Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors.

RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen-activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.

Hydroxytyrosol reduces intracellular reactive oxygen species levels in vascular endothelial cells by upregulating catalase expression through the AMPK-FOXO3a pathway.

Reactive oxygen species are critically involved in the endothelial dysfunction that contributes to atherosclerosis development. Hydroxytyrosol (HT), a main phenolic compound in olive oil and leaves from Olea europaea L., has antiatherogenic properties with powerful antioxidant activity.

Hydroxytyrosol induces proliferation and cytoprotection against oxidative injury in vascular endothelial cells: role of Nrf2 activation and HO-1 induction.

Hydroxytyrosol (HT), a phenolic compound in olive oil and leaves, has been reported to prevent various human pathologies including cardiovascular diseases. This study investigated the effects of HT on proliferation and protection against oxidative stress-induced damage in vascular endothelial cells (VECs) and the molecular mechanism(s) involved. Treatment of VECs with HT increased cell proliferation, promoted wound repair, and protected cells against H(2)O(2) cytotoxicity through the activation of Akt and ERK1/2, but not p38 MAPK.

DNA cleavage characteristics of non-protein enediyne antibiotic N1999A2.

N1999A2 (NA2) is a new non-protein antitumor antibiotic that contains a stable 9-membered ring enediyne chromophore similar to a neocarzinostatin chromophore (NCS-chr). We have compared DNA cleavage reactions between NA2 and NCS-chr, and also clarified some characteristics of DNA strand scission by NA2. It was found that: (1) NA2 is considerably stable in nature, (2) the compound intercalates into base pairs of a DNA minor groove and decreases its base-attacking frequency in the order of T>A>> C>G, (3) the base-sequence specificity 5(')-GGT/3(')-CCA presented by NA2 is significantly related to recognition of the base pair with the naphthoate moiety, and (4) the different cleavage property between NCS-chr and NA2 is associated with the presence or absence of an aminoglycoside residue.