Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1

Functional pancreatic neuroendocrine tumours (PNETs) are mainly represented by insulinoma, which secrete insulin independent of glucose and cause hypoglycaemia. The major genetic alterations in sporadic insulinomas are still unknown. Here we identify recurrent somatic T372R mutations in YY1 by whole exome sequencing of 10 sporadic insulinomas. Further screening in 103 additional insulinomas reveals this hotspot mutation in 30% (34/113) of all tumours. T372R mutation alters the expression of YY1 target genes in insulinomas. Clinically, the T372R mutation is associated with the later onset of tumours. Genotyping of YY1, a target of mTOR inhibitors, may contribute to medical treatment of insulinomas. Our findings highlight the importance of YY1 in pancreatic β-cells and may provide therapeutic targets for PNETs

Biotransformation of dihydrocapsaicin by human intestinal fungi and the inhibitory effects of metabolites against LSD1

Dihydrocapsaicin is the main bioactive component in Capsicum plants, which is widely used in China and India as a food drug and additive. In this study, the biotransformation of dihydrocapsaicin was performed using four cultivated human intestinal fungal strains in vitro. Eight metabolites, including seven previously undescribed metabolites (1 and 3−8) and one known analog (2), were obtained. Numerous spectroscopic data, such as NMR and HRESIMS, were collected to determine their structures. Based on the structures of the dihydrocapsaicin metabolites, the main biotransformation reactions were revealed to be hydroxylation, alcohol oxidation, and lactylation. In particular, the lactylation of hydroxyl groups is mainly mediated by Rhizopus oryzae R2701. In addition, metabolite 1 showed significant inhibitory effect on lysine-specific demethylase 1 (LSD1) (IC50 1.99 μM). Therefore, the biotransformation of dihydrocapsaicin by intestinal fungi afforded various derivatives, which were important resources for developing LSD1 inhibitors and potential application in cancer treatment