Vanadium, abbreviated V, is an early transition metal that readily forms coordination complexes with a variety of biological products such as proteins, metabolites, membranes and other structures. The formation of coordination complexes stabilizes metal ions, which in turn impacts the biodistribution of the metal. To understand the biodistribution of V, V in oxidation state IV in the form of vanadyl sulfate (25, 50, 100 mg V daily) was given orally for 6 weeks to 16 persons with type 2 diabetes. Elemental V was determined using Graphite Furnas Atomic Absorption Spectrometry against known concentrations of V in serum, blood or urine. Peak serum V levels were 15.4±6.5, 81.7±40 and 319±268 ng/ml respectively, and mean peak serum V was positively correlated with dose administered (r=0.992, p=0.079), although large inter-individual variability was found. Total serum V concentration distribution fit a one compartment open model with a first order rate constant for excretion with mean half times of 4.7±1.6 days and 4.6±2.5 days for the 50 and 100 mg V dose groups respectively. At steady state, 24 hour urinary V output was 0.18±0.24 and 0.97±0.84 mg in the 50 and 100 mg V groups respectively, consistent with absorption of 1 percent or less of the administered dose. Peak V in blood and serum were positively correlated (r=0.971, p<0.0005). The serum to blood V ratio for the patients receiving 100 mg V was 1.7±0.45. Regression analysis showed that glycohemoglobin was a negative predictor of the natural log (ln) peak serum V (R2=0.40, p=0.009) and a positive predictor of the euglycemic hyperinsulinemic clamp results at high insulin values (R2=0.39, p=0.010). Insulin sensitivity measured by euglycemic hyperinsulinemic clamp was not significantly correlated with ln peak serum V. Globulin and glycohemoglobin levels taken together were negative predictors of fasting blood glucose (R2=0.49, p=0.013). Although V accumulation in serum was dose-dependent, no correlation between total serum V concentation and the insulin-like response was found in this first attempt to correlate anti-diabetic activity with total serum V. This study suggests that V pools other than total serum V are likely related to the insulin-like effect of this metal. These results, obtained in diabetic patients, document the need for consideration of the coordination chemistry of metabolites and proteins with vanadium in anti-diabetic vanadium complexes.
with vanadium, a representative of a class of antidiabetic compounds, alleviates diabetic hyperglycemia and hyperlipidemia. Oral administration of vanadium compounds in animal models and humans does not cause clinical symptoms of hypoglycemia, a common problem for diabetic patients with insulin treatment. Gene expression, using Affymetrix arrays, was examined in muscle from streptozotocin-induced diabetic and normal rats in the presence or absence of oral vanadyl sulfate treatment. This treatment affected normal rats differently from diabetic rats, as demonstrated by two-way ANOVA of the full array data. Diabetes altered the expression of 133 genes, and the expression of 30% of these genes dysregulated in diabetes was normalized by vanadyl sulfate treatment. For those genes, the ratio of expression in normal animals to the expression in diabetic animals showed a strong negative correlation with the ratio of expression in diabetic animals to the expression in diabetic animals treated with vanadyl sulfate (P ϭ Ϫ0.85). The genes identified belong to six major metabolic functional groups: lipid metabolism, oxidative stress, muscle structure, protein breakdown and biosynthesis, the complement system, and signal transduction. The identification of oxidative stress genes, coupled with the known oxidative chemistry of vanadium, implicates reactive oxygen species in the action of this class of compounds. These results imply that early transition metals or compounds formed from their chemical interactions with other metabolites may act as general transcription modulators, a role not usually associated with this class of compounds. vanadium; microarray; streptozotocin EARLY TRANSITION METALS and their complexes represent a unique class of antidiabetic agents. Specific lowering of diabetic hyperglycemia has been obtained by treatment with chromium (1, 13), tungsten (17), molybdenum (36, 50), and vanadium (V) compounds, with the later the most extensively studied. Although V was first used to treat diabetic patients in 1899 (33), the detailed mechanism of its antidiabetic action remains unclear. Inhibition of phosphotyrosine phosphatase (PTP)-1B is one mechanism by which V compounds may alleviate diabetic symptoms (16); however, alternative mechanisms could also be important contributors. Oral administration of V alleviates symptoms of diabetes in humans (9,14,15,23) and rodents (25, 35) without causing any clinical symptoms of hypoglycemia, although blood glucose levels are slightly lowered in normal animals by V treatment. This differential effect on normal (N) and diabetic (D) animals is seen with many other metabolic processes. For example, diabetic hyperlipidemia is significantly lowered by vanadyl sulfate (VS) treatment, whereas serum lipid levels in N animals are not substantially reduced by VS treatment (35). Given the importance of tight control of blood glucose levels in the diabetic patient, this class of compounds is a promising alternative for the treatment of diabetes.Various strategies are being explored to lo...
Endometriosis is a debilitating disease estimated to affect 10% of reproductive-age women and characterized by the growth of endometrial tissue outside of the uterus. The present study characterizes a human endometrial explant culture model for studying the direct effects of TCDD exposure by assessing the expression of CYP1A1 and CYP1B1 mRNA (Northern blotting), protein (Western blotting), and activity (7-ethoxyresorufin-O-deethylase; EROD) in explants cultured with and without TCDD. Explants were obtained at laparoscopy or laparotomy from women undergoing surgery for tubal ligation, endometriosis, or pelvic pain unrelated to endometriosis. The explants were cultured with 10 nM estradiol (E(2)) or 1 nM E(2) plus 500 nM progesterone (P(4)) with or without TCDD (first 24 h). The expression of CYP1A1 and CYP1B1 mRNA was greatest with 10 nM TCDD and increased up to 72 h after initial exposure. EROD activity increased up to 120 h. Explants from a secretory phase biopsy became reorganized in culture and formed a new epithelial membrane, while maintaining basic endometrial morphology and viability for up to 120 h. At 24 h, TCDD significantly increased CYP1A1 and CYP1B1 mRNA, and at 72 h, TCDD significantly increased EROD activity and CYP1B1 protein compared to explants cultured without TCDD for similar times. CYP1B1 protein also exhibited substantial constitutive expression that was similar in uncultured biopsies, where CYP1B1 protein was immunolocalized in the cytoplasm of epithelial glands, with only occasional patches of protein in the surface epithelial membrane. In explants cultured with and without TCDD exposure, CYP1B1 protein was localized in the cytoplasm of the new surface epithelial membrane and glands closest to the surface. CYP1A1 protein was not detected in uncultured biopsies or explants. Both younger age (age 30 and under) and proliferative phase were associated with higher TCDD-induced EROD activity in specimens treated with E(2):P(4). No significant endometriosis-related differences were observed for any of the biomarkers, but the detection of disease-specific change was limited by small sample size and variability in tissue-cycle phase. The human endometrial explant culture model will be useful for future studies of the effects of dioxin-like compounds on human endometrium in relationship to cycle phase and hormonal exposure.
It is known that styrene is ototoxic and causes cochlear damage starting from the middle turn. However, the cellular mechanism underlying styrene ototoxicity is still unclear. In this study, rats were exposed to styrene by gavage at different doses once a day for varying periods. Styrene levels in the cochlear tissues, styrene-induced permanent hearing loss, cochlear disruptions, and cell death pathways were determined. Styrene concentration in the cochlea varied along with the basilar membrane with the lowest level in the basal turn being consistent with the lowest styrene-induced threshold shift and hair cell loss in this region. After 3 weeks of exposure (5 days per week), a dose-dependent permanent hearing loss and a hair cell loss, especially in the midfrequency region, were observed. The styrene exposure at a dose of 200 mg/kg, which induced a blood level of 6.0 +/- 1.0 microg/g, caused an average of 4.4 +/- 0.5% OHC (outer hair cell) loss and 2-5 dB threshold shift in the cochlear region of 20-70% from the apex. A significant OHC loss was not observed until 7 days of exposure at a dose of 800 mg/kg. Deiters cells appeared to be the most vulnerable target of styrene. When condensed nuclei were observed in Deiters cells after a few days of styrene exposure (800 mg/kg), other cells were still intact. Apoptotic cell death appeared to be the main cell death pathway in the cochlea after styrene exposure. In the styrene-induced apoptotic OHCs, histochemical staining detected activated caspases-9 and 8, indicating that both mitochondrial-dependent pathway and death receptor-dependent pathway were involved in the styrene-induced cell death.
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