Hui Ming Ge

Unprecedented immunosuppressive polyketides from Daldinia eschscholzii, a mantis-associated fungus.

Immunosuppressants are required for an array of medical purposes, such as organ transplantations and the treatment of autoimmune-associated diseases. However, most of the currently available immunosuppressive drugs have been shown to inevitably possess severe adverse effects, such as hepatotoxicity, nephrotoxicity, and hypertension induction. Therefore, there is an urgent need for new therapeutic agents for modulating the autoimmune response. Some microorganisms are a reliable source of immunocompromising compounds, as exemplified by the discovery of cyclosporin A (CsA), rapamycin, and FK506. Symbionts, a diverse microbial community present in plants, insects, and mammals without the generation of any detectable symptoms, are receiving renewed attention for their production of chemically inspiring and biologically potent metabolites, presumably as a result of their long coevolution with hosts. In particular, some insect-associated fungi might have acquired instinctlike capabilities for synthesizing immunoalleviating metabolites from their initial microbe–host interaction through to the final colonization. In continuation of our characterization of new bioactive metabolites from endophyte cultures, this observation tempted us to explore novel immunosuppressive metabolites that could be produced by fungi inhabiting healthy insect organs, such as the mantis gut, which is clearly an important entrance and shelter for symbionts (including quiescent pathogens) and meal-carried “foreign” microbes. As expected, a preliminary screen recognized the presence of an immunosuppressive substance or immunosuppressive substances in a culture of Daldinia eschscholzii IFB-TL01 residing in the gut of the mantis species Tenodera aridifolia, a common predator of many insects that feed on plants harboring endophyte. Subsequent bioassay-guided fractionation of the extract derived from the scaled-up fermentation of the fungus afforded two polyketides, dalesconols A (1) and B

Bioactive Alkaloids from Endophytic Aspergillus fumigatus

Two new alkaloids, named 9-deacetylfumigaclavine C (1) and 9-deacetoxyfumigaclavine C (2), along with 12 known compounds (3-14), were isolated from the culture of Aspergillus fumigatus. The structures of the new compounds were elucidated by comprehensive spectroscopic analyses. Compound 2 showed selectively potent cytotoxicity against human leukemia cells (K562) with an IC(50) value of 3.1 microM, which was comparable to that of doxorubicin hydrochloride, a presently prescribed drug for the treatment of leukemia. Furthermore, 14-norpseurotin (4) significantly induced neurite outgrowth of rat pheochromocytoma cells (PC12) at a 10.0 microM concentration.

Malibatol A regulates microglia M1/M2 polarization in experimental stroke in a PPARγ-dependent manner

BackgroundActivation of microglia plays a crucial role in immune and inflammatory processes after ischemic stroke. Microglia is reported with two opposing activated phenotypes, namely, classic phenotype (M1) and the alternative phenotype (M2). Inhibiting M1 while stimulating M2 has been suggested as a potential therapeutic approach in the treatment of stroke.FindingsIn this study, we indicated that a novel natural anti-oxidant extracted from the Chinese plant Hopea hainanensis, malibatol A (MA), decreased the infarct size and alleviated the brain injury after mice middle cerebral artery occlusion (MCAO). MA inhibited expression inflammatory cytokines in not only MCAO mice but also lipopolysaccharide (LPS)-stimulated microglia. Moreover, treatment of MA decreased M1 markers (CD16, CD32, and CD86) and increased M2 markers (CD206, YM-1) while promoting the activation of nuclear receptor PPARγ.ConclusionsMA has anti-inflammatory effects in MCAO mice in a PPARγ-dependent manner, making it a potential candidate for stroke treatment.

Protecting group-free total synthesis of (-)-lannotinidine B.

The first total synthesis of (-)-lannotinidine B, a unique tetracyclic constitutent of Lycopodium annotinum, has been accomplished in 10 steps with 23% overall yield. The completed short and efficient synthesis is characterized with three highly chemo- and/or stereoselective reductive-amination steps to furnish the desired trans-fused 6/6 bicycle and the aza seven-membered ring system, and a direct intramolecular acyloin condensation to deliver the cyclopentanone moiety, as well as successful application of a protecting group-free strategy and an optimal redox order.

Glycyrrhizic acid as the antiviral component of Glycyrrhiza uralensis Fisch. against coxsackievirus A16 and enterovirus 71 of hand foot and mouth disease.

Abstract Ethnopharmacological relevance The radices of Glycyrrhiza uralensis Fisch. and herbal preparations containing Glycyrrhiza spp. have been used for thousands of years as an herbal medicine for the treatment of viral induced cough, viral hepatitis, and viral skin diseases like ulcers in China. Glycyrrhizic acid (GA) is considered the principal component in Glycyrrhiza spp. with a wide spectrum of antiviral activity. Aim The present study attempt to validate the medicinal use of Glycyrrhiza uralensis for hand, foot and mouth disease (HFMD) and further to verify whether GA is an active antiviral component in the water extract of Glycyrrhiza uralensis. Materials and methods Radices of Glycyrrhiza uralensis Fisch. were extracted with hot water. The chemical contents of the extract were profiled with HPLC analysis. The antiviral activity of the extract and the major components was evaluated against infection of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) on Vero cells. The cytopathic effect caused by the infection was measured with MTT assay. Infectious virion production was determined using secondary infection assays and viral protein expression by immunoblotting analysis. Results The extract at 1000μg/ml suppressed EV71 replication by 1.0 log and CVA16 by 1.5 logs. The antiviral activity was associated with the content of GA in the extract since selective depletion of GA from the extract by acid precipitation resulted in loss of antiviral activity. In contrast, the acid precipitant retained antiviral activity. The precipitant at a concentration of 200μg/ml inhibited EV71 and CVA16 replication by 1.7 and 2.2 logs, respectively. Furthermore, GA dose-dependently blocked viral replication of EV71 and CVA16. At 3mM, GA reduced infectious CVA16 and EV71 production by 3.5 and 2.2 logs, respectively. At 5mM, CVA16 production was reduced by 6.0 logs and EV71 by 4.0 logs. Both EV71 and CVA16 are members of Enterovirus genus, time-of-drug addition studies however showed that GA directly inactivated CVA16, while GA anti-EV71 effect was associated with an event(s) post virus cell entry. Conclusions This study validated the medicinal usefulness of radices Glycyrrhiza uralensis against the etiological agents of HFMD. In addition to the identification of GA as the antiviral component of Glycyrrhiza uralensis against EV71 and CVA16 infection, this study also reveals that GA inhibits EV71 and CVA16 with distinct mechanisms.

Sesquiterpenoids from the Mangrove-Derived Endophytic Fungus Diaporthe sp.

A new sesquiterpenoid, diaporol A (1), possessing a unique tricyclic lactone framework, eight new drimane sesquiterpenoids, diaporols B-I (2-9), and the known compounds 10 and 11 were isolated from a culture of the mangrove-derived endophyte Diaporthe sp. The absolute configurations of 1-5 were determined by low-temperature (100 K) single-crystal X-ray diffraction with Cu Kα radiation. The compounds were evaluated for cytotoxic activity; however, no compound showed significant cytotoxicity against the tested cell lines at a concentration of 20 μM.

Thaxtomin A-deficient endophytic Streptomyces sp. enhances plant disease resistance to pathogenic Streptomyces scabies

Each plant species in nature harbors endophytes, a community of microbes living within host plants without causing any disease symptom. However, the exploitation of endophyte-based phytoprotectants is hampered by the paucity of mechanistic understandings of endophyte-plant interaction. We here reported two endophytic Streptomyces isolates IFB-A02 and IFB-A03 recovered from a stress-tolerant dicotyledonous plant Artemisia annua L. After the determination of their non-pathogenicity at the genomic level and from the toxin (thaxtomin A, TXT) level, the endophytism of both isolates was supported by their successful colonization in planta. Of the two endophytes, IFB-A03 was further studied for the mechanism of endophyte-conferred phytoprotection owing to its plant growth promotion in model eudicot Arabidopsisthaliana. Using the endophyte-Arabidopsis co-cultivation system into which pathogenic Streptomyces scabies was introduced, we demonstrated that IFB-A03 pre-inoculation could activate the salicylic acid (SA)-mediated plant defense responses upon pathogen challenge. Moreover, IFB-A03 was shown to partially rescue the defense deficiency in eds5 (enhanced disease susceptibility 5) Arabidopsis mutants, putatively acting at the upstream of SA accumulation in the defense signaling pathway associated with the systemic acquired resistance (SAR). These data suggest that endophytic Streptomyces sp. IFB-A03 could be a promising candidate for biocontrol agents against S. scabies—a causative pathogen of common scab diseases prevailing in agronomic systems.

Cytotoxic chaetoglobosins from the endophyte Chaetomium globosum.

Two new alkaloids chaetoglobosins V (1) and W (2), together with the six known congeners 3-8, were isolated through bioassay-guided fractionations from the EtOAc extract of a solid culture of Chaetomium globosum IFB-E041. The structures were elucidated by spectroscopic methods including mainly 1D and 2D NMR techniques. Chaetoglobosin W (2) was unique in its possession of an oxolane ring formed via an oxygen bridge between C-3 and C-6. The isolated fungal metabolites exhibited moderate cytotoxic activities against four human cancer cell lines (KB, K562, MCF-7, and HepG2) with their IC(50) values in a range of 18-30 µg/mL.

Immunosuppressive resveratrol aneuploids from Hopea chinensis.

Two novel resveratrol aneuploids, hopeachinols A (1) and B (2), as well as a potent immunosuppressive polyphenol diptoindonesin G (3) were characterized from the ethanol extract of Hopea chinensis stem barks. The structure of the polyphenols was accommodated by comprehensive spectroscopic analysis with the absolute stereochemistry determined by the CD approach coupled with theoretical ECD spectra computer-generated through the Gaussian 03 program. The distinct structure and biological profile of 3 recommended it as a starting molecule for the relevant drug discovery.

Naphthol radical couplings determine structural features and enantiomeric excess of dalesconols in Daldinia eschscholzii

Understanding how simple molecules are pieced together in organisms may aid biotechnological manipulation and synthetic approaches to complex natural products. The mantis-associated fungus Daldinia eschscholzii IFB-TL01 produces the unusually structured immunosuppressants (±)-dalesconols A and B, along with their congener (±)-dalesconol C, with the (-)-enantiomers in excess. Here we report that these structural and stereochemical peculiarities of dalesconols A-C are a result of promiscuous and atropselective couplings of radicals derived from 1,3,6,8-tetrahydroxynaphthalene, 1,3,8-trihydroxynaphthalene and 1,8-dihydroxynaphthalene. The observed (-)-enantiomeric excess is found to depend on the dominance of particular conformers of naphthol dimer intermediates, which are ligands of laccase.