Biotransformation of natural polyacetylene in red ginseng by Chaetomium globosum.

BACKGROUND: Fermentation has been shown to improve the biological properties of plants and herbs. Specifically, fermentation causes decomposition and/or biotransformation of active metabolites into high-value products. Polyacetylenes are a class of polyketides with a pleiotropic profile of bioactivity. METHODS: Column chromatography was used to isolate compounds, and extensive NMR experiments were used to determine their structures. The transformation of polyacetylene in red ginseng (RG) and the production of cazaldehyde B induced by the extract of RG were identified by TLC and HPLC analyses. RESULTS: A new metabolite was isolated from RG fermented by Chaetomium globosum, and this new metabolite can be obtained by the biotransformation of polyacetylene in RG. Panaxytriol was found to exhibit the highest antifungal activity against C. globosum compared with other major ingredients in RG. The fungus C. globosum cultured in RG extract can metabolize panaxytriol to Metabolite A to survive, with no antifungal activity against itself. Metabolites A and B showed obvious inhibition against NO production, with ratios of 42.75 ± 1.60 and 63.95 ± 1.45% at 50 µM, respectively. A higher inhibitory rate on NO production was observed for Metabolite B than for a positive drug. CONCLUSION: Metabolite A is a rare example of natural polyacetylene biotransformation by microbial fermentation. This biotransformation only occurred in fermented RG. The extract of RG also stimulated the production of a new natural product, cazaldehyde B, from C. globosum. The lactone in Metabolite A can decrease the cytotoxicity, which was deemed to be the intrinsic activity of polyacetylene in ginseng.

Inducing Intermediates in Biotransformation of Natural Polyacetylene and A Novel Spiro-γ-Lactone from Red Ginseng by Solid Co-Culture of Two Gut Chaetomium globosum and The Potential Bioactivity Modification by Oxidative Metabolism.

The ω-hydroxyl-panaxytriol (1) and ω-hydroxyl-dihydropanaxytriol (2)-are rare examples of polyacetylene metabolism by microbial transformation, and these new metabolites (1, 2) from fermented red ginseng (FRG) by solid co-culture induction of two Chaetomium globosum should be the intermediates of biotransformation of panaxylactone (metabolite A). The metabolic pathway of panaxylactone was also exhibited. The ingredients of red ginseng (RG) also induced the production of rare 6/5/5 tricyclic ring spiro-γ-lactone skeleton (3). The ω-hydroxylation of new intermediates (1, 2) decreases cytotoxicity and antifungal activity against C. globosum compared with that of its bioprecursor panaxytriol. Additionally, compounds 1 and 2 indicated obvious inhibition against nitric oxide (NO) production, with ratios of 44.80 ± 1.37 and 23.10 ± 1.00% at 50 µM. 1 has an equivalent inhibition of NO production compared with the positive drug. So, the microbial biotransformation that occurred in FRG fermented by gut C. globosum can change the original bioactivity of polyacetylene, which gave a basis about the metabolic modification of red ginseng by intestinal fungus fermentation.

Inducing secondary metabolite production from Daldinia eschscholzii JC-15 by red ginseng medium.

Red ginseng (RG) is one of the most popular herbal medicines and used as a dietary supplement in recent years. The bioactive ingredient in RG can induce the production of novel microbial metabolite from fermented RG. Using the one strain-many compounds strategy, the reinvestigation of the metabolites from Daldinia eschscholzii JC-15 cultured in red ginseng medium led to the isolation of an unprecedented benzopyran-naphthalene hybrid, daldinsin (1) and a new lactone (2). In this research, a new lactone, 8-hydroxylhelicascolide A (2) instead of helicascolide A was produced by the D. eschscholzii JC-15 induced by the red ginseng medium. Compound 1 showed anti-acetylcholinesterase activity with the inhibition ratio of 38.8% at 50 µM. Compound 2 indicated antimicrobial activities against Fusarium Solani, F. oxysporum, and Escherichia coli with MICs at 128 µg/mL. RG is therefore a promising activator in production of novel microbial metabolite.

Benzopyran derivatives from endophytic Daldinia eschscholzii JC-15 in Dendrobium chrysotoxum and their bioactivities.

Five new benzopyran derivatives (2-6) and a new natural product (1) were isolated from endophytic Daldinia eschscholzii in Dendrobium chrysotoxum and determined as (R)-2,3-dihydro-2,5-dihydroxy-2-methylchromen-4-one (1), (2R, 4S)-2,3-dihydro-2-methyl-benzopyran-4,5-diol (2), (R)-3-methoxyl-1-(2,6-dihydroxy phenyl)-butan-1-one (3), 7-O-α-d-ribosyl-5-hydroxy-2-methyl-4H-chromen-4-one (4), 7-O-α-d-ribosyl-2,3-dihydro-5-hydroxy-2-methyl-chromen-4-one (5), daldinium A (6). These compounds were evaluated for their antimicrobial activity, anti-acetylcholinesterase, nitric oxide inhibition, anticoagulant, photodynamic antimicrobial activities and glucose uptake of adipocytes. Some compounds showed photoactive antimicrobial activities and glucose uptake stimulating activities.

New azaphilones and tremulane sesquiterpene from endophytic Nigrospora oryzae cocultured with Irpex lacteus.

Five new metabolites belonging to two backbones of pulvilloric acid-type azaphilone and tremulane sesquiterpene were obtained and their structures were determined by spectral analysis. Based on the biogenesis analysis, tremulane sesquiterpenes were obtained from Irpex lacteus by the stimulation of mixed-culture. The antifungal selectivities of metabolites produced by fungus against their co-culture fungus and common pathogens, exhibited competitive interaction of this mix-culture. The tremulane sesquiterpene conocenol B produced by I. lacteus through the induction of Nigrospora oryzae showed selectivity of anti-fungal activity against its co-culture fungus, N. oryzae, with MICs at 16 µg/mL and 128 µg/mL against I. lacteus. The fungus can metabolize these new compounds to inhibit the growth of co-culture fungus while not inhibiting its own growth. Compound 5 was active against acetylcholinesterase (AChE) with a ratio of 35% at the concentration of 50 µM.

New Azaphilones from Nigrospora oryzae Co-Cultured with Beauveria bassiana.

In this study, the co-culture of Nigrospora oryzae and Beauveria bassiana, the endophytes in the seeds of Dendrobium officinale, were examined for metabolite diversity. Five new azaphilones were isolated, and their structures were determined by spectral analysis. In terms of azaphilones, compound 2 had an unprecedented skeleton, with a bicyclic oxygen bridge. The antifungal selectivities of the metabolite produced by N. oryzae against its co-culture fungus, B. bassiana, and common pathogens exhibited competitive interaction in this mix-culture. Compounds 1 and 2 showed obvious nitric oxide (NO) inhibitory activity with ratios of 37%, and 39%, respectively, at a concentration of 50 µM.

Potential antihyperlipidemic polyketones from endophytic Diaporthe sp. JC-J7 in Dendrobium nobile.

Eleven new polyketones named diaporthsins A-K (1-11) were isolated from the fermentation of Diaporthe sp. JC-J7. The chemical structures of compounds (1-11) were elucidated by spectroscopic methods including HRESIMS, 2DNMR, NMR and chemical methods. Compound 11 features an unusual acyclic polyketone-phenolic polyketone hybrid structure that integrates the characteristics of different fungal metabolites (cytosporone and multiplolide). Compound 3 was the only C12-polyketone obtained in this research. These new polyketones showed inhibitory activity on triglycerides (TG) in steatosis hepatocyte L-02 cells. Among them, compound 5 and (4E)-6,7,9-trihydroxydec-4-enoic acid displayed inhibitory activities on TG in steatotic L-02 cells with inhibition ratios of 26% and 21% at concentration of 5 µg mL-1; also, inhibition ratios of 8-O-acetylmultiplolide A and phomopsisporone A at concentration of 5 µg mL-1 were calculated to be about 24% and 16%, respectively, which were equivalent to the antihyperlipidemic activity of lovastatin. The preliminary structure-activity relationship indicated that acetyl at C-8 can increase the antihyperlipidemic activity of multiplolide A and the glycol ester and hydroxyl at C-6 can also increase the corresponding activity of diaporthsin B.

Phytotoxic, antibacterial, and antioxidant activities of mycotoxins and other metabolites from Trichoderma sp.

A new natural mycotoxin was isolated from the fermentation broth of Trichoderma sp. Jing-8 and the structure was determined as alternariol 1'-hydroxy-9-methyl ether (1), together with twelve known compounds. The structures were elucidated on the basis of their 1D, 2D NMR spectra and mass spectrometric data. Compounds 1, 8 and 9 indicated inhibitions against germination of the seeds of cabbage with MICs < 3 µg/mL. The compound 1 showed the antibacterial activity against Bacillus subtilis and Staphylococcus aureus with MICs at 64 µg/mL. Compound 1 and 3 showed significant DPPH radical-scavenging activities with IC50 at 12 µg/mL, respectively. The OH at C-1' in compound 1 decreased the cytotoxicity of these mycotoxins. A primary structure-activity relationship about the alternariol derivatives was discussed. Compounds 2-7 and 8 were the first time to be isolated from the Trichoderma.

Anti-rheumatic drug iguratimod (T-614) alleviates cancer-induced bone destruction via down-regulating interleukin-6 production in a nuclear factor-κB-dependent manner.

Cytokines are believed to be involved in a "vicious circle" of progressive interactions in bone metastasis. Iguratimod is a novel anti-rheumatic drug which is reported to have the capability of anti-cytokines. In this study, a rat model was constructed to investigate the effect of iguratimod on bone metastasis and it was found that iguratimod alleviated cancer-induced bone destruction. To further explore whether an anti-tumor activity of iguratimod contributes to the effect of bone resorption suppression, two human breast cancer cell lines MDA-MB-231 and MCF-7 were studied. The effect of iguratimod on tumor proliferation was detected by CCK-8 assay and flow cytometry. The effects of iguratimod on migration and invasion of cancer cells were determined by wound-healing and Transwell assays. Results showed that high dose (30 µg/mL) iguratimod slightly suppressed the proliferation of cancer cells but failed to inhibit their migration and invasion capacity. Interestingly, iguratimod decreased the transcription level of IL-6 in MDA-MB-231 cells in a concentration-dependent manner. Moreover, iguratimod partially impaired NF-κB signaling by suppressing the phosphorylation of NF-κB p65 subunit. Our findings indicated that iguratimod may alleviate bone destruction by partially decreasing the expression of IL-6 in an NF-κB-dependent manner, while it has little effect on the tumor proliferation and invasion.