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Hypoglycemic medications that could be coadministered with prebiotics and functional foods can potentially reduce the burden of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM). The efficacy of drugs such as metformin and sulfonylureas can be enhanced by the activity of the intestinal microbiome elaborated metabolites. Functional foods such as prebiotics (e.g., oligofruc tose) and dietary fibers can treat a dysbiotic gut microbiome by enhancing the diversity of microbial niches in the gut. These beneficial shifts in intestinal microbiome profiles include an increased abundance of bacteria such as Faecalibacterium prauznitzii, Akkermancia muciniphila, Roseburia species, and Bifidobacterium species. An important net effect is an increase in the levels of luminal SCFAs (e.g., butyrate) that provide energy carbon sources for the intestinal microbiome in crossfeeding activities, with concomitant improvement in intestinal dysbiosis with attenuation of inflammatory sequalae and improved intestinal gut barrier integrity, which alleviates the morbidity of T2DM. Oligosaccharides administered adjunctively with pharmacotherapy to ameliorate T2DM represent current plausible treatment modalities. [ABSTRACT FROM AUTHOR]

The interaction of histidine-rich glycoprotein (HRG) with human IgG and Clq as well as its role in the formation of insoluble immune complexes were investigated. Enzyme-linked immunosorbent assay (ELISA) and IAsys resonant mirror biosensor results have shown that physiological concentrations of HRG binds strongly to Clq and to IgG. Furthermore, HRG inhibits the formation of insoluble immune complexes (IIC).

The complement receptor Ig (CRIg) is selectively expressed by macrophages. This receptor not only promotes the rapid phagocytosis of bacteria by macrophages but also has anti-inflammatory and immunosuppressive functions. Previous findings have suggested that protein kinase C (PKC) may be involved in the regulation of CRIg expression in human macrophages. We have now examined the role of PKCα in CRIg expression in human monocyte-derived macrophages (MDM). Macrophages nucleofected with plasmid containing short hairpin RNA against PKCα showed markedly reduced expression of PKCα, but normal PKCζ expression, by Western blotting analysis, and vice versa. PKCα-deficient MDM showed increased expression of CRIg mRNA and protein (both the long and short form), an increase in phagocytosis of complement-opsonized Candida albicans, and decreased production of TNF-α and IL-6. TNF-α caused a marked decrease in CRIg expression, and addition of anti-TNF mAb to the TNF-α–producing MDMs increased CRIg expression. PKCα-deficient macrophages also showed significantly less bacterial LPS-induced downregulation of CRIg. In contrast, cells deficient in PKCα showed decreased expression of CR type 3 (CR3) and decreased production of TNF-α and IL-6 in response to LPS. MDM developed under conditions that increased expression of CRIg over CR3 showed significantly reduced production of TNF-α in response to opsonized C. albicans. The findings indicate that PKCα promotes the downregulation of CRIg and upregulation of CR3 expression and TNF-α and IL-6 production, a mechanism that may promote inflammation. [ABSTRACT FROM AUTHOR]

Histidine-rich glycoprotein (HRG) is an abundant serum protein that exhibits many functions in diverse biological systems. In this study, we show that HRG potentiates the ingestion of apoptotic cells by mature human monocyte-derived macrophages (HMDM). HRG bound specifically to apoptotic Jurkat cells and mature HMDM in a saturable and concentration-dependent manner. Purified HRG or HRG in sera increased the number of HMDM-containing apoptotic cells and accelerated the ingestion, while neutralization or depletion of HRG from sera reduced this effect. Anti-FcgammaRI mAb inhibited HRG binding to HMDM, while DNA, but not chromatin, inhibited HRG binding to apoptotic cells, and either anti-FcgammaRI or DNA abrogated the HRG-dependent ingestion. The findings indicate that HRG, by acting as a bridge between DNA on apoptotic cells and FcgammaRI on HMDM, is a key physiological mediator of apoptotic cell clearance by macrophages.