Sodium orthovanadate overcomes sorafenib resistance of hepatocellular carcinoma cells by inhibiting Na+/K+-ATPase activity and hypoxia-inducible pathways.

The resistance to sorafenib highly affects its clinical benefits for treating hepatocellular carcinoma (HCC). Sodium orthovanadate (SOV) is a phosphate analog that displays anti-cancer activities against various types of malignancies including HCC. The present study has demonstrated that SOV is able to overcome sorafenib resistance and strengthens sorafenib in suppressing sorafenib-resistant HCC cells in vitro and in animal models. Similar to its action on parental HCC cells, SOV induced cell cycle arrest at G2/M phases by regulating cyclin B1 and cyclin-dependent kinase 1, and apoptosis by reducing mitochondrial membrane potential, in sorafenib-resistant HCC cells. More importantly, SOV inhibited ATPase activity, which was significantly elevated in sorafenib-resistant HCC cells. SOV also reduced the expression of HIF-1α and HIF-2α and their nuclear translocation, resulting in downregulation of their downstream factors including vascular endothelial growth factor, lactate dehydrogenase-A and glucose transporter 1. Its ability to inhibit ATPase activity and hypoxia-inducible pathways enabled SOV to efficiently suppress both normoxic and hypoxic cells, which compose cancer cell populations inside sorafenib-resistant HCC tumors. The present results indicate that SOV may be a potent candidate drug for overcoming the resistance to sorafenib in treating HCC.

THE EFFECT OF GADOLINIUM ORTHOVANADATE NANOPARTICLES BY NEONATAL INDUCED REPRODUCTIVE DISEASE IN MALE RATS.

For the purpose to develop of method for treatment of male hypofertility the efficiency of gadolinium orthovanadate nanoparticles (NP GdVO4) in rats with neonatal induced reproductive disease, has been investigated. The progeny of intact rats parents were exposed to emotional stress (Maternal separation stressn) and received an excessive amount of the blend of phytoestrogens (Ph) with mother's milk (1st group) from 3 to 22 day life. At the age of 10 months males received NP GdVO4 (0.33 mg/kg; 2nd group) or speman (158 mg/kg; 3rd group) with feed over the 70 days. Sexual behavior and fertility of males were investigated; the integrated indicator of reproductive potential (FI) was calculate and was estimated with the data of animals from group Control who were given vehicle (water). In the 1st group sexual behavior of males was characterized by accelerating sexual responses on female (double shortening of mounting and intromission latency) and a reduced ability to achieve ejaculation and to start the second round of copulations. The less females have been inseminated by these males (67% vs. 91% in Control group), but almost all became pregnant. As a result of the neonatal induction deterioration in the quality of male gametes intrauterine pregnancy loss increased more than twice, and the total number of foetus decreased (on 21%). These changes have led to a reduction of the male integrated indicator of reproductive potential (Fi) in 2.6 times compared with control animals. Using a NP GdVO4 rehabilitated male sexual behaviour indicators to Control group level, resulting in an increase in the number of fertilized females (up to 95%). In pregnant females decreased fetal losses (up to 15.2% vs. 18.1% in control, p<0,05) and increase in the number of fetuses (on 25%, p<0,05) that shows an improvement in the quality of sperm. The integrated indicator of reproductive potential (F1) increased to (8.3 ± 0.5) vs. (3.0 ± 0.3) u. in the 1st group (without treatment), that statistically higher than in groups Control and 3rd. Application of NP GdVO4 in rats with neonatal inductive pathology of the reproductive function and metabolic disorders normalizes sexual behaviour, the quality of sperm that restores male fertility and improves reproductive potential much more efficiently than the reference drug speman.

Beneficial Effect of Protein Tyrosine Phosphatase Inhibitor and Phytoestrogen in Dyslipidemia-Induced Vascular Dementia in Ovariectomized Rats.

BACKGROUND: Estrogen deficiency and increase in protein tyrosine phosphatase (PTPase) activity may be a key mechanism in postmenopausal dyslipidemia-induced vascular dysfunction and dementia. Thus, the present study has been designed to investigate the effect of biochanin A (BCA, a phytoestrogen) and sodium orthovanadate (SOV), an inhibitor of PTPase in dyslipidemia-induced vascular dementia in ovariectomized rats. METHODS: Female Wistar rats were ovariectomized and fed on high fat diet for 4 weeks to produce dyslipidemia. Dyslipidemia was assessed by estimation of serum lipid levels including total cholesterol, triglyceride, HDL, and LDL levels. Dementia was assessed in terms of increase in brain acetylcholinesterase (AChE) activity and attenuation of learning ability (escape latency time) and memory retention (time spent in target quadrant) using Morris water maze. Vascular dysfunction was assessed in terms of attenuation of acetylcholine-induced endothelium-dependent relaxation (isolated carotid ring preparation), mRNA expression of endothelial nitric oxide synthase, and increase in serum thiobarbituric acid reactive species, superoxide anion level. Neurodegeneration was assessed in hippocampus by hematoxylin and eosin staining. BCA (2.5 and 5 mg/kg) and SOV (5 and 10 mg/kg) were administered alone and in low-dose combination to ovariectomized dyslipidemic rats. RESULTS: BCA (2.5 and 5 mg/kg), SOV (5 and 10 mg/kg), and donepezil (1 mg/kg) significantly improves vascular function, and learning and memory ability and decreases the neuronal cell death, oxidative stress, and AChE in ovariectomized dyslipidemic rats. CONCLUSIONS: Thus, it may be concluded that BCA and SOV attenuate vascular dysfunction and dementia in dyslipidemic ovariectomized rats.

A multifunctional biphasic suspension of mesoporous silica encapsulated with YVO4:Eu3+ and Fe3O4 nanoparticles: synergistic effect towards cancer therapy and imaging.

Polyol mediated synthesized luminescent YVO(4):Eu(3+) nanoparticles (NPs) have been encapsulated in mesoporous silica nanoparticles (MSNs) using the sol-gel process. X-ray diffraction and Fourier transform infrared spectroscopy along with transmission electron microscopy confirm the encapsulation of the YVO(4):Eu(3+) NPs in the SiO(2) matrix. N(2) adsorption/desorption analysis confirms the mesoporous nature of the MSNs and YVO(4):Eu(3+)-MSNs. No significant quenching of the YVO(4):Eu(3+) luminescence is observed for YVO(4):Eu(3+)-MSNs. This nanocomposite has been tested as a potential drug carrier. Efficient loading of doxorubicin hydrochloride (DOX), a typical anticancer drug, is observed which reaches up to 93% in 8 mg ml(-1) of YVO(4):Eu(3+)-MSNs. pH sensitive release of DOX is observed, with 54% release for pH 4.3 and 31% in a physiological environment (pH 7.4). Both MSNs and YVO(4):Eu(3+)-MSNs nanocomposites do not show accountable toxicity to two cell lines, i.e. HeLa and MCF-7. However, as desired, toxicity is observed when cells are incubated with DOX loaded YVO(4):Eu(3+)-MSNs. Laser scanning confocal microscopy images confirm the uptake of the nanocomposite in both cell lines. The morphology of the cells (MCF-7) changes after incubation with DOX loaded YVO(4):Eu(3+)-MSNs, indicating an interaction of DOX with the cells. More cytotoxicity to both cell lines with ∼90% killing is observed due to the synergistic effect of magnetic fluid hyperthermia and chemotherapy using a biphasic suspension of superparamagnetic iron oxide magnetic nanoparticles and DOX loaded YVO(4):Eu(3+)-MSNs. In addition, an AC magnetic field triggers an enhanced drug release.

A tea/vanadate decoction delivered orally over 14 months to diabetic rats induces long-term glycemic stability without organ toxicity.

Vanadium can induce potent hypoglycemic effects in type 1 and type 2 diabetes mellitus animals, but toxic adverse effects have inhibited the translation of these findings. Administration of vanadate in a black tea decoction has shown impressive hypoglycemic effects without evidence of toxicity in short-term studies. The purpose of this study was to investigate the hypoglycemic action and the toxic adverse effects of a tea/vanadate (T/V) decoction in diabetic rats over a 14-month treatment period. Streptozotocin-induced type 1 diabetes mellitus rats were orally gavaged with 40 mg sodium vanadate in a black tea decoction only when blood glucose levels were greater than 10 mmol/L. Glycemic status and liver and kidney function were monitored over 14 months. All of the diabetic rats in this treatment group (n = 25) required treatment with the T/V decoction at the start of the study to reduce blood glucose levels to less than 10 mmol/L. Diarrhea was uncommon among the T/V-treated animals during the first week of T/V treatment and was absent thereafter. There was no evidence of liver or kidney dysfunction or injury. From 2 to 6 months, fewer animals required the T/V treatment to maintain their blood glucose levels. After 9 months of treatment, none of the diabetic animals required any T/V to maintain their blood glucose levels at less than 10 mmol/L. Oral administration of a T/V decoction provides safe, long-acting hypoglycemic effects in type 1 diabetes mellitus rats. The typical glycemic signs of diabetes were absent for the last 5 months of the study.

Metallo-allixinate complexes with anti-diabetic and anti-metabolic syndrome activities.

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 ß-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.

Effective control of blood glucose status and toxicity in streptozotocin-induced diabetic rats by orally administration of vanadate in an herbal decoction.

Vanadium compounds have been well recognized for hypoglycemic effects, but questions remain on gastrointestinal disturbance and possible tissue vanadium accumulation thus slowing the acceptance of vanadium compounds as diabetic therapeutic agents. Our intestinal permeability and toxicity studies of vanadium compounds have suggested that the co-administration of vanadate with Salvia miltiorrhiza Bunge decoction could benefit the therapeutic use of hypoglycemic vanadium compounds. In the present paper, we tested the hypoglycemic effects of vanadate ingested in an aqueous extract of S. Bunge using a streptozocin (STZ)-induced diabetic rat model. Oral administration of vanadate in S. Bunge herbal decoction produced a stable (free of hypoglycemic shock) and long-lasting ( approximately 70day) control of blood glucose status. Effective protection of animal organs from hyperglycemic damage was also observed. As expected, the herbal extract significantly alleviated vanadium toxicity, i.e. GI stress and metal accumulation. In addition, the result suggesting that vanadium-induced amelioration of the diabetic state appears to be secondary to the preservation of a functional portion of the pancreatic beta-cells which initially survived STZ-toxicity. These studies provide new insight into the therapeutic treatment of diabetics with vanadium compounds.

Syntheses of vanadyl and zinc(II) complexes of 1-hydroxy-4,5,6-substituted 2(1H)-pyrimidinones and their insulin-mimetic activities.

Control of the glucose level in the blood plasma has been achieved in vitro and in vivo by administration of vanadium and zinc in form of inorganic salts. It has been shown that elements are poorly absorbed in their inorganic forms and required high doses which have been associated with undesirable side effects. Many researchers, therefore, have focused on metal complexes that were prepared from VOSO(4) or ZnSO(4) and low-molecular-weight bidentate ligands. Seven kinds of 1-hydroxy-4,6-disubstituted and 1-hydroxy-4,5,6-trisubstituted-2(1H)-pyrimidinones were synthesized by reaction of N-benzyloxyurea and beta-diketones and subsequent removal of the protecting group. Six kinds of 1-hydroxy-4-(substituted)amino-2(1H)-pyrimidinones were synthesized by the substitution reaction of 1-benzyloxy-4-(1',2',4'-triazol-1'-yl)-2(1H)-pyrimidinone with various alkyl amines or amino acids. Treatment with VOSO(4) and ZnSO(4) or Zn(OAc)(2) afforded vanadyl(IV) and zinc(II) complexes which were characterized by means of (1)H NMR, IR, EPR, and UV-vis spectroscopies, and combustion analysis. The in vitro insulin-mimetic activity of these complexes was evaluated from 50% inhibitory concentrations (IC(50)) on free fatty acid (FFA) release from isolated rat adipocytes treated with epinephrine. Vanadyl complexes of 4,6-disubstituted-2(1H)-pyrimidinones showed higher insulin-mimetic activities than those of 4,5,6-trisubstituted ones. On the other hand, Zn(II) complexes showed lower insulin-mimetic activities than VOSO(4) and ZnSO(4) as positive controls. It was found that the balance of the hydrophilicity and/or hydrophobicity is important for higher insulin-mimetic activity. The in vivo insulin-mimetic activity was evaluated with streptozotocin (STZ)-induced diabetic rats. Blood glucose levels were lowered from hyperglycemic to normal levels after the treatment with bis(1,2-dihydro-4,6-dimethyl-2-oxo-1-pyrimidinolato)oxovanadium(IV) by daily intraperitoneal injections. The improvement in glucose tolerance was also confirmed by an oral glucose tolerance test.

Modulation of glucose transporter (GLUT4) by vanadate and Trigonella in alloxan-diabetic rats.

Oral administration of vanadate is an effective treatment for diabetes in animal models. However, vanadate exerts these effects at high doses and several toxic effects are produced. Low doses of vanadate are relatively safe but are unable to elicit any antidiabetic effect. The present study explored the prospect of using low doses of vanadate in combination with Trigonella seed powder (TSP) to evaluate their antidiabetic effect in alloxan-diabetic rats. Alloxan-diabetic rats were treated with insulin, vanadate, TSP and vanadate and TSP in combination for 3 weeks. The effect of these antidiabetic compounds was examined on general physiological parameters and distribution of glucose transporter (GLUT4) in skeletal muscle by immunoblotting and immunohistochemistry. Treatment of alloxan-diabetic rats with insulin, vanadate, TSP and vanadate in combination with TSP revived normoglycemia and restored the disturbances in the distribution of GLUT4 in skeletal muscle. TSP treatment was only partially effective in the restoration of diabetic alterations. The treatment of diabetic rats with combined doses of vanadate and TSP was most effective in the normalization of plasma glucose levels and correction of altered GLUT4 distribution.

Restoration of ultrastructural and biochemical changes in alloxan-induced diabetic rat sciatic nerve on treatment with Na3VO4 and Trigonella--a promising antidiabetic agent.

Vanadium has been reported to have broad pharmacological activity both in vitro and in vivo. Vanadium compound, sodium orthovanadate, Na3VO4, is well known for its hypoglycaemic effects. However, Na3VO4 exerts these effects at relatively high doses (0.6 mg/ml) and exhibit several toxic effects. In the present study lower doses of Na3VO4 (0.2 mg/ml) are combined with Trigonella foenum graecum seed powder (TSP), another hypoglycaemic agent, to reduce its toxicity without compromising its antidiabetic potential. The efficacy of the lower doses of Na3VO4 has been investigated in restoring the altered glucose metabolism and histological structure in the sciatic nerves in 21 and 60 days alloxan diabetic rats. A portion of the glucose was found to be channelled from the normal glycolytic route to polyol pathway, evident by the reduced hexokinase activity and increased polyol pathway enzymes aldose reductase and sorbitol dehydrogenase activity causing accumulation of sorbitol and fructose in diabetic conditions. Ultrastructural observation of the sciatic nerve showed extensive demylination and axonal loss after eight weeks of diabetes induction. Blood glucose levels increased in diabetic rats were normalized with the lower dose of vanadium and Trigonella treatment. The treatment of the diabetic rats with vanadium and Trigonella prevented the activation of the polyol pathway and sugar accumulations. The sciatic nerves were also protected against the structural abnormalities found in diabetes with Trigonella foenum graecum as well as Na3VO4. Results suggest that lower doses of Na3VO4 may be used in combination with TSP as an efficient antidiabetic agent to effectively control the long-term complications of diabetes in tissues like peripheral nerve.

Complementary inhibition of synoviocyte, smooth muscle cell or mouse lymphoma cell proliferation by a vanadyl curcumin complex compared to curcumin alone.

A novel vanadyl curcumin complex (VO(cur)2) has been synthesized and and its physicochemical properties characterized. Biological characterization included in vitro testing for anti-rheumatic activity in synoviocytes, angiogenesis inhibition in smooth muscle cells and anti-cancer potential in mouse lymphoma cells; as well as in vivo testing for hypoglycemic activity by oral gavage in streptozotocin (STZ)-diabetic rats. VO(cur)2 was more effective as an anti-cancer agent, compared to uncomplexed curcumin or vanadyl ion alone, was more than twice as effective as curcumin alone as an anti-arthritic agent, and was more than four times as effective as curcumin alone in inhibiting smooth muscle cell proliferation. In both acute and chronic screening tests, VO(cur)2 was ineffective as an insulin mimetic agent; however, it also proved to be exceptionally non-toxic, with no evidence of negative symptomatology during a month-long treatment period, at doses up to and including 2.0 mmol kg(-1) day(-1).

Effects of sodium-orthovanadate and Trigonella foenum-graecum seeds on hepatic and renal lipogenic enzymes and lipid profile during alloxan diabetes.

Sodium-orthovanadate (SOV) and seed powder of Trigonella foenum graecum Linn. (common name: fenugreek, family: Fabaceae) (TSP) besides being potential hypoglycemic agents have also been shown to ameliorate altered lipid metabolism during diabetes. This study evaluates the short-term effect of oral administration of SOV and TSP separately and in concert (for 21 days) on total lipid profile and lipogenic enzymes in tissues of alloxan diabetic rats. Diabetic rats showed 4-fold increase in blood glucose. The level of total lipids, triglycerides and total cholesterol in blood serum increased significantly during diabetes. During diabetes the level of total lipids increased significantly (P < 0.001) in liver and in kidney by 48% and 55%, respectively, compared to control. Triglycerides level increased by 32% (P < 0.01) in liver and by 51% (P < 0.005) in kidney, respectively, compared to control. Total cholesterol level also increased significantly in both liver and kidney (P < 0.01 and P < 0.001, respectively). The activities of NADP-linked enzymes; namely glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme (ME), isocitrate dehydrogenase (ICDH), and the activities of lipogenic enzymes namely ATP-citrate lyase (ATP-CL) and fatty acid synthase (FAS) were decreased significantly in liver and increased in kidney during diabetes as compared to control. SOV and TSP administration to diabetic animals prevented the development of hyperglycemia and alteration in lipid profile in plasma and tissues and maintained it near normal. Maximum prevention was observed in the combined treatment with lower dose of SOV (0.2%) after 21 days. We are presenting for the first time effectiveness of combined treatment of SOV and TSP in amelioration of altered lipid metabolism during experimental type-I diabetes.

Codelivery of a tea extract prevents morbidity and mortality associated with oral vanadate therapy in streptozotocin-induced diabetic rats.

Oral administration of vanadate has a strong hypoglycemic effect but results in toxic side effects like life-threatening diarrhea. Tea is known to have potent antidiarrhea effects. We investigated the potential of suspending the vanadate in a tea decoction to reduce the diarrheatic action of vanadate. A concentrated extract of Lichee black tea was, therefore, added to sodium orthovanadate. Streptozotocin (STZ)-induced diabetic rats were orally gavaged with vanadate suspended in water or in the tea decoction, or with the tea extract alone. Blood glucose levels were assessed daily over 11 weeks with levels greater than 10 mmol/L warranting therapeutic intervention. Both the vanadate/water and vanadate/tea solutions acutely reduced blood glucose. The tea extract alone had no effect. The majority of vanadate/water-treated rats developed diarrhea and mortality rates approached 40%. Vanadate/tea-treated diabetic rats experienced no diarrhea or mortality and liver and kidney analyses (plasma ALT and creatinine, blood urea nitrogen [BUN], and urine-specific gravity) were normal. Animals treated with vanadate/tea retained blood glucose levels less than 10 mmol/L for an average of 24 consecutive days without subsequent treatments. Cataract formation was completely prevented. The mechanism of action of vanadate may have involved beta-cell stimulation because vanadate/tea-treated diabetic rats exhibited normal plasma insulin levels. In summary, because of its long-lasting effects, oral administration, and lack of side effects, vanadate/tea represents a potentially important alternative therapy for an insulin-deficient diabetic state.

Caraway and caper: potential anti-hyperglycaemic plants in diabetic rats.

The hypoglycaemic effect of aqueous extracts of Carum carvi (CC) and Capparis spinosa L. (CS) fruit were investigated in normal and streptozotocin (STZ) diabetic rats. After a single dose or 14 daily doses, oral administration of the aqueous CC and CS extracts (20 mg/kg) produced a significant decrease on blood glucose levels in STZ diabetic rats (P < 0.001); the blood glucose levels were nearly normalised 2 weeks after daily repeated oral administration of both aqueous CC and CS extracts (20 mg/kg) (P < 0.001). No highly significant changes on blood glucose levels were noticed in normal rats after both acute and chronic treatments with CS and CC. In addition, no changes were observed in basal plasma insulin concentrations after treatment with these plants in either normal or STZ diabetic rats indicating that the underlying mechanism of this pharmacological activity seems to be independent of insulin secretion. We conclude that aqueous extracts of CC and CS exhibit a potent anti-hyperglycaemic activity in STZ rats without affecting basal plasma insulin concentrations.

Phlorizin-like effect of Fraxinus excelsior in normal and diabetic rats.

The purpose of this study was to determine the underlying mechanism of the hypoglycaemic activity of the aqueous extract perfusion of Fraxinus excelsior L. (FE) in normal and streptozotocin-induced diabetic rats. The aqueous extract was administered intravenously and the blood glucose changes were determined within four hours after starting the treatment. Plasma insulin concentrations and glycosuria were determined. The aqueous extract at a dose of 10 mg/kg/h produced a significant decrease in blood glucose levels in normal rats (P < 0.001) and even more in diabetic rats (P < 0.001). This hypoglycaemic effect might be due to an extra-pancreatic action of the aqueous extract of FE, since the basal plasma insulin concentrations were unchanged after FE treatment. A potent increase of glycosuria was observed both in normal and diabetic rats (P < 0.001). We conclude that aqueous extract perfusion of FE caused a potent inhibition of renal glucose reabsorption. This renal effect might be at least one mechanism explaining the observed hypoglycaemic activity of this plant in normal and diabetic rats.

Metabolic effects of sodium metavanadate in humans with insulin-dependent and noninsulin-dependent diabetes mellitus in vivo and in vitro studies.

To investigate the efficacy and mechanism of action of sodium metavanadate as an oral hypoglycemic agent, five insulin-dependent diabetes mellitus (IDDM) and five noninsulin-dependent diabetes mellitus (NIDDM) patients were studied before and after 2 weeks of oral sodium metavanadate (NaVO3; 125 mg/day). Glucose metabolism measured during a two-step euglycemic insulin clamp was not significantly increased by vanadate therapy in patients with IDDM, but was improved by 29% during the low dose (0.5 mU/kg.min) insulin infusion and 39% during the high dose (1.0 mU/kg.min) in patients with NIDDM. The changes in glucose metabolism were largely accounted for by an increase in nonoxidative glucose disposal, as measured by indirect calorimetry. Basal hepatic glucose production and suppression of hepatic glucose production by insulin were unchanged by vanadate therapy. There was a significant decrease in insulin requirements in the patients with IDDM (39.1 +/- 6.6 to 33.8 +/- 4.7 U/day; P < 0.05). Cholesterol levels significantly decreased in both IDDM (4.53 +/- 0.16 vs. 4.27 +/- 0.22 mmol/L; P = 0.06) and NIDDM (6.92 +/- 0.75 vs. 5.28 +/- 0.46 mmol/L; P < 0.05). After NaVO3 therapy, there was a 1.7- to 3.9-fold increase in basal mitogen-activated protein and S6 kinase activities in mononuclear cells from patients with IDDM and NIDDM that mimicked the effect of insulin stimulation in controls. The most common adverse effect of oral NaVO3 was mild gastrointestinal intolerance. These data suggest that vanadate or related agents may have a potential role as adjunctive therapy in patients with diabetes mellitus.

Inhibition of altered liver cell foci and persistent nodule growth by vanadium during diethylnitrosamine-induced hepatocarcinogenesis in rats.

The effect of vanadium, a recently established trace element, on diethylnitrosamine (DENA)-induced hepatocarcinogenesis was examined in male Sprague-Dawley rats. Rats were divided into four groups (Groups 1-4). While Group 1 served as normal group, initiation of hepatocarcinogenesis was performed in all other groups (Groups 2-4) by a single intraperitoneal injection of DENA (200 mg/kg body weight). Supplementary vanadium at the level of 0.2 and 0.5 ppm (as ammonium monovanadate) added to the drinking water was given to Groups 3 and 4 respectively ad libitum four weeks before DENA administration and continued for 8 or 16 weeks after the carcinogenic insult. Rats were sacrificed at the 12th or 20th week after the experiment began. No significant differences were observed in food and water intakes or in growth rates among the groups. Supplementation with vanadium (in Groups 3 and 4) for 12 or 20 weeks dose-dependently reduced the incidence, total number, multiplicity and altered the size distribution of visible persistent (neoplastic) hepatocyte nodules as compared to DENA control (Group 2). Mean nodular volume and nodular volume as percentage of liver volume were also inhibited upon vanadium supplementations. The morphometric analysis of preneoplastic focal lesions observed in hematoxylin and eosin-stained liver sections revealed the occurrence of a decreased number of altered liver cell foci/cm2 and the average focal area, coupled with a decrement in the percentage area of liver parenchyma occupied by foci in vanadium-supplemented groups (Groups 3 and 4). All these results were found to be more pronounced at the 20th week as compared to the 12th week of the study. However, the results with 0.5 ppm vanadium at the 20th week were mostly at a statistically significant level. The findings of the study suggest that vanadium at a dose of 0.5 ppm may have a potential anticarcinogenic property against chemically induced hepatic neoplasia without any apparent sign of toxicity. This attribute could open new vistas in cancer chemotherapy.

Vanadate, molybdate and tungstate for orthomolecular medicine.

Recent studies indicate that oxyanions, such as vanadate (V) or vanadyl (IV), cause insulin-like effects on rats by stimulating the insulin receptor tyrosine kinase. Tungstate (VI) and molybdate (VI) show the same effects on rat adipocytes and hepatocytes. Results of uncontrolled trials on volunteers accumulated in Japan also suggest that tungstate effectively regulates diabetes mellitus without detectable side effects. Since these oxyanions naturally exist in organisms, oxyanion therapy, the oral administration of vanadate, vanadyl, molybdate, or tungstate, can be considered to be orthomolecular medicine. Therefore, these oxyanions may provide a viable alternative to chemotherapy. Many diseases in addition to diabetes mellitus might also be treated since the implication of these results is that tyrosine kinases are involved in a variety of diseases.

In vivo antidiabetic actions of naglivan, an organic vanadyl compound in streptozotocin-induced diabetes.

The vanadyl (+IV) form of vanadium has been demonstrated to have insulin-mimetic activity in vivo. In an effort to improve the poor gastrointestinal absorption of the ion, an organic complex of vanadyl (naglivan) was synthesized. We tested the antidiabetic effects of naglivan in rats made diabetic with streptozotocin (55 mg/kg, i.v.). Four days after the streptozotocin injection, one diabetic group (DVI) and a control group (CV) were treated with naglivan (50 mg/kg/day, equivalent to 0.06 mmol vanadium/kg/day) by oral gavage. Treatment in the DVI group was supplemented with daily insulin while a second diabetic group (DI) was administered daily titrated doses of insulin alone (Protamine Zinc, s.c.) to achieve stable euglycemia. The dose of exogenous insulin required to maintain normal glucose was significantly lower in the DVI group compared to the DI throughout the treatment period. At the end of week 3, exogenous insulin was withdrawn from both the DVI and DI groups, while naglivan treatment was continued in the CV and DVI groups for an additional 5 weeks. At termination, hearts were isolated and cardiac function (+dP/dt, -dP/dt and left ventricular developed pressure) was assessed in all the animals. After insulin was withdrawn, 4/8 DVI animals which continued to receive naglivan had consistent normoglycemia (as determined by % glycosylated hemoglobin) and an improved cardiac function. All the DI animals and 4/8 DVI rats were hyperglycemic and had depressed heart function despite having similar plasma insulin levels to the euglycemic DVI animals. As with vanadyl sulfate, there were no signs of long-term toxicity with regards to renal or liver function after 8 weeks of treatment. Thus, naglivan is an orally effective form of vanadyl with an oral potency 7.6 times greater than that of vanadyl sulfate (minimum effective dose: 0.06 mmol vanadium.kg-1.day-1) as compared to vanadyl sulfate (0.46 mmol vanadium.kg-1.day-1). The lack of incidence of diarrhea in either control or diabetic animals demonstrates that naglivan could be a more therapeutically desirable form of vanadyl.