Haihong Pang

Naturally occurring phenylethanoid glycosides: potential leads for new therapeutics.

Natural products have long been regarded as excellent sources for drug discovery given their structure diversity and wide variety of biological activities. Phenylethanoid glycosides are naturally occurring compounds of plant origin and are structurally characterized with a hydroxyphenylethyl moiety to which a glucopyranose is linked through a glycosidic bond. To date several hundred compounds of this type have been isolated from medicinal plants and further pharmacological studies in vitro or in vivo have shown that these compounds possess a broad array of biological activities including antibacterial, antitumor, antiviral, anti-inflammatory, neuro-protective, antioxidant, hepatoprotective, immunomodulatory, and tyrosinase inhibitory actions. Given their extensive activity profile, structure-activity relationships analyses of these compounds have been performed in a number of studies to reveal potential leads for future drug design. This article will summarize the major developments in phenylethanoid glycosides-based research in the past decade. The progresses made in phytochemistry and biological activity studies of these compounds will be reviewed. Particular attention will be given to the novel structures identified to date and the prominent therapeutic values associated with these molecules.

Protocatechuic acid induces cell death in HepG2 hepatocellular carcinoma cells through a c-Jun N-terminal kinase-dependent mechanism

Protocatechuic acid (PCA), chlorogenic acid (CA) and luteolin (LT) are plant phenols found in Chinese medicinal herbs such as Lonicera japonica. Cytotoxicity assays showed that PCA, CA and LT (at 100 micromol/L) effectively killed the HepG2 hepatocellular carcinoma cells. Among these three naturally occurring compounds, only PCA was capable of stimulating the c-Jun N-terminal kinase (JNK) and p38 subgroups of the mitogen-activated protein kinase (MAPK) family. Coincidently, PCA-induced cell death was rescued by specific inhibitors for JNK and p38, while the cytotoxicities of CA and LT were partially eliminated by the antioxidant effect of N-acetyl-L-cysteine (NAC). Further investigation demonstrated that the aqueous extract of Lonicera japonica also triggered HepG2 cell death in a JNK-dependent manner, but the amount of PCA alone in this herbal extract was insufficient to contribute the subsequent cytotoxic effect. Collectively, our results suggest that PCA is a naturally occurring compound capable of inducing JNK-dependent hepatocellular carcinoma cell death.

Astragaloside IV and Cycloastragenol Stimulate the Phosphorylation of Extracellular Signal-Regulated Protein Kinase in Multiple Cell Types

Two Chinese herb-derived small molecule telomerase activators, astragaloside IV (AG-IV) and cycloastragenol (CAG), have recently been shown to improve the proliferative response of CD8+ T lymphocytes from HIV-infected patients by upregulating telomerase activity. Here, we examined the signaling mechanism of AG-IV and CAG. Telomerase activity in human embryonic kidney HEK293 fibroblasts was increased upon treatment with increasing concentrations of AG-IV or CAG. Both compounds induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) in a time- and dose-dependent manner in HEK293 cells and HEK-neo keratinocytes. AG-IV and CAG also stimulated ERK phosphorylation in other cell lines of lung, brain, mammary, endothelial, and hematopoietic origins. Use of selective inhibitors and dominant negative mutants revealed the involvement of c-Src, MEK (ERK kinase), and epidermal growth factor receptor in CAG-induced ERK phosphorylation. Our data indicate that AG-IV and CAG may exert their cellular effects through the activation of the Src/MEK/ERK pathway.

New Secoiridoid Glucosides from Ligustrum lucidum Induce ERK and CREB Phosphorylation in Cultured Cortical Neurons

Two new secoiridoid glucosides, namely iso-oleonuezhenide (1) and methyloleoside 7-ethyl ester (2), along with five known ones, oleonuezhenide (3), nuezhenide (4), oleuropein (5), G13 (6), and jaspolyside methyl ester (7), were isolated from the fruits of Ligustrum lucidum. Their structures were assigned based on 1H-NMR, 13C-NMR, and 2D-NMR analyses, in combination with HR-MS experiments and the comparison with literature data of related compounds, as well as on chemical experiments. We have examined the ability of these compounds to activate ERK and CREB in cultured cortical neurons. Our studies demonstrate that compound 1 induces ERK and CREB phosphorylation in primary cortical neurons in a dose- and temporal-dependent manner, suggesting its bioactivity on neurons.

Dammarane saponins from Gynostemma pentaphyllum

Dammarane-type saponins (1-7), together with five known compounds, were isolated from the aerial parts of Gynostemma pentaphyllum. Compounds 1-4, 6 and 7 induced the phosphorylation of ERK protein in primary rat cortical neurons, which indicates their potential neuroactivity. On the other hand, no induction of ERK phosphorylation was observed for HEK293 cells following treatment with saponins 1, 3, 4 and 7.

A new carotenoid glycoside from Rehmannia glutinosa

A new carotenoid glycoside, namely neo-rehmannioside (1), together with five known compounds, 6-O-seco-hydroxyaeginetoyl ajugol (2), oxyrehmaionoside B (3), ajugol (4), geniposidic acid (5) and geniposide (6) was isolated from the 95% ethanol extract of dry roots of Rehmannia glutinosa. The structure of the new compound (1) was determined based on MS, IR, 1-D and 2-D NMR spectral data.

The Aqueous Extract of Radix Glycyrrhizae Stimulates Mitogen-Activated Protein Kinases and Nuclear Factor-κB in Jurkat T-Cells and THP-1 Monocytic Cells

Radix Glycyrrhizae (RG) is a medicinal herb extensively utilized in numerous Chinese medical formulae for coordinating the actions of various components in the recipes and strengthening the body functions. In this report, we demonstrate that the aqueous extract of Radix Glycyrrhizae is capable of stimulating the c-Jun N-terminal kinase and p38 subgroups of mitogen-activated protein kinases (MAPKs), and the nuclear factor-kappaB (NFkappaB) in Jurkat T-lymphocytes. The activation magnitudes of MAPKs and NFkappaB were dose-dependent (EC(50) approximately 1 mg/ml) and time-dependent (maximal around 15-30 minutes). Stimulations of MAPKs and NFkappaB were not associated with changes in intracellular Ca(2+) mobilization. Similar activation profiles of MAPK and NFkappaB were obtained from THP-1 monocytes treated with the extract. In terms of chemotactic activity, the SDF-induced chemotaxis of Jurkat cells and THP-1 cells were inhibited by RG extract at 1-10 mg/ml, while a lower RG concentration (0.1-0.3 mg/ml) potentiated the SDF-induced chemotaxis for the former, but not the latter cell type. Given the fact that MAPKs and NFkappaB are important signaling intermediates for lymphocyte activities, our results suggest that Radix Glycyrrhizae may contain active constituents capable of modulating immuno-responses through various intracellular signaling pathways.