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Abstract
Advanced glycation end-products (AGEs) are studied extensively for their detrimental effects on health. This is largely due to their pro-inflammatory and oxidative characteristics. AGEs can generate a non-specific pro-inflammatory stress on various organs including the immune system, and lead to diseases associated with diet. Surprisingly, little is known about their homologous product, the early glycation products (EGPs). Existing literature show that EGPs exhibit desirable physiochemical properties, which might improve food quality. Thus, understanding the physiologic effects of EGPs could impact their use in food. In this study, the immunoregulatory effects of EGPs were investigated. A food model system was established to produce dietary EGPs and AGEs, and they were studied with the non-reacted mixture employed as control. EGPs at 10 mg/ml in vitro did not inhibit cell viability of human macrophages. Interestingly, EGPs activated macrophages denoted by a general increase in cytokine/chemokine levels with IL-10 and CCL4 being the most up-regulated, suggesting that EGPs have an anti-inflammatory effect. In contrast, AGEs exposure under the same conditions largely decreased the cell viability.To further explore the immunomodulatory effects of EGPs during disease, prostate cancer (PCa) and type 1 diabetes (T1D) animal models were employed. C57BL/6 male mice were subcutaneously transplanted with TRAMP-C2 cells, and EGP gavage (600 mg/kg body weight/day) enhanced PCa cell growth more than AGEs, with the tumor-associated macrophages displaying an M2 polarized phenotype. Further, this effect was enhanced by co-injecting macrophages with the TRAMP-C2 cells. This EGP-driven M2 pre-dominant phenotype was reproduced in a human macrophage-PCa cell (LNCaP) co-culture system. In T1D studies, EGPs decreased the T1D incidence, non-fasting blood glucose levels, insulin resistance, pancreatic immune infiltration, and increased glucose metabolism in NOD mice. These protective effects were accompanied by decreased CD8+ T cells and serum insulin autoantibody levels, and increased splenic CD4+CD25+ T cells, macrophage M2/M1 ratio and serum IL-10 level. This would suggest that EGPs might be beneficial for individuals with T1D or insulitis, but detrimental to PCa patients at advanced stages. Sub-chronic intake of EGPs could have various impacts on human health, and the effect might depend on individuals health and disease status.