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The influence of chronic supply of vanadium compounds on organ weights and body mass in animal diabetes model (NZO)
Abstract
Vanadium is an element that has an effect on improving glucose levels in animals with diabetes. However, its operation is strongly dependent on the chemical structure of compounds of this element. The influence of newly synthesized vanadium compounds on biochemical processes is also unknown. The paper presents the influence of eight new vanadium compounds on organ weights of animals (mice NZO) in whom diabetes was induced by a high-fat diet during 8 weeks. Tested vanadium complexes were administered by 5 weeks. After this time organs were collected and weighed. Tested complexes had a remarkable different effect on organ weights, despite having similar composition ([VO(L)(phen)] and the same co-ligand (1,10-phenanthroline) . This indicate on separate metabolic pathways of these compounds in the body of tested animals and role of the tridentate L Schiff base ligands. The compounds C2, C3 and C5 shoved biggest influence on organs weight and these results suggest influence on the metabolic pathways and therefore are interesting for further investigations.
... With regard to various animal models of diabetes, many reports in this research area have been published and there are ongoing studies focused on this issue, as evidenced by the works by Adam et al. [196] and Krośniak et al. [197]. Briefly, Adam's research group focused on the synthesis of a new anti-diabetic complex containing vanadium(IV) and vitamin A. The authors showed a reduced blood glucose level, a lowered creatinine concentration, and a decrease in the activity of glutamate-pyruvate transaminase (GPT) in the serum of diabetic mice treated with a V(IV)-vitamin A complex, compared to the untreated diabetic mice group. ...
... Briefly, Adam's research group focused on the synthesis of a new anti-diabetic complex containing vanadium(IV) and vitamin A. The authors showed a reduced blood glucose level, a lowered creatinine concentration, and a decrease in the activity of glutamate-pyruvate transaminase (GPT) in the serum of diabetic mice treated with a V(IV)-vitamin A complex, compared to the untreated diabetic mice group. In turn, data from mouse studies conducted by Krośniak et al. [197], in which the influence of eight new V compounds on organs mass were tested, revealed that V complexes had a remarkably different effect on organ weight despite the similar composition and the same co-ligand. As stressed by the authors, this may point to separate metabolic pathways of these compounds in the body and a role of tridentate L Schiff base ligands. ...
Background
Vanadium (V) is an element with a wide range of effects on the mammalian organism. The ability of this metal to form organometallic compounds has contributed to the increase in the number of studies on the multidirectional biological activity of its various organic complexes in view of their application in medicine.
Objective
This review aims at summarizing the current state of knowledge of the pharmacological potential of V and the mechanisms underlying its anti-viral, anti-bacterial, anti-parasitic, anti-fungal, anti-cancer, anti-diabetic, anti-hypercholesterolemic, cardioprotective, and neuroprotective activity as well as the mechanisms of appetite regulation related to the possibility of using this element in the treatment of obesity. The toxicological potential of V and the mechanisms of its toxic action, which have not been sufficiently recognized yet, as well as key information about the essentiality of this metal, its physiological role, and metabolism with certain aspects on the timeline is collected as well. The report also aims to review the use of V in the implantology and industrial sectors emphasizing the human health hazard as well as collect data on the directions of further research on V and its interactions with Mg along with their character.
Results and Conclusions
Multidirectional studies on V have shown that further analyses are still required for this element to be used as a metallodrug in the fight against certain life-threatening diseases. Studies on interactions of V with Mg, which showed that both elements are able to modulate the response in an interactive manner are needed as well, as the results of such investigations may help not only in recognizing new markers of V toxicity and clarify the underlying interactive mechanism between them, thus improving the medical application of the metals against modern-age diseases, but also they may help in development of principles of effective protection of humans against environmental/occupational V exposure.
... Vanadium forms complexes with many organic molecules and is advantageous over vanadium salts with lesser toxic effects and exerts greater biological efficacy at a very low dosage level. In bioinorganic chemistry, their compounds play a significant role in several enzyme-related biochemical responses like stimulating the functions of myosine ATPase, adenylate kinase, choline esterase, dynein, and phosphofructokinase and also inhibiting the functions of tyrosine phosphatase, glycogen synthase, lipoprotein lipase, and adenylate cyclase [9][10][11][12][13]. e inhibition of phosphatase enzymes instigated the interest in understanding the toxicity profile of vanadium in humans [14]. Ligands containing heteroatoms bind to vanadium and form diverse natures of vanadium species including peroxovanadate, polyoxovanadate monooxo, dioxo, and oxoperoxovanadium species [10]. ...
Oxoperoxovanadium (V) complexes [VO (O)2 (nf) (bp)] (1) and [VO (O)2 (ox) (bp)] (2) based on 5-nitro-2-furoic acid (nf), oxine (ox) and 2, 2′ bipyridine (bp) bidentate ligands have been synthesized and characterized by FT-IR, UV-visible, mass, and NMR spectroscopic techniques. The structure of complex 2 shows distorted pentagonal-bipyramidal geometry, as confirmed by a single-crystal XRD diffraction study. The interactions of complexes with bovine serum albumin (BSA) and calf thymus DNA (CT-DNA) are investigated using UV-visible and fluorescence spectroscopic techniques. It has been observed that CT-DNA interacts with complexes through groove binding mode and the binding constants for complexes 1 and 2 are 8.7 × 103 M−1 and 8.6 × 103 M−1, respectively, and BSA quenching constants for complexes 1 and 2 are 0.0628 × 106 M−1 and 0.0163 × 106 M−1, respectively. The ability of complexes to cleave DNA is investigated using the gel electrophoresis method with pBR322 plasmid DNA. Furthermore, the cytotoxic effect of the complexes is evaluated against the HeLa cell line using an MTT assay. The complexes are subjected to density functional theory calculations to gain insight into their molecular geometries and are in accordance with the results of docking studies. Furthermore, based on molecular docking studies, the intermolecular interactions responsible for the stronger binding affinities between metal complexes and DNA are discussed.
... This increase in body weight could be as a result of quick arrest of diarrhoea in the vanadium treated groups thereby reducing body weight loss. In a recent work by Kronsniak et al. [34], they also observed that administration of vanadium complex resulted in significant increase in body weight in animal diabetes model, thereby corroborating our result. ...
Objectives:
Vanadium has been reported to possess relevant therapeutic properties such as anti-diabetic and anti-tumoral. This study aimed at determining the effects of vanadium on experimentally induced colitis in rats.
Methods:
Forty-five male Wistar rats (103 ± 3.90 g, n=15) were used for this study and were divided into three groups. Group 1 (Untreated control) had nothing added to their drinking, while groups 2 and 3 received sodium metavanadate at a dose of 50 and 200 mg/L respectively in their drinking water for 10 weeks. Colitis was thereafter induced by intra colonic administration of 1.50 mL of 6% acetic acid. Animals were sacrificed on day 0 (pre-induction), three- and seven-days post induction. Blood samples were collected for haematological variables and the distal 8 cm of the colon was collected for macroscopic, histological and biochemical (malondialdehyde-MDA, superoxide dismutase-SOD, catalase-CAT, glutathione peroxidase- GPx and nitrite concentration- NO) assessment.
Results:
Low dose vanadium proved beneficial in ameliorating acetic acid-induced colitis by improving both histopathological and haematological changes. Gross observation showed a faster healing rate in vanadium treated groups (50 and 200 mg/L) compared with untreated control at day 3 (40 and 26.20 vs. 2.50%) and day 7 (80 and 66.70 vs. 42%) respectively. Vanadium also appears to exert its beneficial effects on acetic acid-induced colitis via up regulation of antioxidant enzymes (SOD, CAT, GPx) and NO while decreasing the over production of MDA.
Conclusions:
Vanadium at small concentration functions as an essential trace element and may be able to promote healing process during ulcerative colitis.
This review provides an overview of the synthesis, characterization and application of coordination polymers based on N,O-donor Schiff base ligands. The coordination polymers (CPs) represent a novel class of inorganic–organic hybrid materials with tunable compositions and fascinating structures. They are composed of metal ions and organic ligands. Therefore, the nature of the metal ion and type of organic ligand is the most significant factor in constructing targeted coordination polymers with the desired properties. Due to the versatile coordination modes, N,O-donor Schiff base ligands are also used to construct various CPs.
The synthesis, properties, including single crystal structures and biological activity of 16 new vanadium complexes with tridentate ONO Schiff base ligands L based on 5-chloro- and 5-hydroxy-salicylaldehyde and selected hydrazides are presented. Several types of complexes were synthesized at different oxidation state of vanadium: [VO(L)(phen)] (where phen denote 1,10-phenanthroline) with V(IV), [VO(L)(solv)] (where solv denote solvent molecule H2O or EtO⁻) with V(IV or V), [VO2L] and [VOL(H2O)2] with V(V) and [VL2] with V(III). All complexes were characterized by elemental analysis, IR, UV-Vis, EPR spectroscopy, cyclic voltammetry and thermogravimetric measurements. The molecular structures of two V(V) complexes were confirmed by single-crystal X-ray diffraction. The stability of complexes in solution as well as the biological activity - inhibition of human tyrosine phosphatases, were investigated and discussed.
Seventeen complexes of vanadium (III-V) with hydrazido-hydrazone Schiff bases, formed from 5-bromosalicylaldehyde and different hydrazides, are described and characterized by elemental analysis, IR, UV-Vis (in solution and as reflectance spectra) and EPR spectroscopy, cyclic voltammetry and thermogravimetric measurements. The nonoxido complexes show reversible oxidation to V(V), while oxido ones only irreversible processes. The thermogravimetric measurements indicate that Schiff base is released as its components in two separated steps. The detailed EPR measurements show distorted octahedral geometry for oxido complexes with presence of two oxidovanadium(IV) centers attributed to complexes with keto- or enol- form of hydrazide, the ratio of keto : enol form was determined. The biological activity, such as inhibition of human phosphatases (PTP1B, SHP1, SHP2, LAR and CD45), cytotoxicity and glucose uptake in myocytes (C2C12) and adipocytes (3T3-L1) of selected complexes was tested. The obtained results indicate that the strength of tyrosine phosphatases inhibition of tested complexes does not determine the strength of their antidiabetic activity demonstrated in the glucose transport to myocytes and adipocytes. This last effectiveness is much higher than for VOSO4 and BMOV.
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.
Vanadium compounds have been known to have beneficial therapeutic properties since the turn of the century, but it was not until 1965 when it was discovered that those effects could be extended to treating cancer. Some vanadium compounds can combat common markers of cancer, which include metabolic processes that are important to initiating and developing the phenotypes of cancer. It is appropriate to consider vanadium as a treatment option due to the similarities in some of the metabolic pathways utilized by both diabetes and cancer and therefore is among the few drugs that are effective against more than one disease. The development of vanadium compounds as protein phosphatase inhibitors for the treatment of diabetes may be useful for potential applications as an anticancer agent. Furthermore, the ability of vanadium to redox cycle is also important for biological properties and is involved in the pathways of reactive oxygen species. Early agents including vanadocene and peroxovanadium compounds have been investigated in detail, and the results can be used to gain a better understanding of how some vanadium compounds are modifying the metabolic pathways potentially developing cancer. Considering the importance of coordination chemistry to biological responses, it is likely that proper consideration of compound formulation will improve the efficacy of the drug. Future development of vanadium-based drugs should include consideration of drug formulation at earlier stages of drug development.
Diabetes patients suffer from chronic disorders in the metabolism due to high blood sugar caused by anomalies in insulin excretion. Recently, vanadium compounds have been prepared and functionalized to decrease the level of hyperglycemia. Vitamin A boosts beta cell activity; therefore, the lack of this vitamin plays a role in the development of type 2 diabetes. The aim of this article focused on the synthesis of a new anti-diabetic drug formed from the complexation of a vanadium(IV) salt with vitamin A. Vitamin A acts as a unidentate chelate through the oxygen of its –OH group. The vanadium(IV) compound is surrounded by two vitamin A molecules. The [VO(vitamin A)2(H2O)2] compound was synthesized in a binary solvent system consisting of MeOH/H2O (1:1 ratio) in alkaline media at pH = 8. This compound was characterized using Fourier transform infrared spectra (FT-IR), electronic spectra (UV–vis), effective magnetic moment, electron spin resonance (ESR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and thermal analysis (thermogravimetry (TG)–differential thermal analysis (DTA)). Anti-diabetic efficiency for the vanadium(IV) compound was assessed in streptozotocin (STZ)-induced diabetic mice. The results of the animal studies demonstrate the ability of the vanadium(IV) complex to act as an anti-diabetic agent, as measured by improvements of lipid profile, antioxidant activity (superoxide dismutase), malondialdehyde (MDA), glutathione, methionine synthase, and kidney and liver functions.
The present study is characterized towards thespesone isolation from Thespesia populnea (Malvaceae) subsequently it was modified and characterized to study its effect on diabetes related symptoms. The complex is administered to diabetes induced mice with the doses of 5, 10 and 20 mg/kg, p.o. and the effect of complex on level of body weight, lipid profile and blood glucose was studied after 22 days. The results have indicated that diabetic mice shows significant (p < 0.01) decrease in the level of serum triglyceride, plasma glucose and increase in body weight. Hence the present investigation reveals that newly synthesized complex is useful in management of Type-II diabetes mellitus because of its ability to reduce insulin resistance.
There is mounting evidence demonstrating causative links between hyperglycemia, oxidative stress, and insulin resistance, the core pathophysiological features of type 2 diabetes mellitus. Using a combinational approach, we synthesized a vanadium-antioxidant (i.e., l-ascorbic acid) complex and examined its effect on insulin resistance and oxidative stress. This study was designed to examine whether vanadyl(IV)-ascorbate complex (VOAsc) would reduce oxidative stress, hyperglycemia, and insulin resistance in high-fat high-sucrose diet (HFSD)-induced type 2 diabetes in mice. Male C57BL/6J mice were fed a HFSD for 12 weeks to induce insulin resistance, rendering them diabetic. Diabetic mice were treated with rosiglitazone, sodium l-ascorbate, or VOAsc. At the end of treatment, fasting blood glucose, fasting serum insulin, homeostasis model assessment-insulin resistance index, and serum adipocytokine levels were measured. Serum levels of nitric oxide (NO) parameters were also determined. The liver was isolated and used for determination of malondialdehyde, reduced glutathione, and catalase levels, and superoxide dismutase and glutathione peroxidase activities. VOAsc groups exhibited significant reductions in serum adipocytokine and NO levels, and oxidative stress parameters compared to the corresponding values in the untreated diabetic mice. The results indicated that VOAsc is non-toxic. In conclusion, we identified VOAsc as a potentially effective adjunct therapy for the management of type 2 diabetes.
Copyright © 2015 Elsevier GmbH. All rights reserved.
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to abnormalities in either insulin secretion or action. A range of vanadium complexes have been synthesized and demonstrated to be effective in lowering hyperglycemia. Thiamine administration was also reported to prevent deterioration in fasting glucose and insulin levels, and to improve glucose tolerance in hyperglycemic patients. This study has been conducted to evaluate the ionic vanadyl(II) thiamine hydrochloride complex (VC) as a new anti-diabetic candidate. The new complex was characterized by infrared spectroscopy (FT-IR), electronic spectra, magnetic susceptibility, electron spin resonance (ESR), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). The anti-diabetic effect of VC was investigated in comparison to vanadium sulfate in streptozotocin (STZ)-induced diabetic rats. Treatment of diabetic rats with VC versus vanadyl sulfate showed a more potent effect on reducing serum glucose and cholesterol close to normal levels. VC suppressed the diabetes-induced upregulation of hepatic glucose transporter (GLUT)-2, Phosphoenol pyruvate carboxykinase (PEPCK), and hormone-sensitive lipase (HSL) more significantly than vanadyl sulfate. Either vanadyl sulfate or VC restored hepatic sterol regulatory element-binding protein transcription factor-1c (SREBP-1c) and muscle hexokinase (HK) mRNA expression that was downregulated in diabetic group. Pyruvate kinase (PK) mRNA expression was restored more significantly in VC-treated than vanadyl sulfate-treated diabetic rats. These results indicate that the newly synthesized VC could be an effective anti-diabetic candidate as the anti-diabetic activity of the ionic vanadium was enhanced after being modified with the organic ligand, thiamin. The results also suggest that VC achieves its effect most likely through modulating the transcription of energy metabolizing enzymes.
© The Author(s) 2015.
Some experimental animal studies reported that vanadium had beneficial effects on blood total cholesterol (TC) and triglyceride (TG). However, the relationship between vanadium exposure and lipid, lipoprotein profiles in human subjects remains uncertain. This study aimed to compare the serum lipid and lipoprotein profiles of occupational vanadium exposed and non-exposed workers, and to provide human evidence on serum lipid, lipoprotein profiles and atherogenic indexes changes in relation to vanadium exposure.
This cross-sectional study recruited 533 vanadium exposed workers and 241 non-exposed workers from a Steel and Iron Group in Sichuan, China. Demographic characteristics and occupational information were collected through questionnaires. Serum lipid and lipoprotein levels were measured for all participants. The ratios of total cholesterol to high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) to HDL-C and apoB to apoA-I were used as atherogenic indexes. A general linear model was applied to compare outcomes of the two groups while controlling possible confounders and multivariate logistic regression was performed to evaluate the relationship between low HDL-C level, abnormal atherogenic index and vanadium exposure.
Higher levels of HDL-C and apoA-I could be observed in the vanadium exposed group compared with the control group (P < 0.05). Furthermore, atherogenic indexes (TC/HDL-C, LDL-C/HDL-C, and apoB/apoA-I ratios) were found statistically lower in the vanadium exposed workers (P < 0.05). Changes in HDL-C, TC/HDL-C, and LDL-C/HDL-C were more pronounced in male workers than that in female workers. In male workers, after adjusting for potential confounding variables as age, habits of smoking and drinking, occupational vanadium exposure was still associated with lower HDL-C (OR 0.41; 95% CI, 0.27-0.62) and abnormal atherogenic index (OR 0.38; 95% CI, 0.20-0.70).
Occupational vanadium exposure appears to be associated with increased HDL-C and apoA-I levels and decreased atherogenic indexes. Among male workers, a significantly negative association existed between low HDL-C level, abnormal atherogenic index and occupational vanadium exposure. This suggests vanadium has beneficial effects on blood levels of HDL-C and apoA-I.
THE AIM OF THIS STUDY WAS TO INVESTIGATE THE CLINICAL EFFICACY OF VANADIUM COMPLEXES ON TRIGLYCERIDES (TG), TOTAL CHOLESTEROL (CHOL), URIC ACID (UA), UREA (U), AND ANTIOXIDANT PARAMETERS: nonenzymatic (FRAP-ferric reducing ability of plasma, and reduced glutathione-GSH) and enzymatic (glutathione peroxidase-GPx, catalase-CAT, and GPx/CAT ratio) activity in the plasma of healthy male Wistar rats. Three vanadium complexes: [VO(bpy)(2)]SO(4)·2H(2)O, [VO(4,4'Me(2)bpy)(2)]SO(4)·2H(2)O, and Na[VO(O(2))(2)(bpy)]·8H(2)O are administered by gavage during 5 weeks in two different diets such as control (C) and high fatty (F) diets. Changes of biochemical and antioxidants parameters are measured in plasma. All three vanadium complexes statistically decrease the body mass growth in comparison to the control and fatty diet. In plasma GSH was statistically increased in all vanadium complexes-treated rats from control and fatty group in comparison to only control group. Calculated GPX/CAT ratio was the highest in the control group in comparison to others.
Numerous studies, both in vitro and in vivo, have demonstrated the insulin-mimetic properties of vanadium. Chronic oral administration of inorganic and organic compounds of both vanadium(IV) and vanadium(V) reduced plasma glucose levels and restored plasma lipid levels in streptozotocin-diabetic rats. We investigated the acute effects of both vanadyl sulfate and bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium compound, on plasma glucose levels by several routes of administration. Previous studies have shown that chronic administration of vanadyl sulfate has resulted in a sustained euglycemia following withdrawal of the drug. This effect was not observed following the chronic administration of BMOV; therefore, we investigated the effect of increasing the concentration of BMOV on the production of a sustained euglycemic response. An acute plasma glucose lowering effect was obtained with both vanadyl sulfate and BMOV when administered as a single dose by either oral gavage or intraperitoneal injection. In those animals that responded to vanadium treatment, plasma glucose levels were within the normal range within 2 to 6 h when given by i.p. injection or within 4 to 8 h when given by oral gavage. BMOV-treated rats that responded to treatment maintained the euglycemic effect for extended periods, ranging from 1 to 14 weeks following administration. However, vanadyl sulfate treated rats reverted to hyperglycemia within 12 to 24 h, depending on the route of administration. Intravenous administration of BMOV was effective in lowering plasma glucose levels only when administered by continuous infusion. An oral dose-response curve showed that BMOV was 2 to 3 times as potent as vanadyl sulfate. This difference in potency was observed with both oral and intraperitoneal administration, which suggests that the increase in potency with BMOV cannot be totally attributed to increased gastrointestinal absorption. Organic chelation of vanadium may facilitate uptake into vanadium-sensitive tissues. Chronic oral administration of higher concentrations of BMOV did not result in a sustained reduction in plasma glucose following withdrawal of the drug. All diabetic rats eventually responded to increased concentrations of BMOV with a restoration of plasma glucose levels to normal values; however, reversion to the hyperglycemic state occurred within 2 days of withdrawal of treatment. Chronic oral administration of BMOV did not produce a sustained euglycemic effect following withdrawal, but acute administration of the compound by either oral gavage or intraperitoneal injection did produce a long-term reduction in plasma glucose levels. Rats treated chronically with vanadyl sulfate remained euglycemic even after the drug was withdrawn. However, acute treatment produced only a transient euglycemia.
Inorganic vanadium has been shown, both in vivo and in vitro, to have insulin-mimetic properties. A new organic vanadium complex, bis(maltolato)oxovanadium(IV) (BMOV), was developed to increase the absorption of vanadium from the gastrointestinal tract, thereby reducing the dose of vanadium necessary to produce glucose-lowering effects. BMOV was administered in the drinking water for 25 weeks to control and streptozotocin-induced diabetic, male Wistar rats. BMOV treatment produced a stable euglycemic state in 70% of diabetic treated animals. The other 30% of the diabetic treated animals demonstrated fluctuations in glucose control over the entire study period. The initial effective dose of BMOV was 0.45 mmol/kg, which decreased to an effective maintenance dose of 0.18 mmol/kg, significantly lower than the dose of inorganic vanadium salts used in previous studies. BMOV treatment did significantly reduce fluid consumption levels in control treated animals after 10 weeks of therapy; however, the food consumption for control treated animals was only intermittently lower than that for controls. Plasma cholesterol and triglyceride levels were normalized with BMOV treatment for all diabetic treated animals, without a concomitant increase in plasma insulin levels. An oral glucose tolerance test demonstrated that glucose homeostasis in control-treated animals occurred at significantly lower plasma insulin levels than in control animals. BMOV effectively produced the glucose-lowering effects at significantly lower dose than previously used for inorganic vanadium salts, without any overt signs of toxicity.
The in vivo glucose lowering effect of orally administered inorganic vanadium compounds in diabetes was first reported in our laboratory in 1985. While both vanadate and vanadyl forms of vanadium are orally active, they are still not well absorbed. We have synthesized several organic vanadium compounds and one compound, bis(maltolato)oxovanadium(lV) or BMOV, has been extensively investigated. BMOV proved effective in lowering plasma glucose and lipids in STZ-diabetic rats when administered in drinking water over a 25 week period. The maintenance dose (0.18 mmol/kg/day) was approximately 50% of that required for vanadyl sulfate (VS). Secondary complications of diabetes were prevented by BMOV and no marked toxicity was noted. Oral gavage of STZ-diabetic rats with BMOV also reduced blood glucose levels. The ED50 for BMOV was 0.5 mmol/kg, while for VS the estimated ED50 was 0.9 mmol/kg. BMOV was also effective by the intraperitoneal route in STZ-diabetic rats. The ED50 was 0.08 mmol/kg compared to 0.22 mmol/kg for VS. Some animals treated p.o. or i.p. remained euglycemic for up to 14 weeks. An i.v. infusion of BMOV of 0.05 mmol/kg over a 30 min period reduced plasma glucose levels by 50% while VS was not effective.
Multidentate oxidovanadium(IV) complexes with different geometric configurations [VO(ox)(bpy)(H2O)] 1, [VO(ox)(phen)(H2O)] 2, [VO(ida)(bpy)]•2H2O 3, (phen)[VO(ida)(phen)]•4H2O 4, and (Hphen)[VO(H2O)(nta)]•2H2O 5 [ox = oxalic acid, bpy = 2,2’-bipyridine, phen = 1,10-phenanthroline, ida = iminodiacetic acid, nta = nitrilotriacetic acid] have been obtained from the reactions of oxidovanadium sulfate or vanadium pentoxide with oxlates, amino-polycarboxylates and N-heterocycle ligands in neutral solution by the hydrothermal method, which have been fully characterized by elemental, thermogravimetric analyses and single crystal X-ray diffraction, as well as a wide range of spectroscopic techniques, such as FT-IR, UV/Vis, NMR, ESI-MS. The anti-tumor properties of oxidovanadium compounds 1~5 were further evaluated in human HepG2 and SMMC-7721 hepatocellular carcinoma cell linesin vitro. The profiles of cytotoxicity, cell cycle distribution as well as cell apoptosis upon test compounds exposure were determined by MTT and flow cytometryassays. The results showed that compound 2 exhibited a much higher anti-tumor activity than others. The IC50 values of 2 were 5.34±0.034μM and 29.07±0.017μM in SMMC-7721 and HepG2 cells after 48 h treatment, respectively. Furthermore, compound 2 could significantly arrest the cell cycle in S and G2/M phase and further induce cellapoptosis in a dose-dependent manner. The structure-activity relationship (SAR) studies revealed that structural elements, for example, metal components, variations of coordination mode, labile water molecule, chelated ligands etc. probably exert an essential cooperative effect on the antitumoractivity. In short, these findings do not only provide an accessible model system to exploit V-based complexes as potential simple, safe and effective multifunctional antitumor agents, but also open up a rational approach to shed new light on the selection and optimization of ideal drug candidates.
On reaction of 2-hydroxybenzoylhydrazine (H2bh) separately with equimolar amounts of [VIVO(aa)2] and [VIVO(ba)2] in CHCl3 afforded the complexes [VV2O3(HL1)2] (1) and [VV2O3(HL2)2] (2) respectively in good-to-excellent yield [(HL1)2- and (HL2)2-...
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.
New Zealand obese mice (NZO) are characterized by symptoms similar to human metabolic syndrome. Vanadium in different investigations showed anti-diabetic activity but until now an NZO mice model has not been tested with this element. The aim of this study was to investigate anti-diabetic activity of three vanadium compounds (VOSO4, VO(mal)2 and Na(VO(O2)2bpy) x 8H2O) in the NZO model. Metabolic syndrome was induced by special diet (1.5% of cholesterol and 15% of saturated fatty acids) during 8 weeks. In the next 5 weeks, the tested vanadium compounds were administered once daily, in a dose of 0.063 mmol/kg of body mass. At the end of the experiment, glucose, cholesterol, triglycerides and alanine transaminase were measured in the serum. The obtained results showed that the glucose level was decreased nearly to the healthy NZO mice in comparison to the NZO mice with metabolic syndrome. In all groups on the diet with cholesterol, the level of this parameter was statistically higher in comparison to the group without cholesterol addition. Vanadium treatment in a dose 0.063 mmol/kg of body mass does not influence cholesterol, triglycerides and alanine transaminase activity.
The long term studies with dairy goats on the effects of deficient semisynthetic feeding rations in one of 16 elements as reported in the annual proceedings of the Workshops on Minerals and Trace Elements and the International Trace Element Symposia by the University of Jena, Germany, since 1975 until today were reviewed. The development of the complex semisynthetic ration system was particularly important as it enabled to produce significant deficiencies of single elements in long term replicated studies and their interactions with other elements. The studies focused mainly on determining deficiency levels for each of the 16 elements, identifying deficiency symptoms and reasons for them, and establishing evidence for essentiality of the elements according to 7 criteria. Large amounts of analytical data were accumulated showing the changes in organ and tissue contents of the elements under study at normal and deficient levels, and their relation to impaired reproductive efficiency, growth, milk production, health, and mortality of goats and their kids. Histological sections of organs also showed their ultrastructural changes due to the elemental deficiencies. Most element deficiencies caused reproductive failures, reduced growth and milk production, but high mortality, while the control goats thrived on their semisynthetic but sufficient ration, attesting to its completely correct biological value. The identification of the reliable “indicator” organs and tissues for the diagnosis and detection of deficiency status of the specific elements in goats is of particular value to veterinary medicine and animal nutrition.
Metabolic syndrome and the accompanied diabetes mellitus are both important diseases worldwide due to changes of lifestyle and eating habits. The number of patients with diabetes worldwide is estimated to increase to 300 million by 2025 from 150-220 million in 2010. There are two main types of diabetes. In type 1 diabetes, caused by destruction of pancreatic β-cells resulting in absolute deficiency of intrinsic insulin secretion, the patients require exogenous insulin injections several times a day. In type 2 diabetes, characterized by insulin resistance and abnormal insulin secretion, the patients need exercise, diet control and/or several types of hypoglycemics. The idea of using metal ions for the treatment of diabetes originates from the report in 1899. The research on the role of metal ions that may contribute to the improvement of diabetes began. The orally active metal complexes containing vanadyl (oxidovanadium(iv)) ion and cysteine or other ligands were first proposed in 1990, and a wide class of vanadium, copper and zinc complexes was found to be effective for treating diabetes in experimental animals. We noticed a characteristic compound, allixin, which is a non-sulfur component in dry garlic. Its vanadyl and zinc complexes improved both types of diabetes following oral administration in diabetic animals. We then developed a new zinc complex with thioxoallixin-N-methyl (tanm), which is both a sulfur and N-methyl derivative of allixin, and found that this complex improves not only diabetes but also metabolic syndrome. Furthermore, new zinc complexes inspired from the zinc-tanm were prepared; one of them exceeded the activity of zinc-tanm. The mechanism of such complexes was studied in adipocytes. We describe here the usefulness of the development of metal-based complexes in the context of potential therapeutic application for diabetes and metabolic syndrome.
3-Hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy-4-pyrone (maltol and ethyl maltol, respectively) have proven especially suitable as ligands for vanadyl ions, in potential insulin enhancing agents for diabetes mellitus. Both bis(maltolato)oxovanadium(IV) (BMOV), and the ethylmaltol analog, bis(ethylmaltolato)oxovanadium(IV) (BEOV), have the desired intermediate stability for pro-drug use, and have undergone extensive pre-clinical testing for safety and efficacy. Pharmacokinetic evaluation indicates a pattern of biodistribution consistent with fairly rapid dissociation and uptake, binding to serum transferrin for systemic circulation and transport to tissues, with preferential uptake in bone. These bis-ligand oxovanadium(IV) (VOL(2)) compounds have a clear advantage over inorganic vanadyl sulfate in terms of bioavailability and pharmaceutical efficacy. BEOV has now completed Phase I and has advanced to Phase II clinical trials. In the Phase I trial, a range of doses from 10 mg to 90 mg BEOV, given orally to non-diabetic volunteers, resulted in no adverse effects; all biochemical parameters remained within normal limits. In the Phase IIa trial, BEOV (AKP-020), 20 mg, daily for 28 days, per os, in seven type 2 diabetic subjects, was associated with reductions in fasting blood glucose and %HbA1c; improved responses to oral glucose tolerance testing, versus the observed worsening of diabetic symptoms in the two placebo controls.
Investigations were performed to determine baseline parameters for further study of the essentiality and/or toxicity of various vanadium compounds in mammals. Intratracheal injection techniques, chosen to imitate the inhalation mode of administration, and a fairly soluble form of the element, in order to maximize distribution kinetics, were selected as principal variables in the present case. 48 VOCl3 (12.6 μCi/ml/animal) was administered intratracheally to juvenile male Wistar rats. Members randomly selected from each injection group were sacrificed at post-exposure survival times of 15 min, 4 h, 1, 7, 14, 28 and 63 days. Samples of all major organ tissues were analyzed for 48V content by NaI(TI) gamma-ray spectroscopy. More than half of the deposited 48V was removed from the lungs within the first day. Lung clearance rates slowed in later phases of the study with about 3% of the burden remaining after 63 days. Within 15 min of exposure, the vanadium isotope translocated to all measured organs, except the brain, with blood, heart, spleen, liver and kidneys receiving the largest fractions of the activity. Peak uptake activities for most organs occurred between 4 and 24 h after injection with the kidneys maintaining the largest fraction of 48V in the early phases of the study. Bones accumulated activity through the first day and maintained relatively large burdens throughout the 9 week period. The testes also received small fractions of the isotope which persisted during all sacrifice intervals. The clearance of the isotope from the organs examined displayed multiple order rate kinetics. Excretion of the radiotracer occurred by both urinary and fecal means although the urinary route predominated.
Sodium vanadate inhibits the oxidative demethylation of substrates of the cytochrome P-450-dependent monooxygenase system in vivo in mice. [14C]Methacetin and 7-[methoxy-14C] coumarin were used as substrates, and the exhaled 14CO2 was monitored using the technique of the breath test. The inhibition is of short duration and begins to subside after about 10 min. The inhibition is dose-dependent; half-maximal effect is achieved at a dose of approximately 60 mumol/kg. The inhibition pattern is identical for both substrates, although 62% of the label of [14C] methacetin and only 10% of 7-[methoxy-14C] coumarin are enhaled within 1 h. Pretreatment with ascorbic acid (50 mg/kg p.o.) drastically diminishes the observed inhibitory effect of vanadate. Similarly, application of an equimolar dose of vanadyl sulphate produces a comparatively weak retardation of 14CO2 exhalation. The effect of vanadate is thought to occur by its competition for electrons normally transferred to cytochrome P-450.
In the 21st century, patients suffering from diabetes mellitus (DM), a lifestyle-related disease, will increase more than in the 20th century. DM is threatening because of the development of many severe secondary complications, including atherosclerosis, microangiopathy, renal dysfunction and failure, cardiac abnormalities, diabetic retinopathy, and ocular disorders. Generally, DM is classified as either insulin-dependent type 1 or noninsulin-dependent type 2 DM. Type 1 DM is treated only by daily insulin injections; type 2 DM is treated by several types of synthetic therapeutic substances together with a controlled diet and physical exercise. Even with these measures, the daily necessity for several insulin injections can be painful both physically and mentally, whereas the synthetic therapeutic substances used over the long term often have side effects. For those reasons, the creation and development of a new class of pharmaceuticals for treatment of DM in the 21st century would be extremely desirable. In the last half of the 20th century, investigations of the relationships among diseases and micronutrients, such as iron, copper, zinc, and selenium, have been numerous. Research into the development of metallopharmaceuticals involving the platinum-containing anticancer drug, cisplatin, and the gold-containing rheumatoid arthritis drug, auranofin, has also been widespread. Such important findings prompted us to develop therapeutic reagents based on a new concept to replace either insulin injections or the use of synthetic drugs. After many trials, we noticed that vanadium might be very useful in the treatment of DM. Before the discovery of insulin by Banting and Best in 1921 and its clinical trial for treating DM, the findings in 1899, in which orally administered sodium vanadate (NaVO(3)) was reported to improve human DM, gave us the idea to use vanadium to treat DM. However, it has taken a long time to obtain a scientific explanation as to why the metal ion exhibits insulin-mimetic or blood-glucose lowering effects in in vitro and in vivo experiments. After investigations from many perspectives involving biochemistry and bioinorganic chemistry, vanadyl sulfate (VOSO(4)) and its complexes with several types of ligands have been proposed as useful for treating DM in experimental diabetic animals. On the basis of a mechanistic study, this article reports on recent progress regarding the development of antidiabetic vanadyl complexes, emphasizing that the vanadyl ion and its complexes are effective not only in treating or relieving both types of DM but also in preventing the onset of DM.
Vanadium-based drugs lower glucose by enhancing the effects of insulin. Oral vanadium drugs are being tested for the treatment of diabetes. Vanadium accumulates in bone, though it is not known if incorporated vanadium affects bone quality. Nine- to 12-month-old control and streptozotocin-induced diabetic female Wistar rats were given bis(ethylmaltolato)oxovanadium(IV) (BEOV), a vanadium-based anti-diabetic drug, in drinking water for 12 weeks. Non-diabetic rats received 0, 0.25 or 0.75 mg/ml BEOV. Groups of diabetic rats were either untreated or treated with 0.25-0.75 mg/ml BEOV as necessary to lower blood glucose in each rat. In diabetic rats, this resulted in a Controlled Glucose group, simulating relatively well-managed diabetes, and an Uncontrolled Glucose group, simulating poorly managed diabetes. Plasma insulin, glucose and triglyceride assays assessed the diabetic state. Bone mineral density (BMD), mechanical testing, mineral assessment and histomorphometry measured the effects of diabetes on bone and the effects of BEOV on non-diabetic and diabetic bone. Diabetes decreased plasma insulin and increased plasma glucose and triglycerides. In bone, diabetes decreased BMD, strength, mineralization, bone crystal length, and bone volume and connectivity. Treatment was effective in incorporating vanadium into bone. In all treated groups, BEOV increased osteoid volume. In non-diabetic bone, BEOV increased cortical bone toughness, mineralization and bone formation. In controlled glucose rats, BEOV lowered plasma glucose and improved BMD, mechanical strength, mineralization, bone crystal length and bone formation rate. In poorly controlled rats, BEOV treatment slightly lowered plasma glucose but did not improve bone properties. These results suggest that BEOV improves diabetes-related bone dysfunction primarily by improving the diabetic state. BEOV also appeared to increase bone formation. Our study found no negative effects of vanadium accumulation in bone in either diabetic or non-diabetic rats at the dose given.
Since 1985, when Heyliger et al. first reported the in vivo insulin mimetic activity of oral vanadate, extensive studies exploring vanadium chemistry, including the synthesis of novel complexes and their biological effects both in vitro and in vivo have been pursued. Such complexes have emerged as possible potential agents for diabetes therapy. Among the several existing compounds, diketone based vanadium complexes have been chosen for the current study. Two new complexes namely bisdimethylmalonatooxovanadium(IV) and bisdiethylmalonatooxovanadium(IV) have been synthesized and characterized by UV-visible, FTIR and mass spectral studies. The antidiabetic activity of the complexes was proved by animal study. The results show that the above complexes have comparable antidiabetic potential with respect to the standard drug as well as with bisacetylacetonatooxovanadium(IV) which has been studied earlier by Reul et al.
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