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1.  Mechanisms Relevant to the Enhanced Virulence of a Dihydroxynaphthalene-Melanin Metabolically Engineered Entomopathogen 
PLoS ONE  2014;9(3):e90473.
The entomopathogenic fungus Metarhizium anisopliae MA05-169 is a transformant strain that has been metabolically engineered to express dihydroxynaphthalene-melanin biosynthesis genes. In contrast to the wild type strain, the transformant displays a greater resistance to environmental stress and a higher virulence toward target insect host. However, the underlying mechanisms for these characteristics remain unclear; hence experiments were initiated to explore the possible mechanism(s) through physiological and molecular approaches. Although both transformant and wild type strains could infect and share the same insect host range, the former germinated faster and produced more appressoria than the latter, both in vivo and in vitro. The transformant showed a significantly shorter median lethal time (LT50) when infecting the diamondback moth (Plutella xylostella) and the striped flea beetle (Phyllotreta striolata), than the wild type. Additionally, the transformant was more tolerant to reactive oxygen species (ROS), produced 40-fold more orthosporin and notably overexpressed the transcripts of the pathogenicity-relevant hydrolytic enzymes (chitinase, protease, and phospholipase) genes in vivo. In contrast, appressorium turgor pressure and destruxin A content were slightly decreased compared to the wild type. The transformant's high anti-stress tolerance, its high virulence against five important insect pests (cowpea aphid Aphis craccivora, diamondback moth Pl. xylostella, striped flea beetle Ph. striolata, and silverleaf whitefly Bemisia argentifolii) and its capacity to colonize the root system are key properties for its potential bio-control field application.
doi:10.1371/journal.pone.0090473
PMCID: PMC3963850  PMID: 24662974
2.  Cordycepin Regulates GSK-3β/β-Catenin Signaling in Human Leukemia Cells 
PLoS ONE  2013;8(9):e76320.
Background
Leukemia stem cells (LSCs) are a limitless cell source for the initiation and maintenance of leukemia. Activation of the Wnt/β-catenin pathway is required for the survival and development of LSCs. Therefore, targeting β-catenin is considered a therapeutic strategy for the treatment of leukemia. The goal of this study was to explore whether cordycepin, an active component of the traditional medicine Cordyceps sinensis, regulates β-catenin expression in leukemia cells.
Methodology and Principal Findings
In this study, we found that cordycepin significantly suppressed cell proliferation in all malignant cancer cells, including U937, K562, A549, HepG2, SK-Hep1 and MCF7 in a dose-dependent manner. However, cordycepin reduced β-catenin levels in U937, K562 and THP1 leukemia cells and had no effect on other solid cancer cells. In addition, treatment with cordycepin significantly suppressed leukemia colony formation in soft agar assay. Cordycepin enhanced proteasome-dependent degradation and inhibited nuclear translocation of β-catenin in leukemia cells. Cordycepin-reduced β-catenin stability was restored by the addition of a pharmacological inhibitor of GSK-3β, indicating that cordycepin-suppressed β-catenin stability is mediated by the activation of GSK-3β. Furthermore, cordycepin abolished the effect of Wnt3a-induced β-catenin in leukemia cells. In addition, cordycepin-impaired β-catenin is regulated by Akt activation but is not significantly influenced by AMPK or mTOR signal pathways.
Significance
Our findings show for the first time that codycepin selectively reduces β-catenin stability in leukemia but not in other solid tumor cells. This suppressive effect is mediated by regulating GSK-3β. A synergistic combination of cordycepin with other treatments should be used as a novel strategy to eradicate leukemia via elimination of LSCs.
doi:10.1371/journal.pone.0076320
PMCID: PMC3784440  PMID: 24086728
3.  Correction: Generation and Analysis of the Expressed Sequence Tags from the Mycelium of Ganoderma lucidum 
PLoS ONE  2013;8(9):10.1371/annotation/d3ee6fb1-5239-4a09-b197-379d22f27163.
doi:10.1371/annotation/d3ee6fb1-5239-4a09-b197-379d22f27163
PMCID: PMC3776884
4.  Enhancing the Stress Tolerance and Virulence of an Entomopathogen by Metabolic Engineering of Dihydroxynaphthalene Melanin Biosynthesis Genes ▿ †  
Applied and Environmental Microbiology  2011;77(13):4508-4519.
Entomopathogenic fungi have been used for biocontrol of insect pests for many decades. However, the efficacy of such fungi in field trials is often inconsistent, mainly due to environmental stresses, such as UV radiation, temperature extremes, and desiccation. To circumvent these hurdles, metabolic engineering of dihydroxynaphthalene (DHN) melanin biosynthetic genes (polyketide synthase, scytalone dehydratase, and 1,3,8-trihydroxynaphthalene reductase genes) cloned from Alternaria alternata were transformed into the amelanotic entomopathogenic fungus Metarhizium anisopliae via Agrobacterium-mediated transformation. Melanin expression in the transformant of M. anisopliae was verified by spectrophotometric methods, liquid chromatography/mass spectrometry (LC/MS), and confocal microscopy. The transformant, especially under stresses, showed notably enhanced antistress capacity and virulence, in terms of germination and survival rate, infectivity, and reduced median time to death (LT50) in killing diamondback moth (Plutella xylostella) larvae compared with the wild type. The possible mechanisms in enhancing the stress tolerance and virulence, and the significance and potential for engineering melanin biosynthesis genes in other biocontrol agents and crops to improve antistress fitness are discussed.
doi:10.1128/AEM.02033-10
PMCID: PMC3127726  PMID: 21571888

Results 1-4 (4)