Synthesis of vitamin E and aliphatic lipid vanadium(IV) and (V) complexes, and their cytotoxic properties.

Novel vitamin E chelate derivatives and their VIV/V complexes have been synthesized and characterized, and their anticancer properties have been evaluated. The new complexes have been designed to exhibit enhanced cytotoxicity by combining high lipophilicity with the properties of vanadium to induce the formation of reactive oxygen species (ROS). In particular, the ß-tocopherol derivatives with iminodiethanol (ß-tocDEA) and dipicolylamine (ß-tocDPA) as well their VV and VIV complexes, [VVO(ß-tocDEA] and [VIVO(ß-tocDPA] have been synthesized and characterized by Nuclear Magnetic Resonance (NMR), Ultra Violet-Visible (UV-Vis) and Electron Paramagnetic Resonance (EPR) spectroscopies. Although the ß-tocopherol compounds exhibit antioxidant activity their complexes induce formation of radicals. In addition, two vanadium amphiphilic complexes of 2,2'-((2-hydroxyoctadecyl)azanediyl)bis(ethan-1-ol) (C18DEA) and 1-(bis(pyridin-2-ylmethyl)amino)octadecan-2-ol (C18DPA) known to activate O2 and produce ROS were synthesized and characterized (C. Drouza, A. Dieronitou, I. Hadjiadamou, M. Stylianou, J. Agric. Food. Chem., vol. 65, 2017, pp. 4942-4951). The four amphiphilic vanadium complexes exhibit enhanced hydrolytic stability. All compounds found to be cytotoxic for cancer cells exhibiting activity similar or higher to cis-platin.

Oral bioaccessibility and health risk assessment of vanadium(IV) and vanadium(V) in a vanadium titanomagnetite mining region by a whole digestive system in-vitro method (WDSM).

Oral bioaccessibility of vanadium(IV) and vanadium(V) in soil, dust and concentrate fines from a vanadium titanomagnetite mining region was assessed by a whole digestive system in-vitro scheme. The scheme including the addition of sweat and the large intestinal digestion was used to estimate the oral bioaccessibility of vanadium(IV) and vanadium(V) in the whole digestive system for the first time. Higher oral bioaccessibility of vanadium(IV) and vanadium(V) was determined in gastric and small intestinal phases demonstrating that their major roles for vanadium digestion and absorption. The decreasing order of the oral bioaccessibility of vanadium(IV) and vanadium(V) in each digestive phase was stomach, small intestine, large intestine and mouth. Higher oral bioaccessibility of vanadium(V) in the whole digestion indicated its higher risk potential for human than vanadium(IV). Lower oral bioaccessibility of vanadium(IV) and vanadium(V) determined in bionic digestion illustrated detoxicity potential of human body for ingested vanadium. Compared with soil and dust, higher digestion rate of vanadium in vanadium titanomagnetite concentrate fines indicated its higher risk for human, especially for mining workers. Based on vanadium oral bioaccessibility, hazard quotients of the vanadium were much less than the critical level suggested for no non-carcinogenic risks to the populations surrounding the sampling sites. Indeed, compared with the estimations based on total vanadium content, the incorporation of oral vanadium bioaccessibility into risk assessments could give more realistic information.

Essentiality and toxicity of vanadium supplements in health and pathology.

The biological properties of vanadium complexes have become an object of interest due to their therapeutic potential in several diseases. However, the mechanisms of action of vanadium salts are still poorly understood. Vanadium complexes are cofactors for several enzymes and also exhibit insulin-mimetic properties. Thus, they are involved in the regulation of glucose metabolism, including in patients with diabetes. In addition, vanadium salts may also normalize blood pressure and play a key role in the metabolism of the thyroid and of iron as well as in the regulation of total cholesterol, cholesterol HDL and triglyceride (TG) levels in blood. Moreover, in cases of hypoxia, vanadium compounds may improve cardiomyocytes function. They may also exhibit both carcinogenic and anti-cancer properties. These include dose- and exposure-time-dependent induction and inhibition of the proliferation and survival of cancer cells. On the other hand, the balance between vanadium's therapeutic properties and its side effects has not yet been determined. Therefore, any studies on the potential use of vanadium compounds as supplements to support the treatment of a number of diseases must be strictly monitored for adverse effects.

Correlation analysis as a tool to investigate the bioaccessibility of nickel, vanadium and zinc in Northern Ireland soils.

Correlation analyses were conducted on nickel (Ni), vanadium (V) and zinc (Zn) oral bioaccessible fractions (BAFs) and selected geochemistry parameters to identify specific controls exerted over trace element bioaccessibility. BAFs were determined by previous research using the unified BARGE method. Total trace element concentrations and soil geochemical parameters were analysed as part of the Geological Survey of Northern Ireland Tellus Project. Correlation analysis included Ni, V and Zn BAFs against their total concentrations, pH, estimated soil organic carbon (SOC) and a further eight element oxides. BAF data were divided into three separate generic bedrock classifications of basalt, lithic arenite and mudstone prior to analysis, resulting in an increase in average correlation coefficients between BAFs and geochemical parameters. Sulphur trioxide and SOC, spatially correlated with upland peat soils, exhibited significant positive correlations with all BAFs in gastric and gastro-intestinal digestion phases, with such effects being strongest in the lithic arenite bedrock group. Significant negative relationships with bioaccessible Ni, V and Zn and their associated total concentrations were observed for the basalt group. Major element oxides were associated with reduced oral trace element bioaccessibility, with Al2O3 resulting in the highest number of significant negative correlations followed by Fe2O3. spatial mapping showed that metal oxides were present at reduced levels in peat soils. The findings illustrate how specific geology and soil geochemistry exert controls over trace element bioaccessibility, with soil chemical factors having a stronger influence on BAF results than relative geogenic abundance. In general, higher Ni, V and Zn bioaccessibility is expected in peat soil types.

Differential gene regulation by V(IV) and V (V) ions in the branchial sac, intestine, and blood cells of a vanadium-rich ascidian, Ciona intestinalis.

Ascidians are hyperaccumulators that have been studied in detail. Proteins and genes involved in the accumulation process have been identified, but regulation of gene expression related to vanadium accumulation remains unknown. To gain insights into the regulation of gene expression by vanadium in a genome-wide manner, we performed a comprehensive study on the effect of excess vanadium ions on a vanadium-rich ascidian, Ciona intestinalis, using a microarray. RT-PCR and enzyme activity assay were performed from the perspective of redox and accumulation of metal ions in each tissue. Glutathione metabolism-related proteins were significantly up-regulated by V(IV) treatment. Several genes involved in the transport of vanadium and protons, such as Nramp and V-ATPase, were significantly up-regulated by V(IV) treatment. We observed significant up-regulation of glutathione synthesis and degradation pathways in the intestine and branchial sac. In blood cells, expression of Ci-Vanabin4, glutathione reductase activity, glutathione levels, and vanadium concentration increased after V(IV) treatment. V(IV) treatment induced significant changes related to vanadium exclusion, seclusion, and redox pathways in the intestine and branchial sac. It also induced an enhancement of the vanadium reduction and accumulation cascade in blood cells. These differential responses in each tissue in the presence of excess vanadium ions suggest that vanadium accumulation and reduction may have regulatory functions. This is the first report on the gene regulation by the treatment of vanadium-rich ascidians with excess vanadium ions. It provided much information for the mechanism of regulation of gene expression related to vanadium accumulation.

Vanadium--an element of atypical biological significance.

The biological image of the transition element vanadium ferments a great deal of contradiction-from toxicity to essentiality. Importance of this element as micro-nutrient is yet to be unequivocally accepted by biologists and biomedical scientists. In spite of toxicity, it seems interesting to analyze the different biological roles of the element. Vanadium compounds have been proven to be associated with various implications in the pathogenesis of some human diseases and also in maintaining normal body functions. Salts of vanadium interfere with an essential array of enzymatic systems such as different ATPases, protein kinases, ribonucleases and phosphatases. While vanadium deficiency accounts for several physiological malfunctionings including thyroid, glucose and lipid metabolism, etc., several genes are regulated by this element or by its compounds, which include genes for tumor necrosis factor-alpha (TNF-alpha), Interleukin-8 (IL-8), activator protein-1 (AP-1), ras, c-raf-1, mitogen activated protein kinase (MAPK), p53, nuclear factors-kappaB, etc. All these seem to be not far from its recognition as an element of pharmacological and nutritional significance, which is revealed through its increasing therapeutic uses in diabetes. Vanadium is also emerging as a potent anti-carcinogenic agent. This review summarizes the developments related to vanadium biology as a whole by analyzing the general biochemical functions of vanadium.

Influence of chelation and oxidation state on vanadium bioavailability, and their effects on tissue concentrations of zinc, copper, and iron.

Today, vanadium compounds are frequently included in nutritional supplements and are also being developed for therapeutic use in diabetes mellitus. Previously, tissue uptake of vanadium from bis(maltolato)oxovanadium(IV) (BMOV) was shown to be increased compared to its uptake from vanadyl sulfate (VS). Our primary objective was to test the hypothesis that complexation increases vanadium uptake and that this effect is independent of oxidation state. A secondary objective was to compare the effects of vanadium complexation and oxidation state on tissue iron, copper, and zinc. Wistar rats were fed either ammonium metavanadate (AMV), VS, or BMOV (1.2 mM each in the drinking water). Tissue uptake of V following 12 wk of BMOV or AMV was higher than that from VS (p < 0.05). BMOV led to decreased tissue Zn and increased bone Fe content. The same three compounds were compared in a cellular model of absorption (Caco-2 cells). Vanadium uptake from VS was higher than that from BMOV or AMV at 10 min, but from BMOV (250 microM only, 60 min), uptake was far greater than from AMV or VS. These results show that neither complexation nor oxidation state alone are adequate predictors of relative absorption, tissue accumulation, or trace element interactions.

A vanadium/aspirin complex controlled release using a poly(beta-propiolactone) film. Effects on osteosarcoma cells.

A delivery system for vanadium was developed using poly(beta-propiolactone) (PbetaPL) films. The release kinetics of a complex of vanadium (IV) with aspirin (VOAspi) was evaluated with films prepared from polymers of different molecular weights, as well as with variable drug load. A sustained release of vanadium over 7 days was achieved. The drug release kinetics depends on contributions from two factors: (a) diffusion of the drug; and (b) erosion of the PbetaPL film. The experimental data at an early stage of release were fitted with a diffusion model, which allowed determination of the diffusion coefficient of the drug. VOAspi does not show strong interaction with the polymer, as demonstrated by the low apparent partition coefficient (approximately 10(-2)). UMR106 osteosarcoma cells were used as a model to evaluate the anticarcinogenic effects of the VOAspi released from the PbetaPPL film. VOAspi-PbetaPL film inhibited cell proliferation in a dose-response manner and induced formation of approximately half of the thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation. compared to that with free VOAspi in solution. The unloaded PbetaPL film did not generate cytotoxicity, as evaluated by cell growth and TBARS. Thus, the polymer-embedded VOAspi retained the antiproliferative effects showing lower cytotoxicity than the free drug. Results with VOAspi-PbetaPL films suggest that this delivery system may have promising biomedical and therapeutic applications.

Time course effects of vanadium supplement on cytosolic reduced glutathione level and glutathione S-transferase activity.

The influence of vanadium, an important dietary micronutrient, was evaluated on the cytosolic reduced glutathione (GSH) content and glutathione S-transferase (GST) activity in several rat target tissues. Supplementation of drinking water with vanadium at the level of 0.2 or 0.5 ppm for 4, 8, or 12 wk was found to increase the GSH level with a concomitant elevation in GST activity in the liver followed by small intestine mucosa, large intestine mucosa, and kidney. The results were almost dose-dependent and mostly pronounced with 0.5 ppm vanadium after 12 wk of its continuous supplementation. Neither the GSH level nor GST activity was significantly altered in forestomach and lung following vanadium supplementation throughout the study. The levels of vanadium that were found to increase the content of GSH and activity of GST in the liver, intestine, and kidney did not exert any toxic manifestation as evidenced from water and food consumption as well as the growth responses of the experimental animals. Moreover, these doses of vanadium did not impair either hepatic or renal functions as they did not alter the serum activities of glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), sorbitol dehydrogenase (SDH), as well as serum urea and creatinine level. All these results clearly indicate that vanadium under the doses employed in our study has a significant inducing role on GSH content with a concurrent elevation in GST activity in the liver and specific extrahepatic tissues without any apparent sign of cytotoxicity. This attribute of vanadium may have a greater importance in terms of biotransformation and detoxification of xenobiotics, including carcinogens. In addition, since the ability to afford an increment in the endogenous GSH-GST pool by anticarcinogenic natural substances has been found to correlate with their activity to inhibit neoplastic transformation, the trace element vanadium may be considered as a novel anticancer agent.

Vanadium distribution in rats and DNA cleavage by vanadyl complex: implication for vanadium toxicity and biological effects.

Vanadium ion is toxic to animals. However, vanadium is also an agent used for chemoprotection against cancers in animals. To understand both the toxic and beneficial effects we studied vanadium distribution in rats. Accumulation of vanadium in the liver nuclei of rats given low doses of compounds in the +4 or +5 oxidation state was greater than in the liver nuclei of rats given high doses of vanadium compounds or the vanadate (+5 oxidation state) compound. Vanadium was incorporated exclusively in the vanadyl (+4 oxidation state) form. We also investigated the reactions of vanadyl ion and found that incubation of DNA with vanadyl ion and hydrogen peroxide (H2O2) led to intense DNA cleavage. ESR spin trapping demonstrated that hydroxyl radicals are generated during the reactions of vanadyl ion and H2O2. Thus, we propose that the mechanism for vanadium-dependent toxicity and antineoplastic action is due to DNA cleavage by hydroxyl radicals generated in living systems.

Protective role of vanadium in the survival of hosts during the growth of a transplantable murine lymphoma and its profound effects on the rates and patterns of biotransformation.

Vanadium, as ammonium mononium monovanadate, has been found to have anticarcinogenic effect in host mice bearing a transplantable ascitic lymphoma. The potentiating effect of vanadium was supported by biochemical analysis of autopsies relating to markers like microsomal cytochrome P-450, UDP glucuronyl transferase (UDPGT) and cytosolic glutathione-S-transferase (GSHT) in the hepatic tissue of the hosts, which showed substantial alterations in the extent of tumor regression as compared to their lymphoma and normal counterparts, prolonging the survival of the hosts.

DNA cleavage by hydroxyl radicals generated in a vanadyl ion-hydrogen peroxide system.

Vanadyl ion (+4 oxidation state) has been shown to be an effective agent for chemoprotection of cancers in animals. For understanding the mechanism, distribution of vanadium was studied. More vanadium was found to accumulate in the nuclei of the liver of rats when it was given as vanadyl sulfate than when it was given as sodium vanadate (+5 oxidation state). The reactivity of vanadyl ion with DNA was investigated by the DNA cleavage technique and the reaction mechanism by ESR spectroscopy. Incubation of double-strand DNA with vanadyl ion and hydrogen peroxide resulted in marked concentration- and pH-dependent DNA cleavage. Studies by the ESR spin-trap method demonstrated that hydroxyl radicals are generated during the reactions of vanadyl ion with hydrogen peroxide. Thus the antineoplastic action of vanadyl ion is proposed to be due to DNA cleavage by hydroxyl radicals generated in the cells.

Storage and elimination of titanium, aluminum, and vanadium salts, in vivo.

Hamsters were injected with titanium, aluminum, and vanadium salts either intraperitoneally or intramuscularly to study the transport, storage, and elimination of these metals. Blood samples were taken at 4 h or 24 h, and urine samples were taken at 24, 48, and 72 h. The hamsters were then injected weekly for 5 weeks after the initial injection. Blood and portions of the kidneys, liver, lung, and spleen were taken at sacrifice. All samples were analyzed for titanium, aluminum, and vanadium concentrations using graphite furnace atomic absorption spectroscopy (GFAAS). Titanium was found not to be excreted in the urine, was found in low levels in the blood, and was elevated over control in the kidney, liver, and spleen. Aluminum detection via GFAAS showed wide standard deviations and high levels in controls; however, aluminum was found to be excreted in the urine, and to be transported by the blood in the experimental animals. A small amount accumulated in the liver and spleen. Vanadium was excreted in high levels in the urine. A small amount was found in the blood, and the level in the organs was below the reliable detection limits. The rapid excretion of vanadium might be related to its solubility in physiological conditions, while the limited excretion of titanium may be related to its being insoluble in the physiologic environment.

Release and excretion of metal in patients who have a total hip-replacement component made of titanium-base alloy.

Serum concentration and urinary excretion of titanium, aluminum, and vanadium were measured for patients who had a well functioning cementless primary total hip replacement of one of two different designs, for patients who had a loose total hip replacement that was to be revised, and for control subjects who had no implant. Serum concentrations of titanium were elevated approximately twofold in the patients who had a loose implant, compared with the values for the control subjects. No major differences in terms of urine concentration of titanium, serum concentration of aluminum, or urine concentration of aluminum were observed among any of the groups that were studied. Concentrations of vanadium were uniformly low in all groups.

Cellular retention, cytotoxicity and morphological transformation by vanadium(IV) and vanadium(V) in BALB/3T3 cell lines.

Cytotoxicity, morphological transformation and cellular retention have been studied in BALB/3T3 Cl A 31-1-1 cells for ammonium or sodium vanadate [vanadium(V)] and for vanadyl sulphate [vanadium(IV)]. A morphological transformation focus assay showed transforming activity for vanadium(V) (P less than 0.005 at concentrations of 3 x 10(-6) or higher) while vanadium(IV) was not transforming in the cells. Cytotoxicity was higher for vanadium(V) than for vanadium(IV); this was particularly clear at doses from 5 x 10(-6) to 5 x 10(-5) M. The cellular retention of both vanadate and vanadyl compounds at 24, 48 and 72 h incubation was similar. At concentrations lower than 10(-6) M vanadate, the retention was linear with the dose, while at higher exposures the vanadium taken up by the cells levelled off or slightly decreased. Exposure to 10(-6) M and 10(-5) M vanadium(V) for 3 and 24 h as well as to 10(-6) M for 48 and 72 h yielded greater than 94% vanadium in the cytosol, but exposure to a toxic dose (10(-5) M) for 48 and 72 h yielded 20% vanadium associated with cellular organelles, which suggests that some sites in the cytosol become saturated with vanadium. The corresponding gel-filtration experiments indicate that a redistribution of the element among the cytosol components occurs with time.

Bioaccumulation of nickel and vanadium in tissues of the catfish Clarias batrachus.

Bioaccumulation of nickel and vanadium in the tissues of the liver, kidney, gill, and intestine has been studied following 4 days and 30 days of exposure at sublethal concentrations of nickel and vanadium compounds in the catfish Clarias batrachus. Nickel and vanadium have been found to accumulate in all four tissues observed. High concentrations of nickel and vanadium have been found in the order kidney greater than gill greater than liver greater than intestine during the 4 days and 30 days treatment. A dose-response effect was seen, as the concentration of metals in the tissues increased with concentration and exposure time. The effect on bioaccumulation in the specific tissue provides a better basis for monitoring exposures than whole-body analysis.