Antioxidant and ACE enhancing potential of Pankajakasthuri in fluoride toxicity: an in vitro study on mammalian lungs.

Fluoride toxicity occurs due to high concentrations of fluoride in water sources or anthropogenic causes. The aim of the present study was to investigate the effects of an Ayurvedic drug--Pankajakasthuri (PK)--in relation to fluoride-induced toxicity in mammalian lungs. The results indicated that sodium fluoride increased lipid peroxidation and decreased enzymatic and non-enzymatic antioxidants in a concentration-dependent manner in lungs. The antioxidant potential of the lungs was suppressed maximally at 10 ppm fluoride concentration and PK at all three dose levels (i.e., 100, 200 and 300 µl) decreased fluoride induced lipid peroxidation (p < 0.05) and increased the levels of total ascorbic acid, superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase and FRAP values significantly (p < 0.05) in a dose-dependent manner. When PK was examined for its effects on angiotensin-converting enzyme (ACE) activity, in fluoride-induced toxicity, the ACE activity was found to increase (p < 0.0001) in lung homogenates with all three doses. This study indicates that PK, an Ayurvedic drug, improves mammalian lung function by increasing antioxidant potential and ACE activity under the conditions of fluoride toxicity.

Activation of PERK signaling through fluoride-mediated endoplasmic reticulum stress in OS732 cells.

Our proteomical analysis of osteoblasts exposed to fluoride revealed a distinctive upregulation of proteins in osteoblast. These upregulated proteins play key roles in the protein folding. The PRK-like ER kinase (PERK) signaling, one branch of unfolded protein response (UPR) to combat ER stress, is a transcription factor needed for osteoblast proliferation and differentiation. The mechanism of skeletal fluorosis by which fluoride regulates osteoblast is not fully defined. Here we studied the effect of fluoride on PERK signaling genes and x-box binding protein 1 (xbp-1) in OS7232 cells (human osteoblast-like cell line). Meantime, genes associated with bone turnover were examined in this study. We found that early and continuous fluoride exposure increased the binding immunoglobulin protein (BiP) expression and activated the PERK signaling pathway, resulting in activation of transcription factor 4 (ATF4) and nuclear factor erythroid 2-related factor 2 (Nrf2). The altered expression of cbfa1, osteoprotegerin (OPG)/nuclear factor kappa B ligand (RANKL) were viewed in this study. These results showed fluoride impelled a distinctive ER stress response in OS732 cells, primarily by activating PERK and PERK-dependent signaling. Little effects were viewed for activating xbp-1, a common target of the other two canonical sensors of ER stress, ATF6 and IRE1. In this study the altered expression of bone turnover genes were consistent with activation of ER stress and PERK signaling. This study proved that PERK signaling play major roles in action of fluoride on osteoblast, and suggested that bone response in skeletal fluorosis may be due in part to PERK signaling pathway.

Comparative study of p38 MAPK signal transduction pathway of peripheral blood mononuclear cells from patients with coal-combustion-type fluorosis with and without high hair selenium levels.

Coal-combustion-type fluorosis has only been reported in China and its pathogenesis has not been fully understood. Fluoride causes chronic toxic effects and selenium modulates cellular activities through signal transduction in human cells. The present study enrolled three groups of subjects with well-defined serum and urine fluoride and hair selenium: high fluoride+high selenium group, high fluoride group and normal control group. The expressions of p38, NF-kB p65, caspase-3 and p53 genes at both protein and mRNA levels in peripheral blood mononuclear cells (PBMCs) were determined by Western blotting and quantitative real-time RT-PCR, respectively. The results showed that the expressions of p38, NF-kB p65, and caspase-3 protein in high fluoride group were higher than those in the other two groups. The mRNA level of NF-kB p65 and caspase-3 was significantly higher in high fluoride+high selenium group than control and lower than high fluoride group. The mRNA and protein level of p53 was significantly higher in high fluoride+high selenium group than that in other two groups. These results suggest that selenium may influence the protein and gene expression associated with p38 signal transduction pathway and up-regulate p53 expression in PBMCs from patients with coal-combustion-type fluorosis.

[Changes of coenzyme Q content in brain tissues of rats with fluorosis].

Animal models with pathological damage caused by chronic fluorosis to a different extent were duplicated in Wistar rats by feeding them with 66.3 mg/L and 221 mg/L fluorine-containing water for three, five and seven months, respectively. Cholesterol, dolichol and coenzyme Q in animal brain tissues were determined by high performance liquid chromatography. Results showed that no significant difference of cholesterol and dolichol contents in brian tissues between rats with fluorosis and normal controls were detected. Coenzyme Q content of brain tissue in rats fed with fluorine-containing water decreased at early stage of fluorosis, but increased significantly at late stage. It is speculated that changes in content of coenzyme Q could correlate with changes in free radical levels induced by fluorine.

Erythrocyte glutathione metabolism in human chronic fluoride toxicity.

Chronic exposure of humans to toxic levels of fluoride in drinking water resulted in significant increase in blood GSH content with significant increase in the activities of erythrocyte glutathione metabolising enzymes viz., gamma-glutamylcysteine synthetase (E.C. 6.3.2.2), gamma-glutamyltranspeptidase (E.C. 2.3.2.2), GST (E.C. 2.5.1.18), GSH-Px (E.C. 1.11.1.9) and GR (E.C. 1.6.4.2). The data suggested a form of adaptation on the part of the erythrocytes to counteract the oxidative stress in red blood cells of fluorotic patients.

[Non-skeletal forms of fluorosis]. / Neskeletnye formy fliuoroza

Concepts of nonskeletal forms of fluorosis are set forth in the light of the author's own investigations and reports in the available literature. Descriptions of pathology of the central nervous system, skeletal musculature, stomach, liver, kidney, cardiovascular system, retina, and the skin are presented. The evidences obtained indicate that disturbances in soft tissues in chronic intoxication with fluorine develop early, usually long before the onset of typical changes in teeth and skeletal bones; these changes characterize the preskeletal phase of fluorosis.

Changes of ion mobilizations and their related enzyme activities in the blood of fluoride-intoxicated rats.

Fluoride concentrations in plasma 3 hr after a single oral dose of NaF (5 mg/100 g body weight) were increased 26 times above the control, but the concentrations in erythrocytes and red cell membranes were increased only 1.8 and 1.5 times over the respective control levels. Ionic concentrations of magnesium and calcium in erythrocytes and their membranes were significantly changed by fluoride administration, but the ionic concentrations in plasma were not statistically changed in comparison with controls. Acid phosphatase activities in plasma and erythrocytes were significantly decreased by fluoride administration, but alkaline phosphatase activity in the plasma was not changed. Mg2+-activated ATPase activity was significantly elevated in the erythrocyte membrane by fluoride administration; (Na+ + K+)-activated ATPase activity was significantly decreased in the membrane.