Histological and Memory Alterations in an Innovative Alzheimer's Disease Animal Model by Vanadium Pentoxide Inhalation.

Background: Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2O5) causes cytoskeletal alterations suggesting that V2O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer's disease (AD)-like hippocampal cell death. Objective: This work aims to characterize an innovative AD experimental model through chronic V2O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-ß (Aß) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures. Methods: 20 male Wistar rats were divided into control (deionized water) and experimental (0.02 M V2O5 1 h, 3/week for 6 months) groups (n = 10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation. Results: Cognitive results in the T-maze showed memory impairment from the third month of V2O5 inhalation. We also noted NFTs, Aß plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected. Conclusions: This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage.

Effects of Vanadium Inhalation and Sweetened Beverage Ingestion in Mice: Morphological and Biochemical Changes in the Liver.

The aim of this report was to evaluate the morphological and biochemical changes in the liver by the inhalation of vanadium and consumption of sweetened beverages in a subchronic murine model. Forty CD-1 male mice were randomly divided into four groups: control, vanadium (V), sucrose 30% (S), and vanadium-sucrose (V + S). V was inhaled (1.4 mg/m3) for 1h, twice/week; 30% sucrose solution was given orally ad libitum. Blood samples were obtained for AST, ALT, and LDH determination. Liver samples were processed for histological and oxidative stress immunohistochemical evaluation with 4-hydroxynonenal at weeks 4 and 8 of exposure. Regarding liver function tests, a statistically significant increase (P < 0.05) was observed in groups V, S, and V + S at weeks 4 and 8 compared to the control group. A greater number of hepatocytes with meganuclei and binuclei were observed in V and V + S at week 8 compared to the other groups. Steatosis and regenerative changes were more extensive in the eighth week V + S group. 4-Hydroxynonenal immunoreactivity increased in the V + S group at both exposure times compared to the other groups; however, the increment was more evident in the V + S group at week 4 compared to the V + S group at week 8. An increase in De Ritis ratio (>1) was noticed in experimental groups at weeks 4 and 8. Findings demonstrate that in the liver, V, S, and V + S induced oxidative stress and regenerative changes that increased with the length of exposure. Results support possible potentiation of liver damage in areas with high air pollution and high-sweetened beverage consumption.

PTEN inhibitor bpV(HOpic) confers protection against ionizing radiation.

Exposure to Ionizing radiation (IR) poses a severe threat to human health. Therefore, there is an urgent need to develop potent and safe radioprotective agents for radio-nuclear emergencies. Phosphatidylinositol-3-kinase (PI3K) mediates its cytoprotective signaling against IR by phosphorylating membrane phospholipids to phosphatidylinositol 3,4,5 triphosphate, PIP3, that serve as a docking site for AKT. Phosphatase and Tensin Homolog on chromosome 10 (PTEN) antagonizes PI3K activity by dephosphorylating PIP3, thus suppressing PI3K/AKT signaling that could prevent IR induced cytotoxicity. The current study was undertaken to investigate the radioprotective potential of PTEN inhibitor (PTENi), bpV(HOpic). The cell cytotoxicity, proliferation index, and clonogenic survival assays were performed for assessing the radioprotective potential of bpV(HOpic). A safe dose of bpV(HOpic) was shown to be radioprotective in three radiosensitive tissue origin cells. Further, bpV(HOpic) significantly reduced the IR-induced apoptosis and associated pro-death signaling. A faster and better DNA repair kinetics was also observed in bpV(HOpic) pretreated cells exposed to IR. Additionally, bpV(HOpic) decreased the IR-induced oxidative stress and significantly enhanced the antioxidant defense mechanism in cells. The radioprotective effect of bpV(HOpic) was found to be AKT dependant and primarily regulated by the enhanced glycolysis and associated signaling. Furthermore, this in-vitro observation was verified in-vivo, where administration of bpV(HOpic) in C57BL/6 mice resulted in AKT activation and conferred survival advantage against IR-induced mortality. These results imply that bpV(HOpic) ameliorates IR-induced oxidative stress and cell death by inducing AKT signaling mediated antioxidant defense system and DNA repair pathways, thus strengthening its potential to be used as a radiation countermeasure.

Internal dose of vanadium in rats following repeated exposure to vanadyl sulfate and sodium orthovanadate via drinking water.

Vanadium is a ubiquitous environmental contaminant that exists in multiple oxidation states. Humans are exposed to vanadyl (V4+) and vanadate (V5+) from dietary supplements, food, and drinking water and hence there is a concern for adverse human health. The current investigation is aimed at identifying vanadium oxidation states in vitro and in vivo and internal concentrations following exposure of rats to vanadyl sulfate (V4+) or sodium metavanadate (V5+) via drinking water for 14 d. Investigations in simulated gastric and intestinal fluids showed that V4+ was stable in gastric fluid while V5+ was stable in intestinal fluid. Analysis of rodent plasma showed that the only vanadium present was V4+, regardless of the exposed compound suggesting conversion of V5+ to V4+ in vivo and/or instability of V5+ species in biological matrices. Plasma, blood, and liver concentrations of total vanadium, after normalizing for vanadium dose consumed, were higher in male and female rats following exposure to V5+ than to V4+. Following exposure to either V4+ or V5+, the total vanadium concentration in plasma was 2- to 3-fold higher than in blood suggesting plasma as a better matrix than blood for measuring vanadium in future work. Liver to blood ratios were 4-7 demonstrating significant tissue retention following exposure to both compounds. In conclusion, these data point to potential differences in absorption and disposition properties of V4+ and V5+ salts and may explain the higher sensitivity in rats following drinking water exposure to V5+ than V4+ and highlights the importance of internal dose determination in toxicology studies.

The limitations of using the NTP chronic bioassay on vanadium pentoxide in risk assessments.

Regulatory interest in assessing the health effects of vanadium compounds is hindered by the limited chronic toxicity data available. The National Toxicology Program (NTP) conducted a robust chronic inhalation bioassay of crystalline vanadium pentoxide (V2O5), but this study has noteworthy limitations. Multiple dose range-finding studies were conducted at two separate laboratories that showed cross-laboratory differences in lung pathology (inflammation) in both species and likely complicated dose-selection. In mice, the only tissue pathology (inflammation and tumors) was at the site of entry, the respiratory system. Although significantly different from control, because lung tumor incidences were at a maximal level across all concentrations tested, the ability to extrapolate risks to the public is problematic. In rats, lung inflammation and vanadium lung burdens were comparable to those of mice, but lung tumorigenicity was not substantiated, further raising questions about appropriate species extrapolation. Open questions also exist regarding test material chemical characterization, as the laboratory relied on vanadium measurement in test chambers as a surrogate for V2O5. In sum, the NTP V2O5 study does not provide an appropriate dataset for purposes of classification and risk assessment. Additional repeat exposure studies of vanadium compounds are needed and recommendations for future studies are provided.

The neuroprotective effect of bisperoxovandium (pyridin-2-squaramide) in intracerebral hemorrhage.

Background: The authors have recently designed a new compound bisperoxovandium (pyridin-2-squaramide) [bpV(pis)] and verified that bpV(pis) confers neuroprotection through suppressing PTEN and activating ERK1/2, respectively. Intracerebral hemorrhage (ICH) is the second most common cause of stroke and has severe clinical outcome. In this study, we investigate the effect of bpV(pis) in ICH model both in vivo and in vitro. Materials and methods: The novel drug bpV(pis) was synthesized in the Faculty of Pharmacy, Wuhan University School of Medicine. An ICH model was generated on both SD rats and cells. bpV(pis) was injected into intracerebroventricular or culture media. Western blotting was applied to test the signal pathway. To determine the effect of bpV(pis) on PTEN inhibition and ERK1/2 activation, we measured the phosphorylation level of AKT (a direct downstream target of PTEN that negatively regulates AKT) and ERK1/2. FJC, MTT, and LDH were applied to measure the cell viability. Neurobehavioral tests were performed to measure the effect of bpV(pis). Results: The in vivo results showed that intracerebroventricular administration of bpV(pis) significantly alleviates hematoma, the damage of brain-blood barrier and brain edema. The in vitro results demonstrated that bpV(pis) treatment reduces ICH-induced neuronal injury. Western blotting results identified that bpV(pis) exerts a neuroprotective effect by significantly increasing the phosphorylation level of AKT and ERK1/2 after experimental ICH. Neurobehavioral tests indicate that bpV(pis) promotes functional recovery in ICH animals. Conclusion: This study provides first and direct evidence for a potential role of bpV(pis) in ICH therapy.

pH-activated heat shock protein inhibition and radical generation enhanced NIR luminescence imaging-guided photothermal tumour ablation.

Photothermal therapy had great potential in being a new approach of tumour ablation due to their high selectivity and low side effect. However, the shallow penetration depth of near-infrared (NIR) irradiation resulted in the limited curative effect. Herein, a novel nanomedicine was developed based on the indocyanine green-loaded vanadium oxide nanocomposites (VO2-ICG) for pH-activated NIR luminescence imaging-guided enhanced photothermal tumour ablation. In acidic tumour microenvironment, the VO2 NPs were decomposed and released VO2+, which could not only inhibit the function of 60 kDa heat shock protein (HSP60), but also generate hydroxyl radical (OH) by catalysing intratumoral H2O2. Furthermore, the ICG was also released in the decomposition process of VO2 NPs, allowing the pH-activated NIR luminescence imaging and photothermal therapy. The inhibition of HSP60 down-regulated the heat tolerance of cells and the generation of OH up-regulated the intracellular oxidative stress, which enhanced the photothermal therapeutic efficiency. Our work demonstrated a promised method to enhance photothermal therapeutic effect, highlighting the importance of HSP inhibition and OH generation in promoting cell apoptosis under mild hyperthermia.

A novel squaramide compound alleviates cognitive deficits through activation of Akt and Erk1/2 in a rat model of vascular dementia.

Vascular dementia is the second most common type of dementia, yet no effective treatment for it exists. Akt and Erk1/2 signaling pathways are involved in neuronal survival. It has been reported that bisperoxovanadium (pyridin-2-squaramide), a novel squaramide compound, protects against cerebral ischemia injury via activation of Akt and Erk1/2. Here, the potential neuroprotective effect of bisperoxovanadium is shown for the first time in a model of vascular dementia induced in 6-month-old male Sprague-Dawley rats by two-vessel occlusion injury applied to 6-month-old. Following this lesion, bisperoxovanadium (pyridin-2-squaramide) (1 mg/kg/day) was intragastrically administered for four successive weeks. The Morris water maze test estimated cognitive function. The morphological examination was performed by hematoxylin-eosin staining. Akt and Erk1/2 protein abundance were assessed by Western blot. Results showed that bisperoxovanadium (pyridin-2-squaramide) attenuated not only cognitive dysfunction but also alleviated histopathological changes in rats with vascular dementia. Moreover, bisperoxovanadium (pyridin-2-squaramide) ultimately reduced neuronal apoptosis represented by the Bax/Bcl-2 ratio in the CA1 (cornu ammonis 1) region of the hippocampus. Importantly, the levels of p-Akt(ser473) and p-Erk1/2(Thr202/Tyr204>) were increased after treatment with bisperoxovanadium (pyridin-2-squaramide). It is concluded that the novel squaramide compound bisperoxovanadium (pyridin-2-squaramide) might be effective in the treatment of vascular dementia by activation of Akt and Erk1/2.

Influence of Feeding Inorganic Vanadium on Growth Performance, Endocrine Variables and Biomarkers of Bone Health in Crossbred Calves.

The nutritional essentialities of transition element vanadium (V) as micro-nutrient in farm animals have not yet been established, though in rat model, vanadium as vanadate has been reported to exert insulin-mimetic effect and shown to be needed for proper development of bones. The objective of this study was to determine the effect of V supplementation on growth performance, plasma hormones and bone health status in calves. Twenty-four crossbred calves (body weight 72.83 ± 2.5 kg; age 3-9 months) were blocked in four groups and randomly assigned to four treatment groups (n = 6) on body weight and age basis. Experimental animals were kept on similar feeding regimen except that different groups were supplemented with either 0, 3, 6 or 9 ppm inorganic V/kg DM. Effect of supplementation during 150-day experimental period was observed on feed intake, body weight gain, feed efficiency, body measures, endocrine variables, plasma glucose and biomarkers of bone health status. Supplementation of V did not change average daily gain (ADG), dry matter intake (DMI), feed efficiency and body measures during the experimental period. During the post-V supplementation period plasma insulin-like growth factor-1 (IGF-1), triiodothyronine (T3) and thyroxin (T4) concentrations were increased and observed highest in 9 mg V/kg DM fed calves; however, levels of insulin, glucose, parathyroid hormone (PTH) and calcitonin hormones remained similar among calves fed on basal or V-supplemented diets. Bone alkaline phosphatase (Bone-ALP) concentration was increased (P < 0.05); however, plasma protein tyrosine phosphatase (PTP) level decreased (P < 0.05) in 6 and 9 mg V/kg DM supplemented groups. Plasma hydroxyproline (Hyp) and tartrate-resistant acid phosphatase (TRAP) concentration were unchanged by V supplementation. Blood V concentration showed positive correlation with supplemental V levels. These results suggest that V may play a role in modulation of the action of certain endocrine variables and biomarkers of bone health status in growing crossbred calves.

Bis(4,4'-dimethyl-2,2'-bipyridine)oxidovanadium(IV) Sulfate Dehydrate: Potential Candidate for Controlling Lipid Metabolism?

Vanadium is a trace element mainly connected with regulation of insulin metabolism which is particularly important in diabetes. In recent years, organic complexes of vanadium seem to be more interesting than inorganic salts. Nevertheless, the effect of vanadium on lipid metabolism is still a problematic issue; therefore, the main purpose of this study was to investigate the effect of 3 organic complexes of vanadium such as sodium (2,2'-bipyridine)oxidobisperoxovanadate(V) octahydrate, bis(2,2'-bipyridine)oxidovanadium(IV) sulfate dehydrate, and bis(4,4'-dimethyl-2,2'-bipyridine)oxidovanadium(IV) sulfate dihydrate in conjunction with high-fat as well as control diet in nondiabetes model on the following lipid parameters: total cholesterol, triglycerides, and high density lipoprotein as well as activity of paraoxonase 1. All of these parameters were determined in plasma of Wistar rats. The most significant effect was observed in case of bis(4,4'-dimethyl-2,2' bipyridine)oxidovanadium(IV) sulfate dehydrate in rats fed with high-fat diet. Based on our research, bis(4,4'-dimethyl-2,2'-bipyridine)oxidovanadium(IV) sulfate dihydrate should be the aim of further research and perhaps it will be an important factor in the regulation of lipid metabolism.

Ameliorative effect of an oxovanadium (IV) complex against oxidative stress and nephrotoxicity induced by cisplatin.

OBJECTIVE: The present study was designed to investigate the chemoprotective efficacy of an L-cysteine-based oxovanadium (IV) complex, namely, oxovanadium (IV)-L-cysteine methyl ester complex (VC-IV) against cisplatin (CDDP)-induced renal injury in Swiss albino mice. METHODS: CDDP was administered intraperitoneally (5 mg/kg body weight) and VC-IV was administered orally (1 mg/kg body weight) in concomitant and 7 days pre-treatment schedule. RESULTS: CDDP-treated mice showed marked kidney damage and renal failure. Administration of VC-IV caused significant attenuation of renal oxidative stress and elevation of antioxidant status. VC-IV also significantly decreased serum levels of creatinine and blood urea nitrogen, and improved histopathological lesions. Western blot analysis of the kidneys showed that VC-IV treatment resulted in nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) through modulation of cytosolic Kelch-like ECH-associated protein 1. Thus, VC-IV stimulated Nrf2-mediated activation of antioxidant response element (ARE) pathway and promoted expression of ARE-driven cytoprotective proteins, heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1, and enhanced activity of antioxidant enzymes. Interestingly, VC-IV did not alter the bioavailability and renal accumulation of CDDP in mice. DISCUSSION: In this study, VC-IV exhibited strong nephroprotective efficacy by restoring antioxidant defense mechanisms and hence may serve as a promising chemoprotectant in cancer chemotherapy.

Evaluation of cII mutations in lung of male Big Blue mice exposed by inhalation to vanadium pentoxide for up to 8 weeks.

Chronic inhalation of vanadium pentoxide (V2O5) increases the incidence of alveolar/bronchiolar tumors in male and female B6C3F1 mice at 1, 2, or 4 mg/m(3). The genotoxicity of V2O5 has been extensively investigated in the literature with mixed results. In general, tests for gene mutations have been negative. Both positive and negative results were reported for clastogenicity in vitro with some reports suggesting aneugenic potential. In vivo, V2O5 was negative in the mouse micronucleus test (erythrocyte) and comet assay (lung). Previously, K-ras mutations have been detected in the lung tumors in mice exposed to V2O5. Recently, a short-term inhalation study in B6C3F1 mice reported slight induction of 8-oxodGuo DNA lesions in lungs. Because 8-oxodGuo DNA lesions can lead to gene mutations if not repaired or if misrepaired, we have used groups of transgenic Big Blue (BB) mice (B6C3F1) to test whether V2O5 has mutagenic potential in vivo in the tumor target tissue under the conditions of the bioassay. Groups of six male BB mice were exposed to particulate aerosols containing 0, 0.1, or 1 mg/m(3) (tumorigenic concentration) V2O5 for 4 or 8 weeks (6h/day, 5 days/week) and cII mutant frequencies (MFs) were evaluated in the right lungs. A significant increase in lung weight was noted in mice exposed to 1 mg/m(3) V2O5 (P ≤ 0.05) compared to sham control, confirming exposure to an inflammatory level of the test material. The mean MFs (× 10(-6)) of mice in the 4-week exposure groups were 30 (sham control), 39 (0.1 mg/m(3)), and 24 (1 mg/m(3)) while the corresponding values in the 8-week exposure groups were 29, 48, and 17, respectively. None of these cII MFs measured at any time point was significantly higher than the corresponding control MFs (P ≥ 0.1). Overall, these results suggest that mutagenicity is not likely to be an initial key event in the lung tumorigenicity of V2O5.

Quantification of Kras mutant fraction in the lung DNA of mice exposed to aerosolized particulate vanadium pentoxide by inhalation.

This study investigated whether Kras mutation is an early event in the development of lung tumors induced by inhalation of particulate vanadium pentoxide (VP) aerosols. A National Toxicology Program tumor bioassay of inhaled particulate VP aerosols established that VP-induced alveolar/bronchiolar carcinomas of the B6C3F1 mouse lung carried Kras mutations at a higher frequency than observed in spontaneous mouse lung tumors. Therefore, this study sought to: (1) characterize any Kras mutational response with respect to VP exposure concentration, and (2) investigate the possibility that amplification of preexisting Kras mutation is an early event in VP-induced mouse lung tumorigenesis. Male Big Blue B6C3F1 mice (6 mice/group) were exposed to aerosolized particulate VP by inhalation, 6h/day, 5 days/week for 4 or 8 weeks, using VP exposure concentrations of 0, 0.1, and 1 mg/m(3). The levels of two different Kras codon 12 mutations [GGT → GAT (G12D) and GGT → GTT (G12V)] were measured in lung DNAs by Allele-specific Competitive Blocker PCR (ACB-PCR). For both exposure concentrations (0.1 and 1.0mg/m(3)) and both time points (4 and 8 weeks), the mutant fractions observed in VP-exposed mice were not significantly different from the concurrent controls. Given that 8 weeks of inhalation of a tumorigenic concentration of particulate aerosols of VP did not result in a significant change in levels of lung Kras mutation, the data do not support either a direct genotoxic effect of VP on Kras or early amplification of preexisting mutation as being involved in the genesis of VP-induced mouse lung tumors under the exposure conditions used. Rather, the data suggest that accumulation of Kras mutation occurs later with chronic VP exposure and is likely not an early event in VP-induced mouse lung carcinogenesis.

Functional and morphological olfactory bulb modifications in mice after vanadium inhalation.

Neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, have olfaction impairment. These pathologies have also been linked to environmental pollutants. Vanadium is a pollutant, and its toxic mechanisms are related to the production of oxidative stress. In this study, we evaluated the effects of inhaled vanadium on olfaction, the olfactory bulb antioxidant, through histological and ultrastructural changes in granule cells. Mice in control group were made to inhale saline; the experimental group inhaled 0.02-M vanadium pentoxide (V2O5) for 1 hr twice a week for 4 weeks. Animals were sacrificed at 1, 2, 3, and 4 weeks after inhalation. Olfactory function was evaluated by the odorant test. The activity of glutathione peroxidase (GPx) and glutathione reductase (GR) was assayed in olfactory bulbs and processed for rapid Golgi method and ultrastructural analysis. Results show that olfactory function decreased at 4-week vanadium exposure; granule cells showed a decrease in dendritic spine density and increased lipofuscin, Golgi apparatus vacuolation, apoptosis, and necrosis. The activity of GPx and GR in the olfactory bulb was increased compared to that of the controls. Our results demonstrate that vanadium inhalation disturbs olfaction, histology, and the ultrastructure of the granule cells that might be associated with oxidative stress, a risk factor in neurodegenerative diseases.

A comparative study of the toxicological aspects of vanadium pentoxide and vanadium oxide nanoparticles.

Indiscriminate use of vanadium oxide nanoparticles (NPs) in steel industries and their release during combustion of fossil fuels makes it essential to study their toxic potential. Herein, we assessed the toxicological effects of two types of in-house synthesized vanadium oxide NPs in Wistar rats exposed to NPs through inhalation route. V2O5 and VO2 NPs exhibited rod and spherical symmetry, respectively with a mean diameter of 50±20 and 30±10 nm. Assessment of bronchoalveolar lavage fluid parameters demonstrated that VO2 NP-exposed animals had higher levels of lactate dehydrogenase, gamma-glutamyl transpeptidase and alkaline phosphatase as compared to V2O5 NP-exposed animals. The levels of oxidative stress markers malondialdehyde and reduced glutathione also indicated higher toxic potential of VO2 NPs. Moreover, after 7-day recovery, the levels of the above parameters were closer to normal levels only in V2O5-exposed animals. Interestingly, histopathological and immune-histopathology analysis (TNF-α) of lung tissue showed higher damage and inflammatory response in VO2 NP-exposed animals, which persisted even after 7 days of recovery period. Surprisingly, the carcinogenic potential of vanadium oxide NPs came into light which was indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay as well as the decreased levels of p53 and Bax, in lung tissue of NP-exposed animals. Notably, the physiochemical characterization of NPs, especially the shape and the size, play a central role in shaping the toxicity of these NPs and thus should be extensively evaluated for outlining the regulatory guidelines.

Is the hypoglycemic action of vanadium compounds related to the suppression of feeding?

Vanadium compounds exhibit effective hypoglycemic activity in both type I and type II diabetes mellitus. However, there was one argument that the hypoglycemic action of vanadium compounds could be attributable to the suppression of feeding-one common toxic aspect of vanadium compounds. To clarify this question, we investigated in this work the effect of a vanadyl complex, BSOV (bis((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl-2-hydroxy-benzoatato) oxovanadium (IV)), on diabetic obese (db/db) mice at a low dose (0.05 mmol/kg/day) when BSOV did not inhibit feeding. The experimental results showed that this dose of BSOV effectively normalized the blood glucose level in diabetic mice without affecting the body weight growth. Western blotting assays on the white adipose tissue of db/db mice further indicated that BSOV treatment significantly improved expression of peroxisome proliferator-activated receptor γ (PPARγ) and activated AMP-activated protein kinase (AMPK). In addition, vanadium treatment caused a significant suppression of phosphorylation of c-Jun N-terminal protein kinase (JNK), which plays a key role in insulin-resistance in type II diabetes. This is the first evidence that the mechanism of insulin enhancement action involves interaction of vanadium compounds with JNK. Overall, the present work indicated that vanadium compounds exhibit antidiabetic effects irrelevant to food intake suppression but by modulating the signal transductions of diabetes and other metabolic disorders.

Coordination chemistry may explain pharmacokinetics and clinical response of vanadyl sulfate in type 2 diabetic patients.

Vanadium, abbreviated V, is an early transition metal that readily forms coordination complexes with a variety of biological products such as proteins, metabolites, membranes and other structures. The formation of coordination complexes stabilizes metal ions, which in turn impacts the biodistribution of the metal. To understand the biodistribution of V, V in oxidation state iv in the form of vanadyl sulfate (25, 50, 100 mg V daily) was given orally for 6 weeks to 16 persons with type 2 diabetes. Elemental V was determined using Graphite Furnas Atomic Absorption Spectrometry against known concentrations of V in serum, blood or urine. Peak serum V levels were 15.4 ± 6.5, 81.7 ± 40 and 319 ± 268 ng ml(-1) respectively, and mean peak serum V was positively correlated with dose administered (r = 0.992, p = 0.079), although large inter-individual variability was found. Total serum V concentration distribution fit a one compartment open model with a first order rate constant for excretion with mean half times of 4.7 ± 1.6 days and 4.6 ± 2.5 days for the 50 and 100 mg V dose groups respectively. At steady state, 24 hour urinary V output was 0.18 ± 0.24 and 0.97 ± 0.84 mg in the 50 and 100 mg V groups respectively, consistent with absorption of 1 percent or less of the administered dose. Peak V in blood and serum were positively correlated (r = 0.971, p < 0.0005). The serum to blood V ratio for the patients receiving 100 mg V was 1.7 ± 0.45. Regression analysis showed that glycohemoglobin was a negative predictor of the natural log(ln) peak serum V (R(2) = 0.40, p = 0.009) and a positive predictor of the euglycemic-hyperinsulinemic clamp results at high insulin values (R(2) = 0.39, p = 0.010). Insulin sensitivity measured by euglycemic-hyperinsulinemic clamp was not significantly correlated with ln peak serum V. Globulin and glycohemoglobin levels taken together were negative predictors of fasting blood glucose (R(2) = 0.49, p = 0.013). Although V accumulation in serum was dose-dependent, no correlation between total serum V concentration and the insulin-like response was found in this first attempt to correlate anti-diabetic activity with total serum V. This study suggests that V pools other than total serum V are likely related to the insulin-like effect of this metal. These results, obtained in diabetic patients, document the need for consideration of the coordination chemistry of metabolites and proteins with vanadium in anti-diabetic vanadium complexes.

Effects of vanadium complexes supplementation on V, Fe, Cu, Zn, Mn, Ca and K concentration in STZ diabetic rat's spleen.

Abstract: The objective of the study was to assess the effects of five vanadium organic complexes administered with small insulin injection, on V, Fe, Cu, Zn, Mn, Ca and K concentration in STZ (streptozotocin) diabetic rats tissues during a 5-week treatment with the tested complexes. In all groups of animals, metal concentration in a dry spleen samples was investigated by the proton induced X-ray emission (PIXE) method. Obviously, vanadium tissue concentration was higher in vanadium-treated rats. Concentration of vanadium in the spleen was x = 21.3 microg/g of dry sample. Vanadium administration influenced other metals concentration of rats tissues. The most pronounced influence of vanadium was observed on iron concentration in the spleen. All results were calculated for correlation between different groups of animals. Present study showed small interferences between trace element changes in diabetic, or non diabetic rats after vanadium treatment. Measured elements, especially zinc, manganese and copper, are co-factors of enzymes and their content changes can influence on organism homeostasis in diabetes treatment. Understanding and recognizing these relationship may permit better diabetes treatment in the future.

The safe use of a PTEN inhibitor for the activation of dormant mouse primordial follicles and generation of fertilizable eggs.

BACKGROUND: Primordial ovarian follicles, which are often present in the ovaries of premature ovarian failure (POF) patients or are cryopreserved from the ovaries of young cancer patients who are undergoing gonadotoxic anticancer therapies, cannot be used to generate mature oocytes for in vitro fertilization (IVF). There has been very little success in triggering growth of primordial follicles to obtain fertilizable oocytes due to the poor understanding of the biology of primordial follicle activation. METHODOLOGY/PRINCIPAL FINDINGS: We have recently reported that PTEN (phosphatase and tensin homolog deleted on chromosome ten) prevents primordial follicle activation in mice, and deletion of Pten from the oocytes of primordial follicles leads to follicular activation. Consequently, the PTEN inhibitor has been successfully used in vitro to activate primordial follicles in both mouse and human ovaries. These results suggest that PTEN inhibitors could be used in ovarian culture medium to trigger the activation of primordial follicle. To study the safety and efficacy of the use of such inhibitors, we activated primordial follicles from neonatal mouse ovaries by transient treatment with a PTEN inhibitor bpV(HOpic). These ovaries were then transplanted under the kidney capsules of recipient mice to generate mature oocytes. The mature oocytes were fertilized in vitro and progeny mice were obtained after embryo transfer. RESULTS AND CONCLUSIONS: Long-term monitoring up to the second generation of progeny mice showed that the mice were reproductively active and were free from any overt signs or symptoms of chronic illnesses. Our results indicate that the use of PTEN inhibitors could be a safe and effective way of generating mature human oocytes for use in novel IVF techniques.

Hepatic megalocytosis due to vanadium inhalation: participation of oxidative stress.

The aim of this study was to evaluate the morphological changes, liver function test (LFT), and oxidative stress damage caused by thiobarbituric acid reactive substances (TBARS), in mice exposed to vanadium via inhalation. Male CD-1 mice were exposed to vanadium pentoxide (V(2)O(5)) via inhalation (0.02 M), 1 hour twice a week for 6 weeks. At the end of the protocol, controls and exposed mice were killed to evaluate the changes. Histological analysis and LFT were performed to detect the damage. TBARS detection was assessed for oxidative stress. Inflammatory infiltration, binucleation, and meganucleus were detected in the liver of V(2)O(5)-exposed mice (p < 0.05). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were also significantly increased (p < 0.05). Lipid peroxidation was significantly higher in V(2)O(5)-exposed animals compared to controls (p < 0.05). V(2)O(5) exposure induced inflammation and cell damage detected by the increase in ALT and AST levels, as well as histological changes that suggest regenerative changes, such as binucleation and meganucleus.