Abstract
Systemic low-grade inflammation and increased circulating lipopolysaccharide (LPS) contribute to metabolic dysfunction. The inhibitory effects and underlying molecular mechanisms of casein glycomacropeptide (GMP) hydrolysate on the inflammatory response of LPS-stimulated macrophages were investigated. Results showed that the inhibitory effect of GMP hydrolysates obtained with papain on nitric oxide (NO) production were obviously higher than that of GMP hydrolysates obtained with pepsin, alcalase and trypsin (p < 0.05), and the hydrolysate obtained with papain for 1 h hydrolysis (GHP) exhibited the highest inhibitory effect. Compared with native GMP, GHP markedly inhibited LPS-induced NO production in a dose-dependent manner with decreased mRNA level of inducible nitric oxide synthase (iNOS). GHP blocked toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway activation, accompanied by downregulation of LPS-triggered significant upregulation of tumor necrosis factor (TNF)-α and interleukin (IL)-1β gene expression. Furthermore, GHP could neutralize LPS not only by direct binding to LPS, but also by inhibiting the engagement of LPS with the TLR4/MD2 complex, making it a potential LPS inhibitor. In conclusion, these findings suggest that GHP negatively regulates TLR4-mediated inflammatory response in LPS-stimulated RAW264.7 cells, and therefore may hold potential to ameliorate inflammation-related issues.
Highlights
Low-grade systemic inflammation is considered a hallmark of several metabolic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) [1,2,3].Recent insight suggests that an altered composition and diversity of gut microbiota plays an important role in the development of this low-grade inflammatory state
Previous studies have shown that almost all tumor necrosis factor (TNF)-α and significant amounts of inducible nitric oxide synthase existing in adipose tissue were secreted by adipose tissue macrophages in obese subjects [9,10]
To determine and compare the inhibitory activity of GMP hydrolysates on inflammatory responses in LPS-stimulated RAW264.7 macrophages, the effects of GMP hydrolysates prepared by alcalase, pepsin and papain for different periods on LPS-stimulated nitric oxide (NO) production were measured (Figure 1A)
Summary
Low-grade systemic inflammation is considered a hallmark of several metabolic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) [1,2,3].Recent insight suggests that an altered composition and diversity of gut microbiota plays an important role in the development of this low-grade inflammatory state. Continuous subcutaneous LPS infusion, which was coupled with increased expression of toll-like receptor (TLR) 4 and nuclear factor-κB (NF-κB) in mononuclear cells, resulted in elevated secretion of pro-inflammatory mediators, such as nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin (IL)-1β [5,6]. These chemicals, in turn, serve as endogenous mediators of inflammation to trigger insulin resistance, which will favor hyperlipidemia [7].
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