Brusatol

Papillary renal cell carcinoma (pRCC) is the second most frequent renal cancer subtype but has no indicated targeted treatments. MET inhibition may be a treatment for MET‐driven pRCC, but there is a large group of non‐MET‐driven pRCC without targeted therapy. Activation of NRF2‐ARE pathway has been suggested to be involved in pRCC. To study the relevance of the NRF2‐ARE pathway, we characterized 60 pRCCs by copy number analysis and Whole Exome Sequencing. Because stabilisation of NRF2 results in enhanced expression of NQO1, a reductase that prevents production of reactive oxygen species, protein expression of NQO1 was analysed by immunohistochemistry (IHC) from tissue microarrays (TMAs) and by enzymatic activity assay. Finally, patient‐derived pRCC cells (PDCs) were applied for drug profiling with 18 NRF2‐ARE pathway inhibitors. We identified MET mutations in 5%, and mutations in four genes of NRF2‐ARE pathway (NFE2L2, KEAP1, CUL3 and BACH1) in 10% of 60 pRCC samples. IHC analysis of TMAs of 638 renal cancers showed the correlation of the expression of NQO1 with poor survival outcome (p < .001) and high tumour grade (p < .001) and stage (p < .001) in pRCC. NQO1 mRNA, protein levels and enzymatic activity were increased in 56% of matched pRCC tissue samples and patient‐derived cells (PDCs, n = 9). Drug screening revealed that Brusatol and Convallatoxin are potential novel drugs for pRCC. Inhibition of NRF2 represents a novel therapeutic approach for MET‐independent pRCC patients.

Brusatol (BR) is an active compounds isolated from Brucea javanica, a Chinese herbal medicine that is famous for its anti-diarrheal effect. We have previously reported that BR mitigated inflammation in murine ulcerative colitis (UC) models. However, BR's role in intestinal mucosal healing, which is recently established as central strategy for the prevention and treatment of UC, remains unknown. In this study, the ameliorative effect of BR on intestinal mucosal damage was investigated in DSS-induced UC mice. BR significantly alleviated colitis symptoms, improved intestinal barrier function by preventing loss of goblet cells and downregulation of mucins and tight junction proteins, as well as maintained proliferative and apoptotic homeostasis in the colonic epithelium of UC mice. Mechanistically, BR enhanced the level and secretion of IL-22, but inhibited IL-22BP, an inhibitory protein of IL-22, in the blood serum and intestinal tissues of UC mice, as well as in MNK3 cells which is an effective cell model for studying ILC3s. Additionally, BR elevated the expressions of receptors for IL-22 (IL-10R2 and IL-22R1), and activated its downstream STAT3 signaling pathway. Furthermore, the involvement of IL-22 was further investigated by using recombinant IL-22 (rIL-22) and IL-22 antibody (anti-IL-22). BR demonstrated comparable effects with rIL-22 on alleviating intestinal inflammation and repairing intestinal mucosal injury. Treatment with anti-IL-22 abrogated the mucosal protective effects of BR. The present findings shed novel insights into the role of BR in intestinal mucosal healing via activating IL-22/STAT3 signaling pathway in UC.