ABSTRACT
Circulatory markers of low-grade inflammation such as tumor necrosis factor-alpha (TNF-α), interleukin-1 alpha (IL-1α), and interleukin-1 beta (IL-1ß) positively correlate with endothelial damage, atheroma formation, cardiovascular disease, and aging. The natural vitamin K2-menaquinone-7 (MK-7) added to the cell culture of human monocyte-derived macrophages (hMDMs) at the same time as toll-like receptor (TLR) agonists did not influence the production of TNF-α. When the cells were pretreated up to 6 h with MK-7 before treatment with TLR agonists, MK-7 did not inhibit significantly the production of TNF-α after the TLR activation. However, 30 h pretreatment of hMDMs with at least 10 µM of MK-7 effectively and dose dependently inhibited the proinflammatory function of hMDMs. Pretreatment of hMDMs with 10 µM of MK-7 for 30 h resulted in 20% inhibition of TNF-α production after lipopolysaccharide (LPS) activation (P < .05) and 43% inhibition after macrophage-activating lipopeptide (MALP) activation (P < .001). Pathogen-associated molecular pattern (PMPP) activation was inhibited by 20% with MK-7 pretreatment; however, this inhibition was not statistically significant. The 30 h pretreatment of a THP-1-differentiated monocyte cell line with MK-7 resulted in a dose-dependent downregulation of TNFα, IL-1α, and IL-1ß gene expression as evaluated by RNA semiquantitative reverse transcription polymerase chain reaction (RT-PCR). MK-7 is able to modulate immune and inflammatory reactions in the dose-response inhibition of TNF-α, IL-1α, and IL-1ß gene expression and protein production by the healthy hMDMs in vitro.
Subject(s)
Interleukin-1alpha/antagonists & inhibitors , Interleukin-1beta/antagonists & inhibitors , Macrophages/drug effects , Toll-Like Receptors/agonists , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Vitamin K 2/analogs & derivatives , Anti-Inflammatory Agents , Cell Line , Gene Expression/drug effects , Humans , Interleukin-1alpha/genetics , Interleukin-1beta/genetics , Lipopolysaccharides/pharmacology , Tumor Necrosis Factor-alpha/genetics , Vitamin K 2/pharmacologyABSTRACT
Vitamin K occurs widely in foods and has been shown to have a beneficial effect on the cardiovascular system, as well as anticancer, anti-inflammatory, and antiosteoporosis properties. A previous study indicates that long-chain menaquinone-7 may be more bioavailable than vitamin K and short-chain menaquinones. In the present study, acute, subacute toxicity and genotoxicity assays were carried out to evaluate the safety of oral menaquinone-7 in albino Wistar rats. Oral administration of menaquinone-7, at a concentration of 2000 mg/kg, did not cause toxic symptoms in either male or female rats. A subacute toxicity study also proved the safety and tolerance of prolonged treatment (for 90 days) with menaquinone-7 in rats, as evidenced by biochemical, hematological, and urine parameters as well as by histopathological analysis. Genotoxicity and mutagenicity studies were performed by comet, micronucleus, and Ames tests on Salmonella typhimurium strains, which showed cellular safety and nonmutagenicity of menaquinone-7. The results indicate the safety of menaquinone-7 for human consumption.
