ABSTRACT
The study was devoted to identifying the relation between vitamin D3 availability (assessed by the level of circulatory 25OHD3), content of vitamin D3 25-hydroxylase isozymes CYP27A1 and CYP2R1 in hepatic tissue and functional activity of peripheral blood phagocytes in mice with experimental type 1 diabetes. It has been shown that diabetes is accompanied by the development of vitamin D3-deficiency which is characterized by decreased 25OHD3 content in blood serum and determined by changes in tissue expression of the major isoforms of vitamin D3 25-hydroxylase. The level of hepatic CYP27A1 was revealed to be markedly reduced with a concurrent significant augmentation of CYP2R1. Cholecalciferol administration resulted in normalization of tissue levels of both isoforms of vitamin D3 25-hydroxylase and blood serum 25OHD3 content. Diabetes-associated vitamin D3 deficiency correlated with a decrease in phagocytic activity of granulocytes and monocytes, and their ability to produce antibacterial biooxidants such as reactive oxygen and nitrogen forms. Vitamin D3 efficacy to attenuate these abnormalities of immune function was established, indicating an important immunoregulatory role of cholecalciferol in the phagocytic mechanism of antigens elimination implemented by granulocytes and monocytes.
Subject(s)
Cholecalciferol/blood , Cholestanetriol 26-Monooxygenase/metabolism , Diabetes Mellitus, Experimental/immunology , Granulocytes/immunology , Monocytes/immunology , Vitamin D Deficiency/immunology , Animals , Cholecalciferol/administration & dosage , Cholestanetriol 26-Monooxygenase/genetics , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/enzymology , Escherichia coli/immunology , Gene Expression , Granulocytes/drug effects , Liver/drug effects , Liver/enzymology , Liver/immunology , Male , Mice , Mice, Inbred C57BL , Monocytes/drug effects , Phagocytosis/drug effects , Reactive Nitrogen Species/immunology , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/immunology , Reactive Oxygen Species/metabolism , Streptozocin , Vitamin D Deficiency/complications , Vitamin D Deficiency/drug therapy , Vitamin D Deficiency/enzymologyABSTRACT
The mechanisms of glucocorticoid-induced disturbances of liver function is currently not fully clarified. Vitamin D3 was previously shown to play an important role in the regulation of impaired oxidative metabolism and detoxification function of the liver associated with the effects of hepatotoxic compounds. The study was undertaken to define the intensity of oxidative metabolism in the rat liver and survival of hepatocytes after prolonged prednisolone administration and to assess whether vitamin D3 is capable to counter glucocorticoid-induced changes. It has been shown that prednisolone (0.5 mg per animal for 30 days) leads to 1.6-fold increase in the percentage of necrotic cells among isolated hepatocytes as compared with the control. The glucocorticoid-induced impairment of hepatocellular function was accompanied by enhanced generation of reactive oxygen species (ROS), accumulation of TBA-active products and carbonylated proteins but reduced levels of free SH-groups of low molecular weight compounds. It was demonstrated a decrease in the activities of key enzymes of antioxidant system (SOD, catalase, glutathione peroxidase), whereas the activities of pro-oxidant enzymes NAD(P)H-quinone oxidoreductase and semicarbazide-sensitive amine oxidase were shown to be increased. Vitamin D3 (and to greater extent in combination with α-tocopherol) administration (100 IU) on the background of glucocorticoid therapy caused normalizing effects on the level of ROS formation, oxidative modification of biomolecules and activity of antioxidant enzymes resulting in better survival of hepatocytes. These data suggest a potential role of vitamin D3 in the regulation of oxidative metabolism alterations related to hepatotoxic action of glucocorticoids.
Subject(s)
Cholecalciferol/pharmacology , Hepatocytes/drug effects , Liver/drug effects , Prednisolone/pharmacology , Reactive Oxygen Species/metabolism , alpha-Tocopherol/pharmacology , Amine Oxidase (Copper-Containing)/metabolism , Animals , Catalase/metabolism , Female , Glutathione/metabolism , Glutathione Peroxidase/metabolism , Hepatocytes/cytology , Hepatocytes/metabolism , Liver/cytology , Liver/metabolism , Male , Necrosis/chemically induced , Necrosis/pathology , Necrosis/prevention & control , Prednisolone/antagonists & inhibitors , Primary Cell Culture , Protein Carbonylation/drug effects , Quinone Reductases/metabolism , Rats , Rats, Wistar , Reactive Oxygen Species/antagonists & inhibitors , Superoxide Dismutase/metabolism , Thiobarbiturates/metabolismABSTRACT
The aim of this study was to determine the effectiveness of separate and combined administration of vitamin D3 and different forms of bisphosphonate (disodium salt of methylenbisphosphonic acid dihydrate and alendronate) on the function of immune cells in rats with nutritional osteoporosis. It was shown that D-hypovitaminosis leads to reduced 25OHD3, which is a biomarker for vitamin D3 and disturbances of metabolic processes in bone tissue that correlated with osteoporosis manifestation. Immunologic disorders related to nutritional osteoporosis were accompanied by the decrease in phagocytic activity of granulocytes and impaired ability to produce bactericidal oxidants. Inhibition of B-cell immunity also occurred in patholgy. Thus, the present study revealed more pronounced immunomodulatory effects of vitamin D3 on phagocytic immunity, whereas bisphosphonates were effective in improving the humoral immune protection.
