Induction of hepatocyte growth factor production in human dermal fibroblasts by caffeic acid derivatives.

Hepatocyte growth factor (HGF) has mitogenic, motogenic, and morphogenic activities in epithelial cells. Induction of HGF production may be involved in organ regeneration, wound healing and embryogenesis. In this study, we examined the effects of caffeic acid derivatives including 4,5-di-O-caffeoylquinic acid (1) and acteoside (2) on HGF production in Neonatal Normal Human Dermal Fibroblasts (NHDF). Both 4,5-di-O-caffeoylquinic acid (1) and acteoside (2) significantly induced HGF production dose-dependent manner. To know the important substructure for HGF production activity, we next investigated the effect of the partial structure of these caffeic acid derivatives. From the results, caffeic acid (3) showed strong activity on the promotion of HGF production, while hydroxytyrosol (4) and quinic acid (5) didn't show any activity. Our findings suggest that the caffeoyl moiety of caffeic acid derivatives is essential for accelerated production of HGF. The compound which has the caffeoyl moiety may be useful for the treatment of some intractable organ disease.

Inhibition of amyloid ß aggregation by acteoside, a phenylethanoid glycoside.

We examined the effects of acteoside (1a), which was isolated from Orobanche minor, and its derivatives on the aggregation of a 42-mer amyloid ß protein (Aß42) in our search for anti-amyloidogenic compounds for Alzheimer's disease (AD) therapy. Acteoside (1a) strongly inhibited the aggregation of Aß42 in a dose-dependent manner. The structure-activity relationship for acteoside (1a) and related compounds suggests the catechol moiety of phenylethanoid glycosides to be essential for this inhibitory activity.

Protective effects of caffeoylquinic acids on the aggregation and neurotoxicity of the 42-residue amyloid ß-protein.

Alzheimer's disease (AD), a neurodegenerative disorder, is characterized by aggregation of 42-mer amyloid ß-protein (Aß42). Aß42 aggregates through ß-sheet formation and induces cytotoxicity against neuronal cells. Aß42 oligomer, an intermediate of the aggregates, causes memory loss and synaptotoxicity in AD. Inhibition of Aß42 aggregation by small molecules is thus a promising strategy for the treatment of AD. Caffeoylquinic acid (CQA), a phenylpropanoid found widely in natural sources including foods, shows various biological activities such as anti-oxidative ability. Previously, our group reported that 3,5-di-O-caffeoylquinic acid (3,5-di-CQA) rescued the cognitive impairment in senescence-accelerated-prone mice 8. However, structure-activity relationship of CQA derivatives on the aggregation and neurotoxicity of Aß42 remains elusive. To evaluate the anti-amyloidogenic property of CQA-related compounds for AD therapy, we examined the effect of CQA and its derivatives on the aggregation and neurotoxicity of Aß42. In particular, 4,5-di-O-caffeoylquinic acid (4,5-di-CQA) and 3,4,5-tri-O-caffeoylquinic acid (3,4,5-tri-CQA) strongly inhibited the aggregation of Aß42 in a dose-dependent manner. Structure-activity relationship studies suggested that the caffeoyl group in CQA is essential for the inhibitory activity. These CQAs also suppressed the transformation into ß-sheet and cytotoxicity against human neuroblastoma cells of Aß42. Furthermore, 3,4,5-tri-CQA blocked the formation of Aß42 oligomer. These results indicate that 3,4,5-tri-CQA could be a potential agent for the prevention of AD.

Structure-activity relationship of caffeoylquinic acids on the accelerating activity on ATP production.

Caffeoylquinic acid (CQA) is one of the phenylpropanoids which have various bioactivities such as antioxidant, antibacterial, anticancer, antihistamic, and other biological effects. We previously reported that 3,5-di-O-caffeoylquinic acid inhibited amyloid ß(1-42)-induced cellular toxicity on human neuroblastoma SH-SY5Y cells and increased the mRNA expression level of glycolytic enzymes and the intracellular ATP level. To investigate structure-activity relationship on the accelerating activity on ATP production, we synthesized 1,4,5-tri-O-caffeoylquinic acid, 4,5-di-O-caffeoylquinic acid, 3,4,5-tri-O-caffeoylquinic acid, and other derivatives. Additionally, we evaluated intracellular ATP level in SH-SY5Y treated with each CQA derivative. As a result, 3,4,5-tri-O-caffeoylquinic acid showed the highest accelerating activity on ATP production among tested compounds. It was suggested that caffeoyl groups bound to quinic acid are important for activity and the more caffeoyl groups are bound to quinic acid, the higher accelerating activity on ATP production exhibits.