The protective effect of puerarin-loaded mesoporous silicon nanoparticles on alcoholic hepatitis through mTOR-mediated autophagy pathway.

Puerarin, a bioactive flavone compound isolated from Pueraria (Wild.), provides hepatoprotection by anti-inflammatory, anti-alcoholism, and regulating mechanistic target of rapamycin (mTOR). Building evidence suggests that the activation of mTOR reduces liver injuries associated with alcohol consumption and metabolism. However, the poor water solubility, low bioavailability, and short half-life of puerarin hinder its clinical application. The utility of mesoporous silicon nanoparticles (MSNs) can improve traditional Chinese medicine limitations. Stober methods were used to fabricate MSNs@Pue, and the size, zeta potentials and drug encapsulation efficiency were characterized by a series of analytical methods. IVIS Imaging System demonstrated liver-targeted bio-distribution, and then high-throughput sequencing, immunoproteomics and ultrastructure methods indicated autophagy related protective mechanism, followed by curative effect evaluation for the treatment efficacy. An acute-on chronic ethanol-drinking according to Gao-binge model induced alcoholic hepatitis (AH) pathology and resulted in hepatic hyper-autophagy, which was improved with MSNs@Pue administration (puerarin: 30 mM, 42 mg/kg; intravenously [i.v.]). Ethanol-fed mice were found to have increased expression of autophagy-related proteins (Atg3, Atg7, LC3 and p62). In contrast, MSNs@Pue administration significantly decreased the expression of these proteins and alleviated fatty droplets infiltration in damaged liver. Furthermore, acute-on-chronic ethanol feeding also resulted in the activiation of ERK activation and mTOR expression, which were reversed with MSNs@Pue administration and better than the usage of puerarin alone. Results point to MSNs@Pue mediated ERK/mTOR signaling pathway activation as a possible protective strategy to improve AH, which provides a strategy and evidence for treating liver disease using an MSN delivery system.

Protective effects of tranilast on oxazolone-induced rat colitis through a mast cell-dependent pathway.

BACKGROUND: Mast cells in the gut play an important role in the innate and adaptive immune responses that are relevant to human inflammatory bowel disease. However, the contribution of mast cells to the development of inflammatory bowel disease is not well understood. This study aimed to determine the role of mast cells in oxazolone-induced colitis and to explore whether the mast cell membrane stabiliser tranilast could ameliorate colonic inflammation. METHODS: Wild-type rats and mast cell-deficient rats were sensitised and challenged with oxazolone, then treated with tranilast after challenge. Controls were treated with saline. RESULTS: Mast cell-deficient rats presented a weak response to oxazolone, while wild-type rats showed severe ulcerative colitis after stimulation with oxazolone. The mast cell-deficient rats model had a significantly lower disease activity index score than wild-type rats model (1.8±1.64 vs. 8.3±0.58 respectively; P<0.01). Tranilast could reduce the secretion of cytokines, immunoglobulins and myeloperoxidase activity in tranilast treatment groups compared with the model group. The number of mast cells in the wild-type model was higher than in the other groups. There was no significant change in mast cell-deficient rats. CONCLUSION: Mast cells play an important role in oxazolone-induced colitis. The mast cell membrane stabiliser tranilast can ameliorate oxazolone-induced colitis via a mast cell-dependent pathway.