Effects of vanadium complexes with organic ligands on glucose metabolism: a comparison study in diabetic rats.
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1. Vanadium compounds can mimic actions of insulin through alternative signalling pathways. The effects of three organic vanadium compounds were studied in non-ketotic, streptozotocin-diabetic rats: vanadyl acetylacetonate (VAc), vanadyl 3-ethylacetylacetonate (VEt), and bis(maltolato)oxovanadium (VM). A simple inorganic vanadium salt, vanadyl sulphate (VS) was also studied. 2. Oral administration of the three organic vanadium compounds (125 mg vanadium element 1(-1) in drinking fluids) for up to 3 months induced a faster and larger fall in glycemia (VAc being the most potent) than VS. Glucosuria and tolerance to a glucose load were improved accordingly. 3. Activities and mRNA levels of key glycolytic enzymes (glucokinase and L-type pyruvate kinase) which are suppressed in the diabetic liver, were restored by vanadium treatment. The organic forms showed greater efficacy than VS, especially VAc. 4. VAc rats exhibited the highest levels of plasma or tissue vanadium, most likely due to a greater intestinal absorption. However, VAc retained its potency when given as a single i.p. injection to diabetic rats. Moreover, there was no relationship between plasma or tissue vanadium levels and any parameters of glucose homeostasis and hepatic glucose metabolism. Thus, these data suggest that differences in potency between compounds are due to differences in their insulin-like properties. 5. There was no marked toxicity observed on hepatic or renal function. However, diarrhoea occurred in 50% of rats chronically treated with VS, but not in those receiving the organic compounds. 6. In conclusion, organic vanadium compounds, in particular VAc, correct the hyperglycemia and impaired hepatic glycolysis of diabetic rats more safely and potently than VS. This is not simply due to improved intestinal absorption, indicating more potent insulin-like properties. (+info)
Arsenite exposure of cultured airway epithelial cells activates kappaB-dependent interleukin-8 gene expression in the absence of nuclear factor-kappaB nuclear translocation.
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Airway epithelial cells respond to certain environmental stresses by mounting a proinflammatory response, which is characterized by enhanced synthesis and release of the neutrophil chemotactic and activating factor interleukin-8 (IL-8). IL-8 expression is regulated at the transcriptional level in part by the transcription factor nuclear factor (NF)-kappaB. We compared intracellular signaling mediating IL-8 gene expression in bronchial epithelial cells cultured in vitro and exposed to two inducers of cellular stress, sodium arsenite (As(III)), and vanadyl sulfate (V(IV)). Unstimulated bronchial epithelial cells expressed IL-8, and exposure to both metal compounds significantly enhanced IL-8 expression. Overexpression of a dominant negative inhibitor of NF-kappaB depressed both basal and metal-induced IL-8 expression. Low levels of nuclear NF-kappaB were constitutively present in unstimulated cultures. These levels were augmented by exposure to V(IV), but not As(III). Accordingly, V(IV) induced IkappaBalpha breakdown and NF-kappaB nuclear translocation, whereas As(III) did not. However, both As(III) and V(IV) enhanced kappaB-dependent transcription. In addition, As(III) activation of an IL-8 promoter-reporter construct was partially kappaB-dependent. These data suggested that As(III) enhanced IL-8 gene transcription independently of IkappaB breakdown and nuclear translocation of NF-kappaB in part by enhancing transcription mediated by low levels of constitutive nuclear NF-kappaB. (+info)
p56(lck), ZAP-70, SLP-76, and calcium-regulated effectors are involved in NF-kappaB activation by bisperoxovanadium phosphotyrosyl phosphatase inhibitors in human T cells.
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This study investigates the second messengers involved in NF-kappaB activation by the bisperoxovanadium (bpV) phosphotyrosyl phosphatase inhibitors. We first initiated a time course analysis of bpV-mediated activation of the human immunodeficiency virus type-1 long terminal repeat- and NF-kappaB-driven reporter gene. Our results showed a slower and more transient activation of both kappaB-regulated luciferase-encoding vectors by bpV compounds when compared with the action of tumor necrosis factor-alpha (TNF). Time course analyses of NF-kappaB translocation by shift assay experiments further confirmed these results, hence implying distinct pathways of NF-kappaB activation for bpV compounds and TNF. Attempts to characterize the bpV-dependent signaling cascade revealed that the src family protein tyrosine kinase p56(lck) was critical for NF-kappaB induction by bpV. Furthermore, p56(lck) interaction with the intracytoplasmic tail of CD4 markedly enhanced such induction. Optimal activation of NF-kappaB following bpV treatment necessitated downstream effectors of p56(lck) such as the syk family protein tyrosine kinase ZAP-70 and the molecular adaptor SLP-76. Importantly, reduced NF-kappaB activation was observed when capacitative calcium entry was deficient but also upon pharmacological inhibition of calmodulin and calcineurin. Altogether, these results suggest that induction of NF-kappaB by phosphotyrosyl phosphatase bpV inhibitors necessitates both proximal and distal effectors of T cell activation. (+info)
Tyrosine kinase-regulated small GTPase translocation and the activation of phospholipase D in HL60 granulocytes.
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We focus on the mechanisms of regulation of phospholipase D (PLD) activity. Three agonists known to stimulate PLD activity, fMet-Leu-Phe (fMLP), phorbol 12-myristate 13-acetate (PMA) and V4+-OOH, induced a differential translocation of ADP-ribosylation factor (ARF), RhoA, and protein kinase Calpha (PKCalpha), all cofactors for PLD activation. Whereas fMLP recruited all three proteins to membranes, V4+-OOH only elicited RhoA translocation and PMA induced ARF and PKCalpha translocation. Three tyrosine kinases inhibitors, ST-638, methyl 2,5-dihydroxycinnamate, and genistein reduced fMLP-stimulated PLD activity by up to 80%. Furthermore, tyrosine kinase inhibitors reduced the fMLP-induced increase of GTPgammaS-stimulated PLD activity in membranes and recruitment of ARF, RhoA, and PKCalpha to the membrane fraction. The data suggest that a tyrosine phosphorylation event is located upstream of the translocation of ARF, RhoA, and PKCalpha in the signaling pathway leading to PLD activation by fMLP. RO 31-8220, a specific inhibitor of PKC, reduced PMA-induced PLD activity by 80% in intact HL60 granulocytes but enhanced fMLP-stimulated PLD activity by 60%. Although PMA alone had no effect on RhoA recruitment to the membrane fraction, in the presence of RO 31-8220 the levels of membrane-bound RhoA were increased. The levels of membrane-bound ARF and PKCalpha were unaffected by RO 31-8220 during PMA stimulation. In contrast, fMLP-induced recruitment of ARF and RhoA was insensitive to RO 31-8220 but PKCalpha translocation was increased. We propose that RhoA translocation may be regulated by PKC in an ATP-independent manner. Furthermore, increased fMLP-induced PKCalpha translocation in the presence of RO 31-8220 may partially account for the synergistic activation of PLD observed when both fMLP and RO 31-8220 are used together in intact HL60 cells. (+info)
Airway fibrosis in rats induced by vanadium pentoxide.
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Vanadium pentoxide (V(2)O(5)) is a cause of occupational asthma and bronchitis. We previously reported that intratracheal instillation of rats with V(2)O(5) causes fibrosis of the lung parenchyma (J. C. Bonner, P. M. Lindroos, A. B. Rice, C. R. Moomaw, and D. L. Morgan. Am. J. Physiol. Lung Cell. Mol. Physiol. 274: L72-L80, 1998). In this report, we show that intratracheal instillation of V(2)O(5) induces airway remodeling similar to that observed in individuals with asthma. These changes include airway smooth muscle cell thickening, mucous cell metaplasia, and airway fibrosis. The transient appearance of peribronchiolar myofibroblasts, which were desmin and vimentin positive, coincided with a twofold increase in the thickness of the airway smooth muscle layer at day 6 after instillation and preceded the development of airway fibrosis by day 15. The number of nuclear profiles within the smooth muscle layer also increased twofold after V(2)O(5) instillation, suggesting that hyperplasia accounted for thickening of the smooth muscle layer. The majority of cells incorporating bromodeoxyuridine at day 3 were located in the connective tissue surrounding the airway smooth muscle wall that was positive for vimentin and desmin. These data suggest that myofibroblasts are the principal proliferating cell type that contributes to the progression of airway fibrosis after V(2)O(5) injury. (+info)
Selective determination method for vanadium (V) and vanadium (IV) controlling the pH of media for a solid-liquid extraction column.
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Solid-liquid extraction separation based on a speciation method was studied for selective determination of vanadium (IV) and vanadium (V). Both V (IV) and V (V) cations transform to oxo-acid anion along with pH changes in the solution. The pH values for the transition points are different from each other and the difference was utilized in the separation. In the first step, particulate samples are dissolved by strong acids such as 1 M H2SO4 or 85% H3PO4. The pH of the strong acidic sample solutions of V (IV) and V (IV) are adjusted to the range between 3 and 4. In this condition, V (IV) is in the form of cation but V (V) is anion. The pH adjusted solution is applied to an anion exchange column. The solution is expected to contain V (IV) only. The trapped V (V) anion is eluted as VO2+ cation by a pH 1 acid. The author and coworker have already developed an HPLC separation method utilizing this separation concept. However, the HPLC method has some limitations, mainly originated in physical and chemical weaknesses of the HPLC column. In the present study, a firm solid-liquid column is adopted to replace the feeble HPLC column as a separation device. And a simple and convenient pH adjustment technique for making the sample solution is investigated at the same time. With these improvements, the speciation method developed with strong acidic solutions could determine the amount of V (IV) and V (V) in various environmental and biological samples. (+info)
Studies in humans on the mechanism of potent spermicidal and apoptosis-inducing activities of vanadocene complexes.
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We previously demonstrated that bis-cyclopentadienyl (Cp) complexes of vanadium(IV) (vanadocenes) are potent spermicidal and apoptosis-inducing agents. To gain further insight into the structure-function relationships controlling these two properties of vanadocenes, we have synthesized analogues in which the bis-Cp rings were substituted with one or five electron-donating methyl groups. The three complexes included vanadocene dichloride (VDC), bis(methylcyclopentadienyl) vanadium dichloride (VMDC), and bis(pentamethylcyclopentadienyl) vanadium dichloride (VPMDC). The concentration-dependent effect of these vanadocenes on sperm-immobilizing activity (SIA), mitochondrial membrane potential (DeltaPsim), axonemal dynein ATPase activity, and tyrosine phosphorylation of global and axoneme-specific sperm proteins was assessed by computer-assisted sperm analysis, flow cytometry, colorimetry, and immunoblotting, respectively. Apoptosis-inducing ability was quantitated by the two-color flow cytometric terminal dideoxynucleotidyl transferase-based assay that labels 3'-hydroxyl ends of fragmented DNA. All three vanadocenes induced rapid sperm immobilization (T(1/2) < 15 sec). Substitution of the bis-Cp rings by five methyl groups augmented the SIA of VDC by 10-fold. The EC(50) values (50% inhibitory concentration) for VDC, VMDC, and VPMDC were 7.5 microM, 4.3 microM, and 0.7 microM, respectively. Whereas SIA of vanadocenes was apparent at low micromolar concentrations, the apoptosis-inducing property was evident only at higher micromolar concentrations. The concentrations of VDC, VMDC, and VPMDC required for 50% apoptosis were 49 microM, 67 microM, and 153 microM, and for 50% reduction in sperm DeltaPsim were 435 microM, 173 microM, and 124 microM, respectively. Spermicidal activity of vanadocenes was not dependent on the inhibition of ATPase or tyrosine phosphorylation of global and sperm axonemal proteins. Due to the ability of these vanadocene complexes to rapidly generate hydroxyl radicals in the presence of oxidant, our findings provide unprecedented evidence for a novel mechanism of action for spermicidal vanadocenes. The differential concentration-dependent spermicidal and apoptosis-inducing properties of vanadocenes gives them particular utility as a new class of vaginal contraceptives. (+info)
Apoptosis-inducing vanadocene compounds against human testicular cancer.
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We systematically assessed the cytotoxic effects of five metallocene dichlorides containing vanadium (vanadocene dichloride), titanium (titanocene dichloride), zirconium (zircodocene dichloride), molybdenum (molybdocene dichloride), and hafnium (hafnocene dichloride) as the central metal atom and 19 other vanadocene complexes. These compounds were tested against the human testicular cancer cell lines Tera-2 and Ntera-2 using both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and apoptosis assays. Notably, only the vanadium(IV)-containing metallocenes exhibited significant cytotoxicity against Tera-2 and Ntera-2 cells and induced apoptosis within 24 h. Vanadocenes with dithiocyanate [VCp2(SCN)2 x 0.5 H2O] and diselenocyanate [VCp2(NCSe)2] as ancillary ligands were identified as the most potent cytotoxic compounds. Vanadocenes, especially the lead compound VCp2(NCSe)2, may be useful in the treatment of testicular cancer. (+info)