitroprusside (SNP, 0.5 mM), 70–80% of all cells types died after 24 h, significantly more in APPsw cells. There was no further significant change in mitochondrial AIF level and PARP-1 activity compared to corresponding non-treated cells. Only one exception was observed in PC12 control, where SNP significantly inhibits PARP-1 activity. Moreover, SNP significantly activated gene expression for 12/15-LOX in all types of investigated cells. Inhibitors of all LOX isoforms and specific inhibitor of 12-LOX enhanced the survival of cells that were subjected to SNP. We conclude that the LOX pathways may play a role in Aβ toxicity and in nitrosative-stress-induced cell death and that inhibition of these pathways offers novel protective strategies

A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice

Many genetic liver diseases present in newborns with repeated, often lethal, metabolic crises. Gene therapy using non-integrating viruses such as AAV is not optimal in this setting because the non-integrating genome is lost as developing hepatocytes proliferate1,2. We reasoned that newborn liver may be an ideal setting for AAV-mediated gene correction using CRISPR/Cas9. Here we intravenously infuse two AAVs, one expressing Cas9 and the other expressing a guide RNA and the donor DNA, into newborn mice with a partial deficiency in the urea cycle disorder enzyme, ornithine transcarbamylase (OTC). This resulted in reversion of the mutation in 10% (6.7% – 20.1%) of hepatocytes and increased survival in mice challenged with a high-protein diet, which exacerbates disease. Gene correction in adult OTC-deficient mice was lower and accompanied by larger deletions that ablated residual expression from the endogenous OTC gene, leading to diminished protein tolerance and lethal hyperammonemia on a chow diet

Anti-hyperlipidemic effect of carcia papaya L in sprague dawley rats

No Abstract.Nigerian Journal of Natural Products and Medicine Vol. 10 () 2006: pp.69-7

Isolation and identification of fatty acids from berries of sea buckthorn (<i style="">Hippophae rhamnoides)</i><i style=""></i>

2390-2392Five fatty acids, 2-hydroxydecanoic acid, nona-7-enoic acid, undec-9-en-7-ynoic acid, 13-phenyltridecanoic acid and 5, 9, 21-nonacosatrienoic acid have been isolated and characterized from the ethanol extract of the sea buckthorn berries (Hippophae rhamnoides). The structure of new fatty acid namely, undec-9-en-7-ynoic acid (AS-3) has been elucidated by the spectroscopic techniques

Data from: No apparent cost of evolved immune response in Drosophila melanogaster

Maintenance and deployment of the immune system are costly and are hence predicted to trade-off with other resource demanding traits, such as reproduction. We subjected this long standing idea to test using laboratory experimental evolution approach. In the present study, replicate populations of Drosophila melanogaster were subjected to three selection regimes – I (Infection with Pseudomonas entomophila), S (Sham-infection with MgSO4) and U (Unhandled Control). After 30 generations of selection flies from the I-regime had evolved better survivorship upon infection with P. entomophila compared to flies from U and S regimes. However, contrary to expectations and previous reports, we did not find any evidence of trade-offs between immunity and other life-history related traits, such as longevity, fecundity, egg hatchability or development time. After 45 generations of selection, the selection was relaxed for a set of populations. Even after 15 generations, the post-infection survivorship of populations under relaxed selection regime did not decline. We speculate that either there is a negligible cost to the evolved immune response or that trade-offs occur on traits like reproductive behaviour or other immune mechanisms that we have not investigated in this study. Our research suggests that at least under certain conditions, life-history trade-offs might play little role in maintaining variation in immunity

Simultaneous Quantification of Glibenclamide, Simvastatin, and Quercetin by Using LC-UV Method and Its Application to Pharmacokinetic Study in Rats

A sensitive, precise, and simple LC method for the simultaneous quantification of glibenclamide, simvastatin, and quercetin in rat plasma has been developed and validated. The chromatographic separation was achieved on a cyano column (250 mm × 4.6 mm, 5 µm) maintained at room temperature, using isocratic elution with methanol : acetonitrile : 10 mM potassium dihydrogen orthophosphate, pH adjusted to 4.5 with o-phosphoric acid (8 : 32 : 60, v/v) and detected using UV-VIS detector. Plasma samples were deproteinated with 0.1% perchloric acid and acetonitrile for extraction of the glibenclamide, simvastatin, and quercetin which resulted in their high recoveries. LC calibration curves based on the extracts from the rat plasma were linear in the range of 50–1000 ng mL−1 for all the three drugs. The limit of quantification was 50 ng mL−1. The described method was successfully applied to study the pharmacokinetics of glibenclamide, simvastatin, and quercetin following oral administration, in combination to Sprague-Dawley rats

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