Novel Insights into the Bioactive Metabolites of Macrocybe gigantea (Agaricomycetes), Using Gas Chromatography-Mass Spectrometry Combined with Chemoinformatic Approaches.

Macrocybe gigantea is an edible mushroom and has multiple pharmacological properties, including antibacterial, antioxidant, and antitumor activities. However, only a few reports are currently available on the bioactive compounds and bioactivity of this mushroom. Therefore, the present study aimed to explore the unique chemical diversity of the fruiting body of M. gigantea. Species identification was done accurately with morphological and molecular methods, followed by mycochemical extraction in different solvent systems. The ethanolic extract of the fruiting body gave maximum yield, and gas chromatography-mass spectrometry (GC-MS) analysis was performed along with an assessment of antibacterial activity and cell viability by the MTT assay. The GC-MS analysis revealed 50 metabolites, and further cheminformatics analysis of these metabolites revealed their possible biological activities. In addition, the physicochemical and mineral element analysis of M. gigantea revealed the quality and authenticity of the species. Altogether, the current investigation gives a comprehensive overview of the bioactive metabolites of M. gigantea.

Tobacco Carcinogen-Induced Production of GM-CSF Activates CREB to Promote Pancreatic Cancer.

Although smoking is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC), the molecular mechanisms underlying PDAC development and progression in smokers are still unclear. Here, we show the role of cyclic AMP response element-binding protein (CREB) in the pathogenesis of smoking-induced PDAC. Smokers had significantly higher levels of activated CREB when compared with nonsmokers. Cell lines derived from normal pancreas and pancreatic intraepithelial neoplasm (PanIN) exhibited low baseline pCREB levels compared with PDAC cell lines. Furthermore, elevated CREB expression correlated with reduced survival in patients with PDAC. Depletion of CREB significantly reduced tumor burden after tobacco-specific nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) treatment, suggesting a CREB-dependent contribution to PDAC growth and progression in smokers. Conversely, NNK accelerated PanIN lesion and PDAC formation via GM-CSF-mediated activation of CREB in a PDAC mouse model. CREB inhibition (CREBi) in mice more effectively reduced primary tumor burden compared with control or GM-CSF blockade alone following NNK exposure. GM-CSF played a role in the recruitment of tumor-associated macrophages (TAM) and regulatory T cell (Treg) expansion and promotion, whereas CREBi significantly reduced TAM and Treg populations in NNK-exposed mice. Overall, these results suggest that NNK exposure leads to activation of CREB through GM-CSF, promoting inflammatory and Akt pathways. Direct inhibition of CREB, but not GM-CSF, effectively abrogates these effects and inhibits tumor progression, offering a viable therapeutic strategy for patients with PDAC.Significance: These findings identify GM-CSF-induced CREB as a driver of pancreatic cancer in smokers and demonstrate the therapeutic potential of targeting CREB to reduce PDAC tumor growth.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6146/F1.large.jpg Cancer Res; 78(21); 6146-58. ©2018 AACR.