Soon-Ho Yim

Microbial metabolism of the environmental estrogen bisphenol A

Preliminary microbial metabolism studies of bisphenol A (BPA) (1) on twenty six microorganisms have shown thatAspergillus fumigatus is capable of metabolizing BPA. Scale-up fermentation of 1 withA. fumigatus gave a metabolite (2) and its structure was established as bisphenol A-O-β-D-glucopyranoside (BPAG) based on spectroscopic analyses.

Development of a highly visual, simple, and rapid test for the discovery of novel insulin mimetics in living vertebrates.

Diabetes mellitus is a global epidemic with major impacts on human health and society. Drug discovery for diabetes can be facilitated by the development of a rapid, vertebrate-based screen for identifying new insulin mimetic compounds. Our study describes the first development of a zebrafish-based system based on direct monitoring of glucose flux and validated for identifying novel anti-diabetic drugs. Our system utilizes a fluorescent-tagged glucose probe in an experimentally convenient 96-well plate format. To validate our new system, we identified compounds that can induce glucose uptake via activity-guided fractionation of the inner shell from the Japanese Chestnut (Castanea crenata). The best performing compound, UP3.2, was identified as fraxidin and validated as a novel insulin mimetic using a mammalian adipocyte system. Additional screening using sets of saponin- and triazine-based compounds was undertaken to further validate this assay, which led to the discovery of triazine PP-II-A03 as a novel insulin mimetic. Moreover, we demonstrate that our zebrafish-based system allows concomitant toxicological analysis of anti-diabetic drug candidates. Thus, we have developed a rapid and inexpensive vertebrate model that can enhance diabetes drug discovery by preselecting hits from chemical library screens, before testing in relatively expensive rodent assays.

Cytotoxic caffeic acid derivatives from the rhizomes of Cimicifuga heracleifolia

Activity profiling of the n-BuOH extract from Cimicifuga heracleifolia rhizomes led to the identification of three cytotoxic caffeic acid derivatives, carboxymethyl isoferulate (2), cimicifugic acid A (3), and cimicifugic acid B (4) together with a series of structurally related inactive compounds. The extract was separated by time-based fractionation in a gradient HPLC condition, and cytotoxicity of each fraction was evaluated using HCT116 colon cancer cells in vitro. HPLChyphenated spectroscopy including LC/NMR and LC/PDA/MS provided structural information for phenolic compounds contained in the extract, and further preparative isolation of active compounds 2–4 was achieved by semi-preparative HPLC. Compounds 2–4 showed cytotoxic activity against cancer cells in a dose-dependent manner at the concentrations of 2.5–40 μM, and western blotting analysis showed that these compounds increased expression of cleaved poly ADP ribose polymerase (PARP), a critical apoptosis marker.

A new ergostane-type cholesterol biosynthesis inhibitor isolated from Hormoconis resinae

Abstract A new ergostane-type steroid, 3β-hydroxy-1,11-dioxo-ergosta-8,24(28)-diene-4α-carboxylic acid ( 1 ) was isolated from the mold Hormoconis resinae as a cholesterol biosynthesis inhibitor in the Chang liver cell. The absolute stereostructure of 1 was established based on the spectroscopic analyses and modified Moshers method.

Isolation of 4,5-O-Dicaffeoylquinic Acid as a Pigmentation Inhibitor Occurring in Artemisia capillaris Thunberg and Its Validation In Vivo

There is a continual need to develop novel and effective melanogenesis inhibitors for the prevention of hyperpigmentation disorders. The plant Artemisia capillaris Thunberg (Oriental Wormwood) was screened for antipigmentation activity using murine cultured cells (B16-F10 malignant melanocytes). Activity-based fractionation using HPLC and NMR analyses identified the compound 4,5-O-dicaffeoylquinic acid as an active component in this plant. 4,5-O-Dicaffeoylquinic acid significantly reduced melanin synthesis and tyrosinase activity in a dose-dependent manner in the melanocytes. In addition, 4,5-O-dicaffeoylquinic acid treatment reduced the expression of tyrosinase-related protein-1. Significantly, we could validate the antipigmentation activity of this compound in vivo, using a zebrafish model. Moreover, 4,5-O-dicaffeoylquinic acid did not show toxicity in this animal model. Our discovery of 4,5-O-dicaffeoylquinic acid as an inhibitor of pigmentation that is active in vivo shows that this compound can be developed as an active component for formulations to treat pigmentation disorders.

Isolation and Characterization of Isofraxidin 7-O-(6'-O-p-Coumaroyl)-β-glucopyranoside from Artemisia capillaris Thunberg: A Novel, Nontoxic Hyperpigmentation Agent That Is Effective In Vivo.

Abnormalities in skin pigmentation can produce disorders such as albinism or melasma. There is a research need to discover novel compounds that safely and effectively regulate pigmentation. To identify novel modulators of pigmentation, we attempted to purify compounds from a bioactive fraction of the Korean medicinal plant Artemisia capillaris Thunberg. The novel compound isofraxidin 7-O-(6′-O-p-coumaroyl)-β-glucopyranoside (compound 1) was isolated and its pigmentation activity was characterized in mammalian melanocytes. Compound 1 stimulated melanin accumulation and increased tyrosinase activity, which regulates melanin synthesis. Moreover, compound 1 increased the expression of tyrosinase and the key melanogenesis regulator microphthalmia-associated transcription factor (MITF) in melanocytes. Compared to the parent compound, isofraxidin, compound 1 produced greater effects on these pigmentation parameters. To validate compound 1 as a novel hyperpigmentation agent in vivo, we utilized the zebrafish vertebrate model. Zebrafish treated with compound 1 showed higher melanogenesis and increased tyrosinase activity. Compound 1 treated embryos had no developmental defects and displayed normal cardiac function, indicating that this compound enhanced pigmentation without producing toxicity. In summary, our results describe the characterization of novel natural product compound 1 and its bioactivity as a pigmentation enhancer, demonstrating its potential as a therapeutic to treat hypopigmentation disorders.

A cholesterol biosynthesis inhibitor from Rhizopus oryzae

A bile acid derivative, methyl cholate (1), was isolated from EtOAc extract of the fungusRhizopus oryzae as a cholesterol biosynthesis inhibitor. It showed moderate inhibitory activity on cholesterol biosynthesis in human Chang liver cells. Compound1 exhibited inhibitory effect on the later step of cholesterol biosynthesis, indicating that its action mode is different from that of statins that act on the HMG-CoA reductase.

Suppression of influenza B virus replication by sakuranetin and mode of its action: Anti-influenza B virus activity of sakuranetin

This study aimed to investigate in vitro the anti‐influenza B/Lee/40 virus effect of sakuranetin and mode of its action. The sakuranetin exhibited potent antiviral activity against influenza B/Lee/40 virus, reducing the formation of a visible cytopathic effect, with a 50% inhibitory concentration (IC50) of 7.21 μg/ml and no cytotoxicity at a concentration of 100 μg/ml, and the derived therapeutic index (TI) was >13.87. Oseltamivir showed weak anti‐influenza B/Lee/40 virus activity with IC50 of 80.74 μg/ml, 50% cytotoxicity concentration of >100 μg/ml, and TI of >1.24. Sakuranetin also showed effective inhibitory effects when added at the viral attachment, entry, and postentry steps. Moreover, sakuranetin effectively inactivated influenza B/Lee/40 virus infection in dose‐ and temperature‐dependent manners. Sakuranetin indicated an inhibitory effect in viral RNA synthesis in the presence of 100 μg/ml of sakuranetin. Overall, this research revealed that sakuranetin could inhibit influenza B/Lee/40 virus replication and that sakuranetin may be involved in the virus attachment, entry, and postentry. Therefore, sakuranetin is a good candidate for a chemopreventive agent for influenza virus‐related diseases.