Crystals of the model protein lysozyme were grown and soaked with the potential drug VIVO(acetylacetonato)2 at 37°C. X-ray diffraction and electron paramagnetic resonance (EPR) data collected at this temperature reveal that mixed-valence cage-like polyoxidovanadate clusters are formed and covalently bind protein residue side chains at physiological temperature.

Vanadium is a transition metal with important industrial, technological, biological, and biomedical applications widespread in the environment and in living beings. The different reactions that vanadium compounds (VCs) undergo in the presence of proteins, nucleic acids, lipids and metabolites under mild physiological conditions are reviewed. In the environment vanadium is present naturally or through anthropogenic sources, the latter having an environmental impact caused by the dispersion of VCs in the atmosphere and aquifers. Vanadium has a versatile chemistry with interconvertible oxidation states, variable coordination number and geometry, and ability to form polyoxidovanadates with various nuclearity and structures. If a VC is added to a water-containing environment it can undergo hydrolysis, ligand-exchange, redox, and other types of changes, determined by the conditions and speciation chemistry of vanadium. Importantly, the solution is likely to differ from the VC introduced into the system and varies with concentration. Here, vanadium redox, hydrolytic and ligand-exchange chemical reactions, the influence of pH, concentration, salt, specific solutes, biomolecules, and VCs on the speciation are described. One of our goals with this work is highlight the need for assessment of the VC speciation, so that beneficial or toxic species might be identified and mechanisms of action be elucidated.

The efficacy of available treatments for melanoma is limited by side effects and the rapidly emerging resistance to treatment. In this context, the decavanadate compounds represent promising tools to design efficient therapeutic agents. In our study, we synthesized a dimagnesium disodium decavanadate icosahydrate compound (Mg2Na2V10O28·20H2O) and investigated its structure stability as well as its antimelanoma effects. Results showed that the Mg2Na2V10O28·20H2O compound is structured in a monoclinic system with the space group C2/c, stabilized by oxygen vertices, hydrogen bonds, and van der Waals interactions. Interestingly, we found that this newly synthesized compound reduced the viability of human (IGR39, IGR37, and SKMEL28) and murine (B16-F10) melanoma cells in a dose-dependent manner. The IC50 values ranged from 7.3 to 18 μM after 24 h and decreased to 1.4 μM after 72 h of treatment. Notably, this effect was more important than that of cisplatin (IC50 = 3 μM after 72 h of treatment), a chemotherapeutic agent, commonly used in the treatment of malignant melanoma. Furthermore, the cytotoxicity of the decavanadate compound was relatively weak on normal human keratinocytes (HaCaT), with a light effect (IC50 >> 70 μM) observed after 24 h of treatment. Thus, the Mg2Na2V10O28·20H2O compound displayed an advantage over cisplatin, which was reported to be much more aggressive to the keratinocyte cell line (IC50 = 23.9 μM). Moreover, it inhibited dose-dependently the adhesion of IGR39 cells to collagen (IC50 = 2.67 μM) and fibronectin, as well as their migration with an IC50 value of 2.23 μM. More interestingly, its in vivo administration to B16-F10 allografted mice, at the nontoxic dose of 50 μg (2.5 mg/kg), prevented and suppressed by 70% the tumor growth, compared to the nontreated mice. Moreover, this compound has also allowed a recovery against inflammation induced in mice by a mixture of DMBA and croton oil. Thus, all our results showed the potential of the Mg2Na2V10O28·20H2O compound to prevent and efficiently treat the growth and metastasis of melanoma.

A hydrated salt of decavanadate containing diprotonated metforminium(2+) (H2Met2+), hydronium (H3O+) and either neutral biguanide (Bg) or monoprotonated guanylurea (HGU+) exhibits a previously seen complex charge-stabilized hydrogen-bonded network [Chatkon et al. (2022). Acta Cryst. B78, 798-808]. Charge balance is achieved in two ways through substitutional disorder: a 0.6 occupied HGU+ cation is paired with a V10O286- anion, and a 0.4 occupied neutral Bg molecule is paired with a HV10O285- anion, with the remaining charge in both cases balanced by two H2Met2+ dications and one H3O+ monocation. Bg/HGU+ moieties exhibit bifurcated N-H...O hydrogen bonding to the H3O+ cation and are substitutionally/positionally disordered along with the H3O+ cation about an inversion center. The HGU+ V10O286- synthon seen in the previous study occurs again. Bg exhibits bifurcated hydrogen bonding from two amino groups to two rows of cluster O atoms running diagonally across the equatorial plane of the HV10O285- anion with a return hydrogen bond from the cluster H atom to the imino N atom of the Bg. Thus, a Bg...cluster synthon similar to the HGU+...cluster synthon previously reported is found. The disordered moieties occupy spaces with excess volume in the 3-D network structure. Interestingly, when the crystallographic unit cell of the current compound, whose X-ray data was collected at 100 K, is compared with that of a previous compound exhibiting the same supramolecular framework, unit-cell parameter c does not shorten as a and b expectantly do because of the lower data collection temperature. The lack of contraction on unit-cell parameter c is possibly due to the supramolecular structure.

Decavanadate is a polyoxometalate (POMs) that has shown extensive biological activities, including antidiabetic and anticancer activity. Importantly, vanadium-based compounds as well as antidiabetic biguanide drugs, such as metformin, have shown to exert therapeutic effects in melanoma. A combination of these agents, the metformin-decavanadate complex, was also recognized for its antidiabetic effects and recently described as a better treatment than the monotherapy with metformin enabling lower dosage in rodent models of diabetes. Herein, we compare the effects of decavanadate and metformin-decavanadate on Ca2+-ATPase activity in sarcoplasmic reticulum vesicles from rabbit skeletal muscles and on cell signaling events and viability in human melanoma cells. We show that unlike the decavanadate-mediated non-competitive mechanism, metformin-decavanadate inhibits Ca2+-ATPase by a mixed-type competitive-non-competitive inhibition with an IC50 value about 6 times higher (87 μM) than the previously described for decavanadate (15 μM). We also found that both decavanadate and metformin-decavanadate exert antiproliferative effects on melanoma cells at 10 times lower concentrations than monomeric vanadate. Western blot analysis revealed that both, decavanadate and metformin-decavanadate increased phosphorylation of extracellular signal-regulated kinase (ERK) and serine/threonine protein kinase AKT signaling proteins upon 24 h drug exposure, suggesting that the anti-proliferative activities of these compounds act independent of growth-factor signaling pathways.

Diabetic dyslipidemia is caused by hyperglycemia and excessive mobilization of storage lipids, leading to increasing concentrations of triglycerides and total cholesterol. Due to the insulin-mimetic or insulin-enhancer features of vanadium, it has been recognized as a regulator of cell metabolism with hypoglycemic and hypolipidemic properties. The purpose of the current animal systematic review was to evaluate the effect of vanadium administration on diabetic dyslipidemia in diabetic animals.

This is, to our knowledge, the first systematic review with the aim of investigating the relationship between vanadium and diabetic dyslipidemia among diabetes induced animals. Searches were performed in PubMed, Scopus, and web of science databases for animal studies examining the effect of vanadium on diabetic dyslipidemia in diabetic animals.

Of 124 full-text articles assessed, 48 animal studies were included in the present study with minor risk of bias. The majority of the studies confirmed the beneficial effects of different vanadium compounds in at least one of the parameters of lipid profile, especially regarding triglyceride and total cholesterol.

Current findings lend support to assess the long-term effects of different forms and doses of vanadium on lipid profile through well-designed clinical trials.

The consumption of foods rich in carbohydrates, saturated fat, and sodium, accompanied by a sedentary routine, are factors that contribute to the progress of metabolic syndrome (MS). In this way, they cause the accumulation of body fat, hypertension, dyslipidemia, and hyperglycemia. Additionally, MS has been shown to cause oxidative stress, inflammation, and death of neurons in the hippocampus. Consequently, spatial and recognition memory is affected. It has recently been proposed that metformin decavanadate (MetfDeca) exerts insulin mimetic effects that enhance metabolism in MS animals; however, what effects it can cause on the hippocampal neurons of rats with MS are unknown. The objective of the work was to evaluate the effect of MetfDeca on hippocampal neurodegeneration and recognition memory in rats with MS. Administration of MetfDeca for 60 days in MS rats improved object recognition memory (NORt). In addition, MetfDeca reduced markers of oxidative stress and hippocampal neuroinflammation. Accompanied by an increase in the density and length of the dendritic spines of the hippocampus of rats with MS. We conclude that MetfDeca represents an important therapeutic agent to treat MS and induce neuronal and cognitive restoration mechanisms.

Cadmium, one of the more hazardous environmental contaminants, has been proposed as a metabolic disruptor. Vanadium has emerged as a possible treatment for metabolic diseases. Both metals are important in public health. We aimed to investigate whether vanadium treatment is effective against metabolic disturbances caused by chronic exposure to the lowest-observable adverse effect level of cadmium. Male Wistar rats were exposed to cadmium (32.5 ppm) in drinking water for 3 months. Metabolic complications such as overweight, visceral adipose gain, hyperglycemia, impaired glucose tolerance, and dyslipidemia were detected, and low glycogen levels and steatosis were observed in the tissues. Then, the control and treated animals were subdivided and treated with a solution of 5 μM NaVO3/kg/twice a week for 2 months. The control-NaVO3 group did not show zoometric or metabolic changes. A strong interaction of NaVO3 treatment over cadmium metabolic disruption was observed. The vanadium accumulation diminished cadmium concentration in tissues. Also, vanadium interaction improved glucose homeostasis. The major effect was observed on glycogen synthesis, which was fully recovered in all tissues analyzed. Additionally, vanadium treatment prevented overweight and visceral fat accumulation, improving BMI and the percentage of fat. However, NaVO3 treatment did not have an effect on dyslipidemia or steatosis. In conclusion, this work shows that vanadium administration has a strong effect against metabolic disturbances caused by chronic cadmium exposure, observing powerful interaction on glucose homeostasis.

Two mixed-valence octadecavanadates, (NH₄)₂(Me₄N)₅[V^IV₁₂V^V₆O₄₂I]·Me₄NI·5H₂O (V₁₈I) and [{K₆(OH₂)₁₂V^IV₁₁V^V₇O₄₁(PO₄)·4H₂O}_n] (V₁₈P), were synthesized and characterized by single-crystal X-ray diffraction analysis and FTIR, Raman, ⁵¹V NMR, EPR and UV/Vis/NIR spectroscopies. The chemoprotective activity of V₁₈I and V₁₈P towards the alkylating agent diethyl sulfate was assessed in E. coli cultures. The complex V₁₈I was nontoxic in concentrations up to 5.0 mmol L^-1, while V₁₈P presented moderate toxicity in the concentration range 0.10 - 10 mmol L^-1. Conversely, a ca. 35% enhancement in culture growth as compared to cells treated only with diethyl sulfate was observed upon addition of V₁₈I (0.10 to 2.5 mmol L^-1), while the combination of diethyl sulfate with V₁₈P increased the cytotoxicity presented by diethyl sulfate alone. ⁵¹V NMR and EPR speciation studies showed that V₁₈I is stable in solution, while V₁₈P suffers partial breakage to give low nuclearity oxidometalates of vanadium(V) and (IV). According to the results, the chemoprotective effect depends strongly on the direct reactivity of the polyoxidovanadates (POV) towards the alkylating agent. The reaction of diethyl sulfate with V₁₈I apparently produces a new, rearranged POV instead of poorly-reactive breakage products, while V₁₈P shows the formation and subsequent consumption of low-nuclearity species. The correlation of this chemistry with that of other mixed-valence polyoxidovanadates, [H₆V^IV₂V^V₁₂O₃₈PO₄]^5- (V₁₄) and [V^IV₈V^V₇O₃₆Cl]^6- (V₁₅), suggests a relationship between stability in solution and chemoprotective performance.

The experimental data collected over the past 15 years on the interaction of decavanadate(V) (V10O286-; V10), a polyoxometalate (POM) with promising anticancer and antibacterial action, with G-actin, were rationalized by using several computational approaches (docking, density functional theory (DFT), and molecular dynamics (MD)). Moreover, a comparison with the isostructural and more stable decaniobate(V) (Nb10O286-; Nb10) was carried out. Four binding sites were identified, named α, β, γ, and δ, the site α being the catalytic nucleotide site located in the cleft of the enzyme at the interface of the subdomains II and IV. It was observed that the site α is preferred by V10, whereas Nb10 is more stable at the site β; this indicates that, differently from other proteins, G-actin could contemporaneously bind the two POMs, whose action would be synergistic. Both decavanadate and decaniobate induce conformational rearrangements in G-actin, larger for V10 than Nb10. Moreover, the binding mode of oxidovanadium(IV) ion, VIVO2+, formed upon the reduction of decavanadate(V) by the -SH groups of accessible cysteine residues, is also found in the catalytic site α with (His161, Asp154) coordination; this adduct overlaps significantly with the region where ATP is bound, accounting for the competition between V10 and its reduction product VIVO2+ with ATP, as previously observed by EPR spectroscopy. Finally, the competition with ATP was rationalized: since decavanadate prefers the nucleotide site α, Ca2+-ATP displaces V10 from this site, while the competition is less important for Nb10 because this POM shows a higher affinity for β than for site α. A relevant consequence of this paper is that other metallodrug-protein systems, in the absence or presence of eventual inhibitors and/or competition with molecules of the organism, could be studied with the same approach, suggesting important elements for an explanation of the biological data and a rational drug design.

Benzylamine and methylamine activate glucose uptake in adipocytes. For tyramine, this effect has even been extended to cardiomyocytes.

To investigate the effects of catecholamines and other amines on glucose uptake.

A screening compared 25 biogenic amines on 2-deoxyglucose (2-DG) uptake activation in rat adipocytes. Pharmacological approaches and transgenic mouse models were then used to decipher the mode of action of several hits.

In rat adipocytes, insulin stimulation of 2-DG uptake was reproduced with catecholamines. 100 µmol/L or 1 mmol/L adrenaline, noradrenaline, dopamine and deoxyepinephrine, maximally activated hexose transport only when sodium orthovanadate was added at 100 µmol/L. Such activation was similar to that already reported for benzylamine, methylamine and tyramine, well-recognized substrates of semicarbazide-sensitive amine oxidase (SSAO) and monoamine oxidase (MAO). Several, but not all, tested agonists of β-adrenoreceptors (β-ARs) also activated glucose transport while α-AR agonists were inactive. Lack of blockade by α- and β-AR antagonists indicated that catecholamine-induced 2-DG uptake was not mediated by AR stimulation. Adipocytes from mice lacking β1-, β2- and β3-ARs (triple KO) also responded to millimolar doses of adrenaline or noradrenaline by activating hexose transport in the presence of 100 µmol/L vanadate. The MAO blocker pargyline, and SSAO inhibitors did not block the effects of adrenaline or noradrenaline plus vanadate, which were blunted by antioxidants.

Catecholamines exert unexpected insulin-like actions in adipocytes when combined with vanadium. For limiting insulin resistance by activating glucose consumption at least in fat stores, we propose that catecholamine derivatives combined with vanadium can generate novel complexes that may have low toxicity and promising anti-diabetic properties.

Since the 1970s, the biological role of vanadium compounds has been discussed as insulin-mimetic or insulin-enhancer agents. The action of vanadium compounds has been investigated to determine how they influence the insulin signaling pathway. Khan and coworkers proposed key proteins for the insulin pathway study, introducing the concept "critical nodes". In this review, we also considered critical kinases and phosphatases that participate in this pathway, which will permit a better comprehension of a critical node, where vanadium can act: a) insulin receptor, insulin receptor substrates, and protein tyrosine phosphatases; b) phosphatidylinositol 3'-kinase, 3-phosphoinositide-dependent protein kinase and mammalian target of rapamycin complex, protein kinase B, and phosphatase and tensin homolog; and c) insulin receptor substrates and mitogen-activated protein kinases, each node having specific negative modulators. Additionally, leptin signaling was considered because together with insulin, it modulates glucose and lipid homeostasis. Even in recent literature, the possibility of vanadium acting against metabolic diseases or cancer is confirmed although the mechanisms of action are not well understood because these critical nodes have not been systematically investigated. Through this review, we establish that vanadium compounds mainly act as phosphatase inhibitors and hypothesize on their capacity to affect kinases, which are critical to other hormones that also act on common parts of the insulin pathway.

Metabolic syndrome (MS) results from excessive consumption of high-calorie foods and sedentary lifestyles. Clinically, insulin resistance, abdominal obesity, hyperglycemia, dyslipidemia, and hypertension are observed. MS has been considered a risk factor in the development of dementia. In the brain, a metabolically impaired environment generates oxidative stress and excessive production of pro-inflammatory cytokines that deteriorate the morphology and neuronal function in the hippocampus, leading to cognitive impairment. Therapeutic alternatives suggest that phenolic compounds can be part of the treatment for neuropathies and metabolic diseases. In recent years, the use of Gallic Acid (GA) has demonstrated antioxidant and anti-inflammatory effects that contribute to neuroprotection and memory improvement in animal models. However, the effect of GA on hippocampal neurodegeneration and memory impairment under MS conditions is still unclear. In this work, we administered GA (20 mg/kg) for 60 days to rats with MS. The results show that GA treatment improved zoometric and biochemical parameters, as well as the recognition memory, in animals with MS. Additionally, GA administration increased hippocampal dendritic spines and decreased oxidative stress and inflammation. Our results show that GA treatment improves metabolism: reducing the oxidative and inflammatory environment that facilitates the recovery of the neuronal morphology in the hippocampus of rats with MS. Consequently, the recognition of objects by these animals, suggesting that GA could be used therapeutically in metabolic disorders that cause dementia.

Polyoxometalates (POMs) are promising inorganic inhibitors for P-type ATPases. The experimental models used to study the effects of POMs on these ATPases are usually in vitro models using vesicles from several membrane sources. Very recently, some polyoxotungstates, such as the Dawson anion [P2W18O62]6-, were shown to be potent P-type ATPase inhibitors; being active in vitro as well as in ex-vivo. In the present study we broaden the spectrum of highly active inhibitors of Na+/K+-ATPase from basal membrane of epithelial skin to the bi-capped Keggin-type anion phosphotetradecavanadate Cs5.6H3.4PV14O42 (PV14) and we confront the data with activity of other commonly encountered polyoxovanadates, decavanadate (V10) and monovanadate (V1). The X-ray crystal structure of PV14 was solved and contains two trans-bicapped α-Keggin anions HxPV14O42(9-x)-. The anion is built up from the classical Keggin structure [(PO4)@(V12O36)] capped by two [VO] units. PV14 (10 μM) exhibited higher ex-vivo inhibitory effect on Na+/K+-ATPase (78%) than was observed at the same concentrations of V10 (66%) or V1 (33%). Moreover, PV14 is also a potent in vitro inhibitor of the Ca2+-ATPase activity (IC50 5 μM) exhibiting stronger inhibition than the previously reported activities for V10 (15 μM) and V1 (80 μM). Putting it all together, when compared both P-typye ATPases it is suggested that PV14 exibited a high potential to act as an in vivo inhibitor of the Na+/K+-ATPase associated with chloride secretion.

The influence of three functionalized hexavanadates (V₆): Na₂ [V₆O₁₃{(OCH₂)₃CCH₃}₂], [H₂]₂ [V₆O₁₃{(OCH₂)₃CCH₂OCOCH₂CH₃}₂] and [(C₄H₉)₄N]₂ [V₆O₁₃{(OCH₂)₃CCH₂OOC(CH₃)₂-COOH}₂ on Na⁺/K⁺-ATPase activity, was investigated in vitro. Including compounds already tested by Xu et al. (Journal of Inorganic Biochemistry 161 (2016) 27-36), all functionalized hexavanadates inhibit the activity of Na⁺/K⁺-ATPase in a dose-dependent manner but with different inhibitory potencies. Na₂ [V₆O₁₃{(OCH₂)₃CCH₃}₂] was found to have the best inhibition properties - showing 50% inhibition IC₅₀ = 5.50 × 10^-5 M, while [(C₄H₉)₄N]₂ [V₆O₁₃{(OCH₂)₃CCH₂OOC(CH₃)₂-COOH}₂] showed the lowest inhibitory power, IC₅₀ = 1.31 × 10^-4 M. In order to understand the bioactivity of functionalized hexavanadates series, we have also used a combined theoretical approach: determination of electrostatic potential from ab initio theoretical calculations and computation of the molecular interaction field (MIF) surface.

Vanadium compounds have been primarily investigated as potential therapeutic agents for the treatment of various major health issues, including cancer, atherosclerosis, and diabetes. The translation of vanadium-based compounds into clinical trials and ultimately into disease treatments remains hampered by the absence of a basic pharmacological and metabolic comprehension of such compounds. In this review, we examine the development of vanadium-containing compounds in biological systems regarding the role of the physiological environment, dosage, intracellular interactions, metabolic transformations, modulation of signaling pathways, toxicology, and transport and tissue distribution as well as therapeutic implications. From our point of view, the toxicological and pharmacological aspects in animal models and humans are not understood completely, and thus, we introduced them in a physiological environment and dosage context. Different transport proteins in blood plasma and mechanistic transport determinants are discussed. Furthermore, an overview of different vanadium species and the role of physiological factors (i.e., pH, redox conditions, concentration, and so on) are considered. Mechanistic specifications about different signaling pathways are discussed, particularly the phosphatases and kinases that are modulated dynamically by vanadium compounds because until now, the focus only has been on protein tyrosine phosphatase 1B as a vanadium target. Particular emphasis is laid on the therapeutic ability of vanadium-based compounds and their role for the treatment of diabetes mellitus, specifically on that of vanadate- and polioxovanadate-containing compounds. We aim at shedding light on the prevailing gaps between primary scientific data and information from animal models and human studies.

Ultra-trace elements or occasionally beneficial elements (OBE) are the new categories of minerals including vanadium (V). The importance of V is attributed due to its multifaceted biological roles, i.e., glucose and lipid metabolism as an insulin-mimetic, antilipemic and a potent stress alleviating agent in diabetes when vanadium is administered at lower doses. It competes with iron for transferrin (binding site for transportation) and with lactoferrin as it is secreted in milk also. The intracellular enzyme protein tyrosine phosphatase, causing the dephosphorylation at beta subunit of the insulin receptor, is inhibited by vanadium, thus facilitating the uptake of glucose inside the cell but only in the presence of insulin. Vanadium could be useful as a potential immune-stimulating agent and also as an antiinflammatory therapeutic metallodrug targeting various diseases. Physiological state and dose of vanadium compounds hold importance in causing toxicity also. Research has been carried out mostly on laboratory animals but evidence for vanadium importance as a therapeutic agent are available in humans and large animals also. This review examines the potential biochemical and molecular role, possible kinetics and distribution, essentiality, immunity, and toxicity-related study of vanadium in a biological system.

Cytosine, a DNA and RNA building-block, and Metformin, the most widely prescribed drug for the treatment of Type 2 Diabetes mellitus were made to react separately with ammonium or sodium metavanadates in acidic aqueous solutions to obtain two polyoxovanadate salts with a 6:1 ratio of cation-anion. Thus, compounds [HCyt]6[V10O28]·4H2O, 1 and [HMetf]6[V10O28]·6H2O, 2 (where HCyt = Cytosinium cation, [C4H6N3O]+ and HMetf = Metforminium cation, [C4H12N5]+) were obtained and characterized by elemental analysis, single crystal X-ray diffraction, vibrational spectroscopy (IR and Raman), solution 51V-NMR, thermogravimetric analysis (TGA-DTGA), as well as, theoretical methods. Both compounds crystallized in P1 ¯   space group with Z' = 1/2, where the anionic charge of the centrosymmetric ion [V10O28]6- is balanced by six Cytosinium and six Metforminium counterions, respectively. Compound 1 is stabilized by π-π stacking interactions coming from the aromatic rings of HCyt cations, as denoted by close contacts of 3.63 Å. On the other hand, guanidinium moieties from the non-planar HMetf in Compound 2 interact with decavanadate μ2-O atoms via N-H···O hydrogen bonds. The vibrational spectroscopic data of both IR and Raman spectra show that the dominant bands in the 1000-450 cm-1 range are due to the symmetric and asymmetric ν(V-O) vibrational modes. In solution, 51V-NMR experiments of both compounds show that polyoxovanadate species are progressively transformed into the monomeric, dimeric and tetrameric oxovanadates. The thermal stability behavior suggests a similar molecular mechanism regarding the loss of water molecules and the decomposition of the organic counterions. Yet, no changes were observed in the TGA range of 540-580°C due to the stability of the [V10O28]6- fragment. Dispersion-corrected density functional theory (DFT-D) calculations were carried out to model the compounds in aqueous phase using a polarized continuum model calculation. Optimized structures were obtained and the main non-covalent interactions were characterized. Biological activities of these compounds are also under investigation. The combination of two therapeutic agents opens up a window toward the generation of potential metalopharmaceuticals with new and exciting pharmacological properties.

Vanadium(IV/V) compounds have been studied as possible metallopharmaceutical drugs against diabetes mellitus. However, mechanisms of action and toxicological threshold have been tackled poorly so far. In this paper, our purposes were to evaluate the metabolic activity on dyslipidemia and dysglycemia, insulin signaling in liver and adipose tissue, and toxicology of the title compound. To do so, the previously reported bisammonium tetrakis 4-(N,N-dimethylamino)pyridinium decavanadate, the formula of which is [DMAPH]4(NH4)2[V10O28]·8H2O (where DMAPH is 4-dimethylaminopyridinium ion), was synthesized, and its dose-response curve on hyperglycemic rats was evaluated. A Long-Evans rat model showing dyslipidemia and dysglycemia with parameters that reproduce metabolic syndrome and severe insulin resistance was generated. Two different dosages, 5 µmol and 10 µmol twice a week of the title compound (equivalent to 2.43 mg·V/kg/day and 4.86 mg·V/kg/day, resp.), were administered intraperitoneal (i.p.) for two months. Then, an improvement on each of the following parameters was observed at a 5 µmol dose: weight reduction, abdominal perimeter, fatty index, body mass index, oral glucose tolerance test, lipid profile, and adipokine and insulin resistance indexes. Nevertheless, when the toxicological profile was evaluated at a 10 µmol dose, it did not show complete improvement, tested by the liver and adipose histology, as well as by insulin receptor phosphorylation and GLUT-4 expression. In conclusion, the title compound administration produces regulation on lipids and carbohydrates, regardless of dose, but the pharmacological and toxicological threshold for cell regulation are suggested to be up to 5 µmol (2.43 mg·V/kg/day) dose twice per week.

Ischemic stroke recovery is poor in diabetic mellitus (DM). Vanadium compounds (vanadium) relieve DM signs, but their influences on cerebral ischemia/reperfusion injury (I/RI) are inconclusive. Herein, the intensity of I/RI was inspected in vanadium-treated DM rats.

Rats made diabetic with a single intravenous dose of streptozocin (39 mg/kg). Normal and DM rats used water or vanadyl solution for 45 days. Under isoflurane anesthesia, right middle cerebral artery occlusion was performed for 60 minutes and 12 hours reperfusion. Ischemic rats were divided into untreated-control normal (ICN) and diabetic (ICD), vanadium-treated normal (IVTN) and diabetic (IVTD) groups (n=14 each). After neurological deficit score (NDS) test, the rats were sacrificed and their brain removed and stained with triphenyltetrazolium chloride (TTC) to measure cerebral infarct volume (CIV, mm³) or Evans blue extravasation (EBE, μg/g wet-tissue). Data analysis was performed using one-way ANOVA and Tukey's test (SPSS software, version 21.0) and P values <0.05 were considered statistically significant.

Blood glucose (BG, mg/dL) was similar in ICN and IVTN, elevated in IVTD and ICD (245±6 vs. 344±2, P<0.001). The increased CIV in ICN and IVTN was similar (48±2 and 34±5), very high in ICD but lower in IVTD (249±37 vs. 110±16, P<0.001). EBE was absent in non-lesioned hemispheres, similarly increased in lesioned hemispheres of ICN and IVTN (14±1 and 13±1). EBE in IVTD was significantly lower than ICD (21±2 vs. 33±5, P=0.01).

I/RI was moderate in normoglycemia and did not change with vanadium. Hyperglycemia robustly intensified I/RI. Vanadium ameliorated hyperglycemia and reduced I/RI. Nonetheless, more investigations are required to link the mechanisms of vanadium on DM and stroke injuries.

EXAFS and XANES experiments were used to assess decavanadate interplay with actin, in both the globular and polymerized forms, under different conditions of pH, temperature, ionic strength, and presence of ATP. This approach allowed us to simultaneously probe, for the first time, all vanadium species present in the system. It was established that decavanadate interacts with G-actin, triggering a protein conformational reorientation that induces oxidation of the cysteine core residues and oxidovanadium (VIV) formation. The local environment of vanadium's absorbing center in the [decavanadate-protein] adducts was determined, a V-SCys coordination having been verified experimentally. The variations induced in decavanadate's EXAFS profile by the presence of actin were found to be almost totally reversed by the addition of ATP, which constitutes a solid proof of decavanadate interaction with the protein at its ATP binding site. Additionally, a weak decavanadate interplay with F-actin was suggested to take place, through a mechanism different from that inferred for globular actin. These findings have important consequences for the understanding, at a molecular level, of the significant biological activities of decavanadate and similar polyoxometalates, aiming at potential pharmacological applications.

In the second part of the 1980s, and in the 1990s, a number of investigators demonstrated -mainly in streptozotocin-induced (STZ) diabetic rats-that the vanadate and vanadyl forms of vanadium possessed a number of insulin-like effects in various cells. It was hypothesized that oral vanadium could be an alternative treatment to parenteral insulin in the therapy of diabetes mellitus. However, the long-term and/or chronic administration of vanadium compounds should also mean tissue vanadium accumulation and risks of toxicity. The purpose of this review was to revise the current-state-of-the-art on the use of vanadium in the treatment of human diabetes. It has been conducted more than three decades after the first report on the beneficial insulin-mimetic effects of oral vanadium administration in STZ-diabetic rats. Although the antidiabetic effects of vanadium in STZ-diabetic rodents are well supported, in the few studies on human patients with positive results, that are available in the literature, vanadium compounds were administered during very short periods. We conclude that vanadium administration for the treatment of human diabetes is misplaced.