USP11 promotes renal tubular cell pyroptosis and fibrosis in UUO mice via inhibiting KLF4 ubiquitin degradation.

The pyroptosis of renal tubular epithelial cells leads to tubular loss and inflammation and then promotes renal fibrosis. The transcription factor Krüppel-like factor 4 (KLF4) can bidirectionally regulate the transcription of target genes. Our previous study revealed that sustained elevation of KLF4 is responsible for the transition of acute kidney injury (AKI) into chronic kidney disease (CKD) and renal fibrosis. In this study, we explored the upstream mechanisms of renal tubular epithelial cell pyroptosis from the perspective of posttranslational regulation and focused on the transcription factor KLF4. Mice were subjected to unilateral ureteral obstruction (UUO) surgery and euthanized on D7 or D14 for renal tissue harvesting. We showed that the pyroptosis of renal tubular epithelial cells mediated by both the Caspase-1/GSDMD and Caspase-3/GSDME pathways was time-dependently increased in UUO mouse kidneys. Furthermore, we found that the expression of the transcription factor KLF4 was also upregulated in a time-dependent manner in UUO mouse kidneys. Tubular epithelial cell-specific Klf4 knockout alleviated UUO-induced pyroptosis and renal fibrosis. In Ang II-treated mouse renal proximal tubular epithelial cells (MTECs), we demonstrated that KLF4 bound to the promoter regions of Caspase-3 and Caspase-1 and directly increased their transcription. In addition, we found that ubiquitin-specific protease 11 (USP11) was increased in UUO mouse kidneys. USP11 deubiquitinated KLF4. Knockout of Usp11 or pretreatment with the USP11 inhibitor mitoxantrone (3 mg/kg, i.p., twice a week for two weeks before UUO surgery) significantly alleviated the increases in KLF4 expression, pyroptosis and renal fibrosis. These results demonstrated that the increased expression of USP11 in renal tubular cells prevents the ubiquitin degradation of KLF4 and that elevated KLF4 promotes inflammation and renal fibrosis by initiating tubular cell pyroptosis.

Changes in physicochemical and gut microbiota fermentation property induced by acetylation of polysaccharides from Cyperus esculentus.

In this study, the impact of acetylation on physicochemical, digestive behavior and fermentation characteristics of Cyperus esculentus polysaccharides (CEP) was investigated. Results indicated that the acetylation led the molecules to be more likely aggregated, followed by a higher crystallinity, a lower apparent viscosity and a higher ratio of G" to G' (tan δ). Importantly, the acetylated polysaccharides (ACEP) had a lower digestibility, but its molecular weight was lower than that of original polysaccharides (CEP) following a simulated saliva-gastrointestinal digestion. Gut microbiota fermentation indicated that both polysaccharides generated outstanding short-chain fatty acids (SCFAs), in which the acetylated polysaccharides had a faster fermentation kinetics than the original one, followed by a quicker reduction of pH and a more accumulation of SCFAs, particularly butyrate. Fermentation of both polysaccharides promoted Akkermansia, followed by a reduced richness of Klebsiella. Importantly, the current study revealed that the fermentation of acetylated polysaccharides enriched Parabacteroides, while fermentation of original ones promoted Bifidobacterium, for indicating their individual fermentation characteristics and gut environmental benefits.

Structurally manipulated antioxidant peptides derived from wheat bran: Preparation and identification.

Bioactive peptide's development is facing two challenges in terms of its lower yield and limited understanding of structurally orientated functionality. Therefore, peptides were prepared from wheat bran via a cocktail enzyme for achieving a higher level of hydrophobic amino acids than traditional method. The obtained peptides exhibited great antioxidant activities against H2O2-induced oxidative stress in HepG2 cells. Among them, 91 bioactive peptides were selected through the virtual screening, and their N-terminal and C-terminal contained many hydrophobic amino acids. Then the peptides with capacity to interact with Keap1 were identified by in silico simulation, because Keap1 acts as a sensor of redox insults. The results revealed that peptides DLDW and DLGL demonstrated the highest binding affinities, and a bridge was formed between Asp of DLGL and Arg415 of Klech domain, contributing to interfering Keap1-Nrf2 interaction. These findings implied a potential application of wheat bran peptides as nutraceuticals and health-promoting ingredients.