The role of CDK8 in mesenchymal stem cells in controlling osteoclastogenesis and bone homeostasis.

Bone marrow mesenchymal stem cells (MSCs) are critical regulators of postnatal bone homeostasis. Osteoporosis is characterized by bone volume and strength deterioration, partly due to MSC dysfunction. Cyclin-dependent kinase 8 (CDK8) belongs to the transcription-related CDK family.

Pharmacokinetic model analysis of interaction between phenytoin and capecitabine.

Objective: Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine.

[A case of toxicity caused by drug interaction between capecitabine and phenytoin in patient with colorectal cancer].

We present a case of toxicity caused by a drug interaction between capecitabine and phenytoin (PHT). The drug combination elevated the plasma level of PHT in a patient on chemotherapy with capecitabine for colorectal cancer. Our patient was a 44-year-old woman diagnosed with epilepsy in her 20's, being treated with valproic acid (VPA) and PHT.

Synthesis and biological activity of optically active NCL-1, a lysine-specific demethylase 1 selective inhibitor.

Optically active (1S,2R)-NCL-1 and (1R,2S)-NCL-1 were synthesized and evaluated for their lysine-specific demethylase 1 inhibitory activity and cell growth inhibitory activity. In enzyme assays, the (1S,2R)-isomer was approximately four times more potent than the (1R,2S)-isomer. In cell growth inhibition assays, the two isomers showed similar activity in HEK293 cells and SH-SY5Y cells, whereas the (1S,2R)-isomer showed approximately four times more potent activity than the (1R,2S)-isomer in HeLa cells.

Identification of cell-active lysine specific demethylase 1-selective inhibitors.

Lysine specific demethylase 1 (LSD1) plays a key role in the regulation of gene expression by removing the methyl groups from methylated Lys4 of histone H3 (H3K4). Here we report the identification of the first small-molecule LSD1-selective inhibitors. These inhibitors show in vivo H3K4-methylating activity and antiproliferative activity and should be useful as lead structures for anticancer drugs and as tools for studying the biological roles of LSD1.

Inhibition of human sirtuins by in situ generation of an acetylated lysine-ADP-ribose conjugate.

A new type of small-molecular sirtuin inhibitor was designed on the basis of the proposed catalytic mechanism for deacetylation of acetylated lysine substrates by sirtuins. Among the compounds thus designed and synthesized, we found that 2k, which contains an ethoxycarbonyl group at the alpha position to the acetamide of acetylated lysine substrate analogue 1, showed potent inhibitory activity in an in vitro assay using recombinant SIRT1, with high selectivity over SIRT2 and SIRT3. Mechanistic study by means of kinetic analysis, mass spectroscopy, and computation indicated that the enol form of compound 2k nucleophilically attacks NAD(+) in the active site of SIRTs to afford the stable compound 2k-ADP-ribose conjugate 5, leading to inhibition of the enzyme activity.

Insulinomimetic zinc(II) complexes with natural products: in vitro evaluation and blood glucose lowering effect in KK-Ay mice with type 2 diabetes mellitus.

In vitro insulinomimetic activities of Zn(II) complexes with three natural products, betaine, L-lactic acid, and D-(-)-quinic acid (qui), were found in rat adipocytes treated with epinephrine in terms of the inhibition of free fatty acid release. Based on the results, the blood glucose lowering effect in KK-A(y) mice with type 2 diabetes mellitus was observed by daily i.p.