Two new labdane diterpenes (1 and 2) were isolated from the fruiting bodies of Ramaria formosa. The structures of these compounds were established by extensive spectroscopic studies and chemical evidence. The inhibitory activity of compounds 1 and 2 against human neutrophil elastase (HNE) was evaluated in vitro. Compounds 1 and 2 inhibited HNE activity moderately. The IC50 values for compounds 1 and 2 were 36.4 ± 1.2 and 40.8 ± 1.5 μM, respectively; the IC50 value for the positive control, EGCG, was 12.5 ± 0.8 μM. In addition, the mechanism by which 2 inhibited HNE was a mixed-type noncompetitive inhibition, with a Ki of 41.5 ± 1.8 μM.
Two new sesquiterpene derivatives (1 and 2), ramarin A (1) and ramarin B (2), together with three known compounds (3-5) were isolated from the fruiting bodies of Ramaria formosa. The structures of the two sesquiterpenes were established by extensive spectroscopic studies and chemical evidence. The inhibitory activity of the isolated compounds (1-5) against human neutrophil elastase (HNE) was evaluated in vitro. All compounds tested inhibited HNE by 35-30% at the highest concentration used (100 µM), whereas the positive control, epigallocatechin gallate (EGCG), exhibited 60% inhibition at 100 µM.Key words Ramaria formosa; Gomphaceae; sesquiterpene; human neutrophil elastase Human neutrophil elastase (HNE), a serine protease found primarily in the azurophilic granules of neutrophils, has broad substrate specificity and can cleave not only elastin but also other extracellular matrix (ECM) proteins, such as collagen, fibronectin, laminin, and proteoglycans.1) With aging, skin elasticity is decreased significantly by elastase activity, resulting in skin sagging and wrinkling.2) Thus, developing pharmacological inhibitors of HNE might provide a therapeutic approach for preventing skin sagging and wrinkling in aging.Many species of mushrooms have been used in folk medicine around the world for thousands of years. They produce various classes of secondary metabolites, many of which possess interesting biological activities and have the potential to be developed as therapeutic agents.3-5) Thus, mushrooms have been the focus of much attention in the search for specific pharmacologically significant compounds.Ramaria formosa (PERS.) QUÉL. is a coral fungus of the genus Ramaria in the family Gomphaceae, found primarily in Europe and North America. Previous studies revealed that the crude extract of R. formosa exhibited antimicrobial, anti-oxidant, and antitumor activities.6,7) Cellulase activity was also detected in a culture of R. formosa. 8) Recently, a novel ribonuclease purified from R. formosa was reported to exhibit human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitory activity. 9) However, there is no reported study of the secondary metabolites of this mushroom.In searching for novel HNE inhibitors from higher fungi, we found that an ethyl acetate (EtOAc)-soluble fraction of the methanol (MeOH) extract of the fruiting bodies of R. formosa had considerable HNE-inhibitory activity (IC 50 =40.6 µg/mL). Further studies on this fraction resulted in the isolation of two new sesquiterpene derivatives (1 and 2), together with three known compounds (3-5). This report describes the isolation and structural determination of these sesquiterpene derivatives, and the characterization of their inhibitory effects against HNE. Results and DiscussionMeOH extract of the fruiting bodies of R. formosa was suspended in H 2 O and partitioned successively with n-hexane, EtOAc, and n-BuOH. The EtOAc-soluble fraction, which inhibited HNE activity significantly, was subjected to a series of chromatographic procedures, leading t...
Clitocybin A is a novel anti-wrinkle cosmetic agent produced by the strain from a Korean native mushroom Clitocybe aurantiaca. In this study, fermentation, extraction, and purification conditions for a large scale production of clitocybin A were optimized, and its cytotoxicity and inhibition activity on the expression of matrix metalloproteinase-1 (MMP-1) were characterized. The mass production of anti-wrinkle agent was achieved according to the 300 L fermentation process with a fedbatch cultivation using the modified yeast-maltose (YM) broth, and a total of 12.5 kg of cell mass was obtained in a 120 L culture broth for 14 days. After extraction and purification, clitocybin A was identified by HPLC. The cytotoxicity of clitocybin A was examined by the MTT assay. When assayed at 100 and 200 µg/ml concentrations, clitocybin A showed no cytotoxicity, demonstrating safety. The inhibition activity of clitocybin A on the expression of MMP-1 was examined against UV irradiation. Oleanolic acid (control group) showed a relatively low MMP-1 inhibiting activity (ca. 16.7%) at 10 µg/ml and showed increased cytotoxicity at higher concentrations. In contrast, clitocybin A showed no cytotoxicity at 100 µg/ml, and exhibited a relatively high MMP-1-inhibiting activity (33.1%). These findings indicate that clitocybin A may be a safe and effective anti-wrinkle agent for use in functional cosmetics.
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