RESUMEN
Introduction: Febuxostat is a novel inhibitor of xanthine oxidase that suppresses cell adhesion molecules-mediated (CAMs) inflammation by activating KLF6. In this study, we explored the therapeutic function and potential mechanisms of febuxostat against allergic rhinitis (AR). Methods: We investigated the role of febuxostat through in vitro cell and in vivo animal experiments. Human nasal epithelial cells (hNECs) were cultured with histamine as an in vitro model. To establish the AR animal model, rats were exposed to ovalbumin. Rats were randomly grouped into control, model, 7.5 mg/kg febuxostat, and 15 mg/kg febuxostat groups. Results: In the in vitro study, we found significantly increased release of lactate dehydrogenase, elevated production of inflammatory factors and chemokines, and upregulated CAMs in histamine-treated hNECs. However, these results were significantly reversed for the 10 and 20 µM febuxostat treatments. The enhanced adhesion between hNECs and monocytes induced by histamine was dramatically repressed by febuxostat. In the vivo experiments, we observed that febuxostat ameliorated the increased sneezing times, the number of nose scratching episodes, and elevated HE pathological scores as well as alleviated the inflammation in nasal mucous tissues of AR mice. We found that KLF6, which was downregulated in histamine-treated hNECs, was significantly upregulated by febuxostat. The inhibitory effects of febuxostat on the expression levels of CAMs and adhesion between histamine-treated hNECs and monocytes were significantly abolished by the knockdown of KLF6. Conclusion: Febuxostat alleviates AR by inhibiting inflammation and monocyte adhesion in human nasal epithelial cells through the regulation of KLF6.
RESUMEN
Pyracantha fortuneana fruits are consumed as a dietary supplement in China and attenuate obesity and metabolic disorders. Obesity is known to be associated with intestinal barrier dysfunction driven by hyperglycemia and gut dysbiosis. However, whether the health benefits of P. fortuneana fruits are linked with the intestinal barrier function (IBF) remains unknown. This study aimed to evaluate the restorative effects of P. fortuneana fruit extract (PFE) on the IBF. Sprague Dawley rats were fed with a chow, a high-fat diet (HFD), or a PFE-supplemented diet for 8 weeks. Results showed that PFE intervention ameliorated HFD-induced intestinal barrier dysfunction by attenuating impaired structural integrity, reducing the elevated lactulose/mannitol ratio, and improving the mRNA and protein expression levels of tight junction proteins in HFD-fed rats. The ameliorations were associated with a beneficial effect on glycolipid homeostasis, as evidenced from the PFE decreasing intestinal absorptive capacity based on the d-xylose excretory rate, lowering the expression of GLUT2 and inhibiting digestive enzyme activities. The proanthocyanidins in the PFE showed greater in vitro inhibition on α-amylase, α-glucosidase, and lipase compared with triterpenoid saponins. Furthermore, the ameliorations on the IBF were also associated with effects on the microbial composition based on 16S rRNA gene sequence analysis. Several bacterial groups, which were linked with gut barrier integrity, were modulated after PFE administration, that is, Actinobacteria, Bacteroidaceae, Corynebacteriaceae, Lactobacillaceae, and S24-7 were elevated and the HFD-induced increase in Clostridia, Ruminococcaceae, Oscillospira, and Flexispira was restored. These data provide evidence for the ameliorative effect of the PFE on diet-induced intestinal barrier functional alternations in association with its capacity to modulate glycolipid digestion and gut microbiota in HFD-fed obese rats.