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Journal Article 2014; 35(3): 224-229 PubMed PMID: 24977973 Citation  Keywords:  Alzheimer Disease:genetics, Amyloid Precursor Protein Secretases:genetics, Amyloid beta-Peptides:antagonists & inhibitors, Amyloid beta-Protein Precursor:metabolism, Cells, Cultured, Gene Expression Regulation, Enzymologic:drug effects, Humans, Insulin:ph.   

OBJECTIVE: Amyloid-beta (Abeta) is a 36-43 amino acid peptide that is derived by processing of the beta-amyloid precursor protein (APP). Abeta plays a central role in the development of Alzheimer's disease (AD). Although growing evidence suggests that insulin has important functions in Abeta metabolism, the underlying mechanisms are still unknown.

METHODS: Using an SH-SY5Y cell line overexpressing human APP Swedish mutant (APPsw), we evaluated the effect of insulin on APP processing and Abeta production by using western blot analysist.

RESULTS: Our data showed that administration of insulin reduced the Abeta generation in culture media with a concomitant decreases in the levels of beta-secretase BACE1, secreted extracellular domain (sAPPbeta) and a fragment of 99 amino acids (C99) in APPsw cells. We further showed that insulin increased the levels of alpha-secretase ADAM10, a secreted extracellular domain secreted (sAPPa) and a fragment of 83 amino acids (C83) in APPsw cells.

CONCLUSION: Our present data suggest that insulin could inhibit Abeta production through modulation of APP processing by increasing cleavage at the a-secretase site and decreased cleavage at the beta-secretase sites....

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Journal Article 2012; 33(Suppl 3): 48-52 PubMed PMID: 23353843 Citation  Keywords:  Animals, Aryl Hydrocarbon Hydroxylases:antagonists & inhibitors, Cholesterol, Dietary:pharmacology, Cytochrome P-450 CYP2C9, Cytochrome P450 Family 2, Fluorobenzenes:pharmacology, Gene Expression Regulation, Enzymologic:drug effects, Humans, Hydroxymethyl.   

OBJECTIVES: The aim of this study was to investigate whether rosuvastatin affects expression and activity of rat CYP2C6. This cytochrome P450 is considered to be a counterpart of human CYP2C9, which metabolizes many drugs, including diclofenac, ibuprofen or warfarin.

DESIGN: Male hereditary hypertriglyceridemic (HHTg) rats were fed standard laboratory diet (STD) or high cholesterol diet (HCD: STD + 1% of cholesterol w/w + 10% of lard fat w/w) for 21 days. A third group of rats were fed high a cholesterol diet with rosuvastatin added (0.03% w/w). Expression of CYP2C6 was measured in liver samples using real-time PCR (mRNA level) and Western blotting (protein level). Formation of diclofenac metabolites (typical enzyme activity of CYP2C6) was analyzed using HPLC with UV detection.

RESULTS: Administration of rosuvastatin to HHTg rats resulted in significantly increased mRNA expression and enzyme activity in HCD-fed animals; changes of CYP2C6 protein were non-significant. These results suggest that CYP2C6 expression and activity are positively affected by rosuvastatin in hereditary hypertriglyceridemic rats after intake of HCD.

CONCLUSION: The results presented open the possibility that in humans, rosuvastatin may affect the metabolism of many drugs by influencing expression and activity of CYP2C6 (counterpart of human CYP2C9). Further studies are needed to elucidate the effects of this statin on CYP2C9 in humans....

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