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Environmental exposure to vanadium has been on the increase in recent time. This metal is a known toxicant. The current study was conducted to investigate the reproductive toxicity of sodium metavanadate (SMV) in male African giant rats. Administration of SMV was done intraperitoneally daily for 14 consecutive days at a dosage of 3 mg/kg body weight. Sterile water was administered to the control group. Serum reproductive hormones, sperm reserve and quality as well as testicular ultrastructural changes following SMV treatment were analysed. Results showed SMV-exposed AGR group had statistically decreased concentrations of testosterone (4.7 ng/ml), FSH (3.4 IU/L) and LH (3.8 IU/L). Also, SMV-treated group had statistically decreased sperm motility and mass activity with increased percentage of abnormal morphophenotypes of spermatozoa and upregulation of P53 immunopositive cells. Ultrastructural study revealed vacuolation of germ and Sertoli cells cytoplasm and nucleus, and mitochondrial swelling and vacuolations were also observed. There was severe disintegration of the seminiferous tubules, atrophy and degeneration of myeloid cells and apoptosis of the Leydig, Sertoli and germ cells. In conclusion, intraperitoneal SMV exposure exerts severe adverse effects on some serum reproductive hormones, reduction in the sperm reserve and quality, apoptosis and degenerative changes of the Leydig, Sertoli and germ cells which can lead to infertility.

ATP-utilizing enzymes play key roles in hair bundles, the mechanically sensitive organelles of sensory hair cells in the inner ear. We used a fluorescent ATP analog, EDA-ATP-Cy3 (Cy3-ATP), to label ATP-binding proteins in two different preparations of unfixed hair-cell stereocilia of the mouse. In the first preparation, we lightly permeabilized dissected cochleas, then labeled them with Cy3-ATP. Hair cells and their stereocilia remained intact, and stereocilia tips in rows 1 and 2 were labeled particularly strongly with Cy3-ATP. In many cases, vanadate (Vi) traps nucleotides at the active site of myosin isoforms and presents nucleotide dissociation. Co-application with Vi enhanced the tip labeling, which is consistent with myosin isoforms being responsible. By contrast, the actin polymerization inhibitors latrunculin A and cytochalasin D had no effect, suggesting that actin turnover at stereocilia tips was not involved. Cy3-ATP labeling was substantially reduced—but did not disappear altogether—in mutant cochleas lacking MYO15A; by contrast, labeling remained robust in cochleas lacking MYO7A. In the second preparation, used to quantify Cy3-ATP labeling, we labeled vestibular stereocilia that had been adsorbed to glass, which demonstrated that tip labeling was higher in longer stereocilia. We found that tip signal was reduced by ~ 50% in Myo15ash2/sh2 stereocilia as compared to Myo15ash2/+stereocilia. These results suggest that MYO15A accounts for a substantial fraction of the Cy3-ATP tip labeling in vestibular hair cells, and so this novel preparation could be utilized to examine the control of MYO15A ATPase activity in situ.

Decavanadate is a polyoxometalate (POMs) that has shown extensive biological activities, including antidiabetic and anticancer activity. Importantly, vanadium-based compounds as well as antidiabetic biguanide drugs, such as metformin, have shown to exert therapeutic effects in melanoma. A combination of these agents, the metformin-decavanadate complex, was also recognized for its antidiabetic effects and recently described as a better treatment than the monotherapy with metformin enabling lower dosage in rodent models of diabetes. Herein, we compare the effects of decavanadate and metformin-decavanadate on Ca2+-ATPase activity in sarcoplasmic reticulum vesicles from rabbit skeletal muscles and on cell signaling events and viability in human melanoma cells. We show that unlike the decavanadate-mediated non-competitive mechanism, metformin-decavanadate inhibits Ca2+-ATPase by a mixed-type competitive–non-competitive inhibition with an IC50 value about 6 times higher (87 μM) than the previously described for decavanadate (15 μM). We also found that both decavanadate and metformin-decavanadate exert antiproliferative effects on melanoma cells at 10 times lower concentrations than monomeric vanadate. Western blot analysis revealed that both, decavanadate and metformin-decavanadate increased phosphorylation of extracellular signal-regulated kinase (ERK) and serine/threonine protein kinase AKT signaling proteins upon 24 h drug exposure, suggesting that the anti-proliferative activities of these compounds act independent of growth-factor signaling pathways., This work was funded by the Spanish Ministry of Science, Innovation and Universities through grant RTI2018-094629-B-I00 to WL, and Fundação para a Ciência e a Tecnologia (FCT) (PTDC/MED-ONC/4167/2020 “ENDURING”) to BIF.

Purpose: Our previous study indicated that sodium orthovanadate (vanadate), a strong inhibitor of p53, effectively suppressed the lethality from the hematopoietic (HP) and gastrointestinal (GI) syndromes after 12 Gy total-body irradiation (TBI) in mice. This conclusion, however, was inconsistent with the fact that p53 plays a radioprotective role in the intestinal epithelium. The death after TBI of around 12 Gy was attributed to a combined effect of HP and GI syndromes. To verify the effect from prophylactic administration of p53 inhibitor on protection of HP and GI syndromes, in this study, the radioprotective effects from vanadate were investigated in TBI and lower half-body irradiation (partial-body irradiation: PBI) mouse models. Methods: Female ICR mice were given a single injection of vanadate or vehicle, followed by a lethal dose of TBI or PBI. Radioprotective effects of vanadate against the irradiations were evaluated by analyzing survival rate, body weight, hematopoietic parameters, and histological changes in the bone marrow and intestinal epithelium. Results: TBI-induced HP syndrome was effectively suppressed by vanadate treatment. After TBI, the vanadate-treated mice retained better bone marrow cellularity and showed markedly higher survival rate compared to the vehicle-treated animals. In contrast, vanadate did not relieve loss of intestinal crypts and failed to rescue mice from GI death after PBI. Conclusion: Vanadate is a p53 inhibitor that has been shown to be beneficial as a radiation protective agent against HP but was not effective in protecting against acute GI radiation injury.

The therapeutic application of vanadium compounds is plagued by their poor bioavailability and potential adverse effects. Herein, 1 nm polyoxovanadate (POV) clusters are functionalized with alkyl chains of various lengths and studied for the effect of surface engineering on their preclinical pharmacokinetics and typical insulin-sensitizing activity. The concentrations of surface engineered POVs in plasma, urine, and feces are monitored after a single administration to rats. The POVs exhibit a two-compartment profile of in vivo kinetics, and the surface engineering effect plays an important role in renal clearance of the POVs comparable to small molecules. POVs functionalized with long alkyl chains show much shorter elimination half time tsub1/2β/suband higher elimination fractions (50%) within 48 h than pristine POVs, suggesting favorable elimination kinetics to mitigate the possible side effects of vanadium. Meanwhile, long alkyl chain modification leads to a 76% increment of oral bioavailability in contrast to unmodified POVs. As suggested by glucose tolerance tests and sub-chronic toxicity tests, the above two factors contribute to the enhanced therapeutic efficacy of POVs while mitigating their adverse effects. The surface engineering protocol provides a feasible approach to the optimization of the bioavailability and pharmacokinetic properties of POVs for promoted insulin-sensitizing activities.

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

Sphingosine-1-phosphate phosphatase (SPP) catalyzes the dephosphorylation of sphingosine-1-phosphate (S1P) into sphingosine, the reverse reaction of sphingosine kinase. In mammals, S1P acts as a potent signaling molecule that regulates cell proliferation, migration, and immunity. In Leishmania, S1P production is crucial for the synthesis of ethanolamine and choline phospholipids, and cell survival under stress conditions. To better understand the roles of S1P, we characterized a SPP ortholog in Leishmania major which displays activity towards S1P but not structurally similar lipids such as ceramide-1-phosphate or lysophosphatidic acid. While this enzyme is found in the endoplasmic reticulum in mammalian cells, L. major SPP is localized at the Golgi apparatus. Importantly, chromosomal SPP alleles cannot be deleted from L. major even with the addition of a complementing episome, suggesting that endogenously expressed SPP is essential. Finally, SPP overexpression in L. major leads to a slower growth rate and heightened sensitivity to brefeldin A and sodium orthovanadate. Together, these results suggest that the equilibrium between S1P and sphingosine is vital for the function of Golgi apparatus in Leishmania.

Although Ag-based materials are efficient against antibiotic-resistant bacteria, their high toxicity to living organisms represents a major challenge for obtaining useful products. In this work, we report the bactericidal activity of Ag

Sporadic Alzheimer's disease (sAD) is the most common type of dementia and progressive neurodegenerative disease. To establish the sAD model, intracerebroventricular (ICV) streptozotocin (STZ) at a dose of 3 mg/kg was administered bilaterally in rats on a stereotaxic apparatus. Behavioral tests such as Morris water maze (MWM), novel object recognition (NOR) and open field test were performed to evaluate cognitive and locomotor functions. Two treatment doses (5 mg/kg and 10 mg/kg) of sodium orthovanadate (SOV) and rivastigmine (2 mg/kg) were given orally to ICV-STZ induced rats for 21 days. Cortical and hippocampal tissues were dissected. Estimation of oxidative stress, mitochondrial dysfunction as complex I, II, III, IV activity, cholinergic function as acetylcholinesterase activity, ELISA for phosphorylated tau protein and insulin degrading enzyme (IDE), neuroinflammation as NF-κB gene expression and insulin signaling functioning as Q-RT-PCR for IR, IRS-1, PI3K, AKT, GSK-3β gene expression were performed. Behavioral results with SOV and rivastigmine treatment revealed decreased escape latency and increased discrimination index in MWM and NOR respectively. Treatment results with SOV also demonstrated attenuation of oxidative imbalance, improved mitochondrial activity, and reversed IDE and tau pathology. SOV treatment upregulated gene expression of IR, IRS-1, PI3K, and AKT, and downregulated that of GSK-3β. SOV results were compared with standard drug rivastigmine. Conclusively, the memory enhancement by SOV was mediated through oxidative balance, mitochondrial enzyme complex activation, and improved insulin signaling regulation. However, the primary mechanism of SOV remained attenuation of tau pathology by the upregulation of IRS-1/PI3K/AKT/GSK-3β pathway and reversal of insulin resistance in terms of IDE. Hence, in sAD paradigm, SOV contributed to memory improvement evident with the findings of behavioral studies, which can further potentially have clinical significance in AD.

To investigate the effect of vanadyl trehalose (VT) on oxidative stress and reduced glutathione/glutathione-S-transferase (GSH/GSTs) pathway gene expression in mouse gastrointestinal tract, as well as the protective effects of vitamin C (VC) and reduced glutathione (GSH). Thirty male Kunming mice were randomly divided into five groups: control group (group A), VT group (group B), VC + VT group (group C), GSH + VT group (group D) and VC + GSH + VT group (group E). The content of reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) activity and the expressions of glutamate-cysteine ligase catalytic subunit (GCLC), glutathione synthetase (GSS), regulated through glutathione reductase (GSR) and glutathione-S-transferase pi (GSTpi) in stomach and duodenum in vanadyl trehalose treated group were lower than those in group A (P

The luteinizing hormone receptor (LHR), a G protein-coupled receptor (GPCRs), can initiate signaling in the presence of some vanadium-containing compounds as a result of vanadium compound interactions with the membrane lipids and/or the cell membrane lipid interface. The ability of LHR expressed in CHO cells to initiate signaling in the presence of highly charged and water-soluble polyoxovanadates (POV) including Na3[H3V10O28] (V10) and two mixed-valence heteropolyoxovanadates, K(NH4)4[H6V14O38(PO4)]·11H2O (V14) and [(CH3)4N]6[V15O36(Cl)] (V15), was investigated here. Interactions of the vanadium compounds with CHO cells decreased the packing of membrane lipids, drove aggregation of LHR and increased signal transduction by LHR. Cell responses were comparable to, or in the case of V14 and V15, greater than those seen for cells treated with human chorionic gonadotropin (hCG), a naturally-occurring LHR ligand produced in early pregnancy in humans. POV effects were observed for CHO cells where LHR was expressed at 10 000 or 32 000 LHR per cell but not when LHR was overexpressed with receptor numbers >100 000 LHR per cell. To determine which POV species were present in the cell medium during cell studies, the speciation of vanadate (V1), V10, V14 or V15 in cell medium was monitored using 51V NMR and EPR spectroscopies. We found that all the POVs initiated signaling, but V15 and V10 had the greatest effects on cell function, while V1 was significantly less active. However, because of the complex nature of vanadium compounds speciation, the effects on cell function may be due to vanadium species formed in the cell medium over time.

Vanadium is a ubiquitous environmental contaminant although there are limited data to assess potential adverse human health impact following oral exposure. In support of studies investigating the subchronic toxicity of vanadyl sulfate (V(4+)) and sodium metavanadate (V(5+)) following perinatal exposure via drinking water in male and female rats, we have determined the internal exposure and urinary excretion of total vanadium at the end of study. Water consumption decreased with increasing exposure concentration following exposure to both compounds. Plasma and urine vanadium concentration normalized to total vanadium consumed per day increased with the exposure concentration of vanadyl sulfate and sodium metavanadate suggesting absorption increased as the exposure concentration increased. Additionally, females had higher concentrations than males (in plasma only for vanadyl sulfate exposure). Animals exposed to sodium metavanadate had up to 3-fold higher vanadium concentration in plasma and urine compared to vanadyl sulfate exposed animals, when normalized to total vanadium consumed per day, demonstrating differential absorption, distribution, metabolism, and excretion properties between V(5+) and V(4+) compounds. These data will aid in the interpretation of animal toxicity data of V(4+) and V(5+) compounds and determine the relevance of animal toxicity findings to human exposures.

Goltsev A, Babenko N, Gaevska Yu, Bondarovych M, Dubrava T, Ostankova L, Volkova N, Klochkov V. Toxicity of Nanocomplexes Containing Gadolinium Orthovanadate Nanoparticles and Cholesterol. Biological Trace Element Research. 2022, Jan 13. https://doi.org/10.1007/s12011-021-03019-z Previous studies have shown the ability of nanocomplexes (NCs), which consist of nanoparticles (NPs) of orthovanadates of rare earth metals (GdYVO4:Eu3+) and cholesterol, to inhibit the growth of Ehrlich’s ascites carcinoma (EAC). However, the biosafety of these NCs remains unclear. Our objective was to investigate the acute and subchronic toxicity of NCs. NCs were administered to BALB/c mice in NPs concentration of 5.9; 29.5; 59.1; and 118.2 mg/kg. Acute toxicity was induced by a single administration of NCs, subchronic-by repeated daily administration of NCs for 14 days. On day 15 and on day 31 for acute and subchronic toxicity, respectively, the percentage of animal survival, body weight, condition of visceral organs, and activities of γ-glutamyl transferase (GGT) and glucose-6-phosphate dehydrogenase (G-6-PDH) were determined. It was found that administration of NCs in the concentration of 5.9 mg/kg and 29.5 mg/kg of NPs did not influence on survival of animals or have a negative impact on their performance status, morphological and quantitative characteristics of visceral organs, and activities of the GGT and G-6-PDH in the liver. For acute toxicity, the semi-lethal dose (LD50) of nanocomplexes was determined (118.2 mg/kg of NPs). As to subchronic toxicity, it was found that repeated (for 14 days) administration of NCs containing 59.1 mg/kg of NPs decrease survival of animals to 50%. The coefficient of accumulation (Cacum = 7) indicates the low accumulative ability of NCs upon long-term use. Thus, from the LD50 and accumulation coefficient, NCs can be referred to as low-toxic substances and used in conditionally therapeutic doses in oncological practice to develop nanostructured formulations of drugs.

Diabetes mellitus, a complex and heterogeneous disease associated with hyperglycemia, is a leading cause of mortality and reduces life expectancy. Vanadium complexes have been studied for the treatment of diabetes. The effect of complex [VO(bpy)(mal)]·H

The increasing risk of acute large-scale exposure of ionising irradiation on the population underlines the necessity of developing effective radioprotective and mitigating agents. The aim of this work was to investigate the effect of sodium orthovanadate pre-treatment on mice exposed to high doses of gamma rays (from 5 to 13 Gy). The determination of median lethal dose within 30 days confirmed that orthovanadate applied to total-body-irradiated mice intra-peritoneally has a radioprotective but not a mitigating effect. With orthovanadate pre-treatment, the composition of cellularity in the bone marrow improved substantially and the main lymphocyte populations restored during the first month after irradiation. These findings contribute to ‘gap-filling’ in radioprotective effects and demonstrate the importance of haematological parameters in radiation–response prediction.

Primary Objective: Eph/Ephrin signaling is inhibitory for developing axons and blocking Eph pathways enhances regeneration after spinal cord injury. It was hypothesized that inhibition of Eph signaling promotes cellular and behavioral recovery after traumatic brain injury (TBI). Research design: Lateral fluid percussion (LFP) injury was performed on wildtype (WT) and EphA6 knockout (KO) mice. EphA6-Fc, Ephrin-A5-Fc fusion proteins, and sodium orthovanadate were used to alter the signaling pathway. Immunohistochemistry and tissue explants revealed cellular changes. Rotarod tests demonstrated vestibulomotor function. Outcomes: The EphA6 receptor expression is upregulated following LFP. Uninjured EphA6 KO mice exhibit greater neurite density and clustered Ephrin-A5-Fc causes growth cone collapse in vitro. After LFP, EphA6 KO mice demonstrate longer neurites and decreased neuronal cell death and astrocytosis compared to WT mice. Blocking EphA signaling by soluble EphA6-Fc fusion protein reduces cell death and improves motor function following LFP whereas clustered Ephrin-A5-Fc exacerbates cell death and neurodegeneration. Sodium orthovanadate rescues growth cone collapse in vitro as well as cell death and neurodegeneration in vivo. Conclusions: Eph/Ephrin signaling plays an inhibitory role following TBI. Targeting the Eph signaling pathway with Fc fusion proteins and pharmacological agents can be a novel strategy to counter the damaging effects of TBI. Abbreviations: LFP: lateral fluid percussion; TBI: traumatic brain injury; KO: knockout; WT: wildtype; PTP2: protein phosphotyrosine phosphatase 2; Tg: transgenic; YFP: yellow fluorescent protein; ATM: atmospheres; RT-qPCR: Real-time-quantitative PCR; dpi: days post injury; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; DAPI: 4',6-diamidino-2-phenylindole; PBS: phosphate buffered saline; GFAP: glial fibrillary acidic protein; FLJC: fluorojade C; CA: cornu ammonis; SEM: standard error of the mean; ANOVA: analysis of variance; PLSD: posthoc least significant difference.

The vanadate-derivative dipotassium bisperoxo (5-hydroxy-pyridine-2-carboxylic) oxovanadate (V) (bpV(HOpic)), a pharmacological inhibitor of phosphatase and tensin homolog (PTEN), has been used in ovarian follicle culture systems for activation of follicular growth in vitro and suggested to be responsible for primordial follicle survival through indirect Akt activation. For pig ovarian tissue, it is still not clear which culture medium needs to be used, as well as which factors and hormones could influence follicular development; this also applies to bpV(HOpic) exposure. Therefore, ovarian cortical strips from pigs were cultured in 1 µM bpV(HOpic) (N = 24) or control medium (N = 24) for 48 hr. Media were then replaced with control medium and all tissue pieces incubated for additional 4 days. The strips were embedded in paraffin for histological determination of follicle proportions at the end of the culture period and compared to histological sections from tissue pieces without cultivation, which had been embedded right after preparation; comparison of healthy follicles for each developmental stage was performed to quantify follicle survival and activation. After 6-day culture, follicle activation occurred in tissue samples from both cultured groups but significantly more follicles showed progression of follicular development in the presence of 1 µM bpV(HOpic). The amount of non-vital follicles was not significantly increased during cultivation. BpV(HOpic) affects pig ovarian follicle development by promoting the initiation of follicle growth and development, similar as in rodent species and humans.

Background:Diabetes is a metabolic disorder, whose incidences are increasing day by day. Various classes of anti-diabetic drugs are clinically approved by the Food and Drug Administration (FDA) for the treatment of diabetes mellitus, but unfortunately, none of them is able to treat this condition. Thus, the exploration of novel mechanistic pathways of existing molecules may help to develop more safe and effective anti-diabetic agents. Sodium orthovanadate is a well known common laboratory agent used to preserve the protein tyrosyl phosphorylation state of the protein.Methods:The data related to sodium orthovanadate and diabetes mellitus has been collected from Pubmed.Results:Various reports have indicated the potential of sodium orthovanadate as Protein Tyrosine Phosphatase (PTP1B) inhibitors which play an important role in the pathogenesis of diabetes. However, safety of Sodium orthovanadate is still questionable.Conclusion:The sodium orthovanadate could be developed as an anti-diabetic agent. However, further studies are required to confirm its safety profile in the treatment of diabetes mellitus before starting a clinical trial.

Ahmed M Naglah,1,2 Moamen S Refat,3,4 Mohamed A Al-Omar,1 Mashooq A Bhat,5 Hamad M AlKahtani,5 Asma S Al-Wasidi6 1Department of Pharmaceutical Chemistry, Drug Exploration & Development Chair (DEDC), College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 2Peptide Chemistry Department, Chemical Industries Research Division, National Research Centre, Cairo 12622, Egypt; 3Chemistry Department, Faculty of Science, Taif University, Taif 21974, Saudi Arabia; 4Department of Chemistry, Faculty of Science, Port Said University, Port Said, Egypt; 5Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 6Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia Background: This study aimed to design a compound with folic acid (FAH2) and vanadyl (IV) for use in the treatment of diabetes.Materials and methods: A novel vanadyl (IV) FAH2 complex was synthesized and characterized [(FA2-)(VO2+)]·3H2O. The speculated structure of this folate complex was determined using physicochemical techniques including microanalytical analysis, conductivity studies, spectroscopic examination, magnetic measurements, thermogravimetric analyses, and morphological X-ray powder diffraction, and scanning and transmission electron microscopies. The anti-diabetic therapeutic potential of the complexes was tested in a 30-day streptozotocin-induced diabetes rat model.Results: The conductivity test of the complex implied electrolyte behavior. The spectroscopic assessments of the isolated dark yellow solid complex revealed that FAH2 acts as a bidentate ligand. The coordination process with two vanadyl (IV) ions occurred through the deprotonation of both carboxyl groups of FAH2 in a regular square pyramid arrangement at a 2(FA)2-: 2(VO)2+ molar ratio. XRD, SEM, and TEM analyses revealed the complex crystalline nature of the complex. Treating diabetic rats with vanadyl (IV) FAH2 complex significantly improved many biological parameters relevant to diabetes pathology with minimal toxicity.Conclusion: The data generated in this study indicate that the synthesized vanadyl (IV) folate complex acts as a model of anti-diabetic agent. Keywords: diabetes, vanadyl, folic acid, spectroscopic, streptozotocin, vitamin B9

Modified Fe3O4 magnetic nanoparticles (magnetic nanocarrier) technology have found the proper place in separation and purification techniques, such as protein and enzyme purification, mostly due to its easy and fast operational procedure by using an external permanent magnet. Herein, Fe3O4 magnetic nanoparticles were prepared, and surface modification was performed with vanadate and phosphate salts to yield four various model of magnetic nanocarriers. Affinity ligands which are used for immobilization on the nanocarriers leading to the development of appropriative nanocarriers for the affinity separation of alkaline phosphatase from the bovine milk. The findings showed that the use of sodium hexametaphosphate affinity ligand attached to the carrier with an 18-atom linker leads to better separation of alkaline phosphatase from the bovine milk with 14.1-fold purification efficiency. All results confirmed that our designed nanocarriers can purify alkaline phosphatase using a fast and low-cost approach.

Effect of prolong use of orthovanadate nanoparticles (GdVO

Targeted drug delivery enhances drug efficiency and selectivity without affecting normal cells. Luminescent nanoparticles can be used for tumor imaging as well as selective tumor targeting for drug delivery. In this research, LaVO4 :Eu3+ was synthesized, the luminescent nanocrystal was coated by surface polymerization of levodopa in the presence of Paclitaxel (PTX), and then NL2 peptide was coupled on the surface of polymer-coated luminescent nanoparticles. Next, the capability of the modified drug was examined by in vitro and in vivo experiments. MTT assay on SK-BR-3 cell line (as breast cancer cells) and fluorescent microscopy results indicate that this modification decreases significantly drug toxicity and increases its selectivity. In addition, in vivo experiments confirm more capability of the NL2-functionalized nanocomposite for reducing tumor size, drug distribution in the body, and more aggregation of PTX in tumor tissue. Overall, it is concluded that tumor imaging is possible using luminescent LaVO4 :Eu3+ core and NL2 peptide increases significantly the specificity of PTX in combination with a functionalized luminescent polymeric carrier.

Vanadium is a ubiquitous environmental contaminant that exists in multiple oxidation states. Humans are exposed to vanadyl (V(4+)) and vanadate (V(5+)) 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 (V(4+)) or sodium metavanadate (V(5+)) via drinking water for 14 d. Investigations in simulated gastric and intestinal fluids showed that V(4+) was stable in gastric fluid while V(5+) was stable in intestinal fluid. Analysis of rodent plasma showed that the only vanadium present was V(4+), regardless of the exposed compound suggesting conversion of V(5+) to V(4+) in vivo and/or instability of V(5+) 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 V(5+) than to V(4+). Following exposure to either V(4+) or V(5+), 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 V(4+) and V(5+) salts and may explain the higher sensitivity in rats following drinking water exposure to V(5+) than V(4+) and highlights the importance of internal dose determination in toxicology studies.

Oxidative stress (OS) is a mechanism underlying metal-induced toxicity. As a redox-active element, vanadium (V) can act as a strong prooxidant and generate OS at certain levels. It can also attenuate the antioxidant barrier and intensify lipid peroxidation (LPO). The prooxidant potential of V reflected in enhanced LPO, demonstrated by us previously in the rat liver, prompted us to analyze the response of the nuclear factor erythroid-derived 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2-Keap1) system involved in cellular regulation of OS to administration of sodium metavanadate (SMV, 0.125 mg V/mL) and/or magnesium sulfate (MS, 0.06 mg Mg/mL). The levels of some Nrf2-dependent cytoprotective and detoxifying proteins, i.e., glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), glutamate cysteine ligase catalytic subunit (GCLC), glutathione synthetase (GSS), NAD(P) H dehydrogenase quinone 1 (NQO1), UDP-glucumno-syltransferase 1 (UGT1), and heme oxygenase 1 (HO-1); glutathione (GSH); metallothionein (MT1); and glutamate-cysteine ligase (GCL) mRNA were measured. We also focused on the V-Mg interactive effects and trends toward interactive action as well as relationships between the examined indices. The elevated levels of Nrf2, GCL mRNA, and GCL catalytic subunit (GCLC) confirm OS in response to SMV and point to the capacity to synthesize GSH. The results also suggest a limitation of the second step in GSH synthesis reflected by the unchanged glutathione synthetase (GSS) and GSH levels. The positive correlations between certain cytoprotective/detoxifying proteins (which showed increasing trends during the SMV and/or MS administration, compared to the control) and between them and malondialdehyde (MDA), the hepatic V concentration/total content, and/or V dose (discussed by us previously) point to cooperation between the components of antioxidant defense in the conditions of the hepatic V accumulation and SMV-induced LPO intensification. The V-Mg interactive effect and trend are involved in changes in Nrf2 and UGT1, respectively. The p62 protein has to be determined in the context of potential inhibition of degradation of Keap1, which showed a visible upward trend, in comparison with the control. The impact of Mg on MT1 deserves further exploration.

Aquaculture and farming industries have been seriously threatened by the illegal use of antibiotics as feed-additives to benefit the animal growth. Although various conventional chemical sensing approaches have been widely explored for the trace-level detection of antibiotics, the effective and accurate monitoring techniques are still highly demanded. Herein, we propose a novel surface-enhanced Raman scattering (SERS) substrate with the heterogeneous integration of silver nanoparticles (Ag NPs) on silver vanadate nanorods (β-AgVO3 NRs) for the ultrasensitive detection of popular antibiotic, chloramphenicol (CAP). The photochemical decoration of Ag NPs on the surface of β-AgVO3 NRs remarkably enhances the Raman signal intensity of CAP molecules by the synergistic action of the mechanisms of electromagnetic and chemical enhancement. The structural features of Ag-NPs@β-AgVO3-NRs favor the formation of hotspots at the interface between NPs and NRs by enhanced surface area and numerous active sites for the interaction with CAP molecules. The SERS measurement of CAP molecules on the Ag-NPs@β-AgVO3-NRs shows a trace-level limit of detection (10−10 M), high uniformity (5.29%), good reproducibility (3.89%), and high analytical enhancement factor (2.05 × 108). The proposed SERS substrate possesses excellent detection ability in monitoring real samples like tap water, milk and eye drops.

Sodium metavanadate (NaVO3) exhibits important physiological effects including insulin-like, chemoprevention and anticancer activity. However, the effects of NaVO3 on breast cancer and underlying mechanisms are still unclear. In this study, our results revealed that NaVO3 was able to inhibit proliferation of murine breast cancer cells 4T1 with IC50 value of 8.19 μM and 1.92 μM at 24 h and 48 h, respectively. The mechanisms underlying the inhibition activity were that NaVO3 could increase reactive oxygen species (ROS) level in a concentration-dependent way, arrest cells at G2/M phase, diminish the mitochondrial membrane potential (MMP), finally promote the progress of apoptosis. Furthermore, NaVO3 also exhibited a dose-dependent anticancer activity in breast cancer-bearing mice that led to the shrinkage of tumor volume (about 50%), lower microvessel density, less propagating cells and more apoptotic cells in vivo, as compared to the saline group. Therefore, NaVO3 may act as a potential chemotherapeutic agent in breast cancer treatment.

A T cell receptor (TCR) mediates antigen-induced signaling through its associated CD3ε, δ, γ, and ζ, but the contributions of different CD3 chains remain elusive. Using quantitative mass spectrometry, we simultaneously quantitated the phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of all CD3 chains upon TCR stimulation. A subpopulation of CD3ε ITAMs was mono-phosphorylated, owing to Lck kinase selectivity, and specifically recruited the inhibitory Csk kinase to attenuate TCR signaling, suggesting that TCR is a self-restrained signaling machinery containing both activating and inhibitory motifs. Moreover, we found that incorporation of the CD3ε cytoplasmic domain into a second-generation chimeric antigen receptor (CAR) improved antitumor activity of CAR-T cells. Mechanistically, the Csk-recruiting ITAM of CD3ε reduced CAR-T cytokine production whereas the basic residue rich sequence (BRS) of CD3ε promoted CAR-T persistence via p85 recruitment. Collectively, CD3ε is a built-in multifunctional signal tuner, and increasing CD3 diversity represents a strategy to design next-generation CAR.

Background Despite tremendous progress has been achieved in tumor theranostic over the past decade, accurate identification and complete eradication of tumor cells remain a great challenge owing to the limitation of single imaging modality and therapeutic strategy. Results Herein, we successfully design and construct BiVO4/Fe3O4@polydopamine (PDA) superparticles (SPs) for computed tomography (CT)/photoacoustic (PA)/magnetic resonance (MR) multimodal imaging and radiotherapy (RT)/photothermal therapy (PTT) synergistic therapy toward oral epithelial carcinoma. On the one hand, BiVO4 NPs endow BiVO4/Fe3O4@PDA SPs with impressive X-ray absorption capability due to the high X-ray attenuation coefficient of Bi, which is beneficial for their utilization as radiosensitizers for CT imaging and RT. On the other hand, Fe3O4 NPs impart BiVO4/Fe3O4@PDA SPs with the superparamagnetic property as a T2-weighted contrast agent for MR imaging. Importantly, the aggregation of Fe3O4 NPs in SPs and the presence of PDA shell greatly improve the photothermal conversion capability of SPs, making BiVO4/Fe3O4@PDA SPs as an ideal photothermal transducer for PA imaging and PTT. By integrating advantages of various imaging modalities (CT/PA/MR) and therapeutic strategies (RT/PTT), our BiVO4/Fe3O4@PDA SPs exhibit the sensitive multimodal imaging feature and superior synergistic therapeutic efficacy on tumors. Conclusions Since there are many kinds of building blocks with unique properties appropriating for self-assembly, our work may largely enrich the library of nanomateirals for tumor diagnosis and treatment.

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

Biomedical application of rare-earth-based nanoparticles attracts much attention due to their unique optical and redox properties and quite low toxicity. Earlier, we found age-related beneficial effects of rare-earth-based orthovanadate nanoparticles (OV NPs) on the prooxidant/antioxidant balance in liver and blood of Wistar rats, as reported by Nikitchenko et al. (Biol Trace Elem Res (2020). https://doi.org/10.1007/s12011-020-02196-7 ). However, the question remained unclear whether OV NPs' redox activity directly defines the protection ability. In the present work, antiradical, antioxidant, and membrane-protective properties of GdYVO

The BiVO4 photocatalyst plays a very important role in photocatalytic reactions attributed to its unique crystalline structure, size, morphology and surface area. Herein, we report a facet-dependent monoclinic scheelite BiVO4 (m-BiVO4) photocatalyst with uniform truncated square (18 sided) hexagonal bipyramidal shape synthesized by a template-free and surfactant-free solvothermal method using ethylene glycol solvent under cost-effective and mild reactions. The structural, morphological and optical properties of the m-BiVO4 photocatalyst are widely characterized. The photocatalytic activity of the m-BiVO4 photocatalyst is tested towards 20 ppm methylene blue (MB) dye aqueous solution as a pollutant model under visible light irradiation. Enhanced visible-light driven photoactivity with dye degradation efficiency of approx. 91% at a rate of 0.388 × 10−2 min−1 is obtained, presumably due to the presence of high-active (040) facets. Zebrafish embryo toxicity test of treated MB dye solution reveals the degradation and toxicity reduction of the MB dye. Moreover, the recycling experiment validates that the m-BiVO4 photocatalyst has a great structural stability with reliable performance. This work may provide a lucid and expedient strategy to synthesize highly crystalline (040) facet-dependent semiconductor photocatalyst toward dye degradation and obviously industrial wastewater remediation.

VEGFR2 and VEGF-A play a pivotal role in the process of angiogenesis. VEGFR2 activation is regulated by protein tyrosine phosphatases (PTPs), enzymes that dephosphorylate the receptor and reduce angiogenesis. We aim to study the effect of PTPs blockade using bis(maltolato)oxovanadium(IV) (BMOV) on in vivo wound healing and in vitro angiogenesis. BMOV significantly improves in vivo wound closure by 45% in C57BL/6JRj mice. We found that upon VEGFR2 phosphorylation induced by endogenously produced VEGF-A, the addition of BMOV results in increased cell migration (45%), proliferation (40%) and tube formation (27%) in HUVECs compared to control. In a mouse ex vivo, aortic ring assay BMOV increased the number of sprouts by 3 folds when compared to control. However, BMOV coadministered with exogenous VEGF-A increased ECs migration, proliferation and tube formation by only 41%, 18% and 12% respectively and aortic ring sprouting by only 1-fold. We also found that BMOV enhances VEGFR2 Y951 and p38MAPK phosphorylation, but not ERK1/2. The level of phosphorylation of these residues was the same in the groups treated with BMOV supplemented with exogenous VEGF-A and exogenous VEGF-A only. Our study demonstrates that BMOV is able to enhance wound closure in vivo. Moreover, in the presence of endogenous VEGF-A, BMOV is able to stimulate in vitro angiogenesis by increasing the phosphorylation of VEGFR2 and its downstream proangiogenic enzymes. Importantly, BMOV had a stronger proangiogenic effect compared to its effect in coadministration with exogenous VEGF-A.

Aim: To evaluate the effects of orally administered gadolinium orthovanadate GdVO4:Eu3+ nanoparticles (VNPs) on the course of chronic carrageenan-induced intestinal inflammation. Methods: Samples of small intestinal tissue were collected from four groups of rats (intact, after administration of VNPs, with carrageenaninduced intestinal inflammation, with carrageenan-induced intestinal inflammation orally exposed to VNPs) to assess the intestinal morphology and HSP90α expression. Levels of seromucoid, C-reactive protein, TNF-α, IL-1β and IL-10 were determined in blood serum. Results: Oral exposure to VNPs was associated with neither elevation of inflammation markers in blood serum nor HSP90α overexpression in the small intestine, i.e. no toxic effects of VNPs were observed. Carrageenan-induced intestinal inflammation was accompanied by higher levels of TNF-α and IL-1β, as well as HSP90α upregulation in the intestinal mucosa, compared with controls. Administration of VNPs to rats with enteritis did not lead to statistically significant changes in concentrations of circulating pro-inflammatory cytokines with the trend towards their increase. Conclusion: No adverse effects were observed in rats orally exposed to VNPs at a dose of 20 μg/kg during two weeks. Using the experimental model of carrageenan-induced enteritis, it was demonstrated that VNPs at the dose used in our study did not affect the course of intestinal inflammation.

Vanadium is an important ultra-trace element nowadays attracting attention with particular emphasis on medical application. But the therapeutic application of vanadium-based drugs is still questionable and restricted due to some toxic side effects. It was found that unique redox properties of vanadium in nanoform provided antioxidant activity and prevented oxidative disturbance in cells in vitro. Though, on the organism level, ambiguous effects of vanadium-based nanoparticles were observed. In this study, the age-related features of prooxidant/antioxidant balance in blood serum and liver mitochondrial and postmitochondrial fractions of 3 and 18-month-old Wistar male rats treated with orthovanadate nanoparticles (GdVO

Background. Oxidized low-density lipoprotein (Ox-LDL) is a crucial pathogenic factor for vascular diseases, which can induce the proliferation of vascular smooth muscle cells (VSMCs). Genistein is the main component of soybean isoflavone. Genistein has a variety of pharmacological properties in the treatment of vascular diseases and a promising clinical application. Large-conductance calcium-activated potassium (BKCa) channels are the primary type of potassium channels in VSMCs, which regulate various biological functions of VSMCs. However, whether genistein exerts an antiproliferation effect on Ox-LDL-stimulated VSMCs remains unclear. The current study is aimed at elucidating the effect of genistein on the Ox-LDL-stimulated proliferation of VSMCs and its possible molecular mechanism, especially the electrophysiological mechanism related to BKCa channels. Methods. Monoculture VSMC was obtained by an acute enzyme-dispersing method. The proliferation of cells was measured by CCK-8, cell cycle, and proliferating cell nuclear antigen (PCNA) expression. The BKCa whole-cell currents were measured by patch-clamp. Results. Ox-LDL treatment induced the proliferation of VSMCs, upregulated the BKCa protein expression, and increased the density of BKCa currents, while genistein significantly inhibited these effects caused by Ox-LDL. BKCa channels exerted a regulatory role in the proliferation of VSMCs in response to Ox-LDL. The inhibition of BKCa channels suppressed Ox-LDL-stimulated VSMC proliferation, while the activation of BKCa channels showed the opposite effect. Moreover, genistein suppressed the activity of BKCa, including protein expression and current density in a protein tyrosine kinase- (PTK-) dependent manner. Conclusion. This study demonstrated that genistein inhibited the Ox-LDL-mediated proliferation of VSMCs by blocking the cell cycle progression; the possible molecular mechanism may be related to PTK-dependent suppression of BKCa channels. Our results provided novel ideas for the application of genistein in the treatment of vascular diseases and proposed a unique insight into the antiproliferative molecular mechanism of genistein.

Hyperthyroidism can cause glucose metabolism disorders and insulin resistance. Insulin resistance in muscle and adipose tissues has been extensively studied, whereas investigations on β-cell insulin resistance are limited. This study preliminarily explored the effects of high T3 levels on β-cell line (MIN6) insulin resistance, as well as the roles of endoplasmic reticulum stress (ERS). In this study, we treated β-cell line with T3, with or without an inhibitor of phosphotyrosine phosphatases (PTPs, sodium vanadate) or ERS inhibitor (4-PBA). The results indicated that high levels of T3 significantly inhibited insulin secretion in β-cell line. In addition, we observed an upregulation of p-IRS-1ser307 and downregulation of Akt. These results can be corrected by sodium vanadate. Moreover, high T3 levels upregulate the ERS-related proteins PERK, IRE1, ATF6, and GRP78, as well as ERS-related apoptosis CHOP and caspase-12. Similarly, this change can be corrected by 4-PBA. These results suggest that high T3 levels can induce insulin resistance in β-cell line by activating ERS and the apoptotic pathway.

Depression is a psychiatric disorder characterized by low-esteem, anhedonia, social deficit, and lack of interest. Decreased brain-derived neurotrophic factor (BDNF) and impaired tropomyosin kinase B receptor (TrkB receptor) signaling are associated with depression. In our study, depressive-like behavior was induced in mice by chronic unpredictable mild stress (CUMS) model. Various behavioral tests like tail suspension test (TST), open field test (OFT), sucrose preference test (SPT); biochemical analyses for corticosterone, reduced glutathione (GSH), lipid peroxidation (LPO), superoxide dismutase (SOD), nitric oxide (NO) and enzyme-linked immunosorbent assay (ELISA) for BDNF were performed. Body weight was measured every week. CUMS induced depressive-like behavior was found to be associated with increased oxidative stress in the brain and serum corticisterone with subsequent reduction of BDNF. Sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor already reported to elevate BDNF levels, was used as the test drug. Sodium orthovanadate (5 mg/kg, 10 mg/kg) and fluoxetine (FLX-10 mg/kg) was given to mice orally for 21days before 30 min of stress induction. The behavioral tests reflected depressive-like behavior in CUMS, which was attenuated by both SOV and fluoxetine. SOV at 10 mg/kg demonstrated significant results in the present study characterized by decreased malondialdehyde levels (MDA/LPO), NO levels, and increased GSH level and SOD activity in both the cortex and hippocampus. Besides, ELISA has revealed the significant elevation of BDNF levels in the treatment groups (SOV-5 mg/kg, 10 mg/kg and FLX-10 mg/kg) as compared to the disease group (CUMS). Therefore, the treatment with SOV appeared to reverse both oxidative and nitrosative stress. Decreased serum corticosterone levels observed with SOV (510 mg/kg), FLX-10 mg/kg, FLX (10 mg/kg) + SOV (5 mg/kg); and SOV-10 mg/kg per-se treatment and elevated BDNF level with SOV (510 mg/kg), FLX-10 mg/kg were associated with attenuation of depressive-like behavior. The findings of this preliminary study indicate that SOV has the potential to restore antidepressant-like effects or prevent stress-induced anhedonia and so further molecular mechanisms are warranted for clinical translation.

Previous studies have confirmed that protein tyrosine phosphatase 1B (PTP1B) can promote tumour progression in non-small cell lung cancer (NSCLC). Vanadyl alginate oligosaccharides (VAOS) is a new coordination compounds that possesses a good PTP1B inhibitory activity. However, the potent anticancer efficacy of VAOS in human NSCLC requires further study. In this study, VAOS exhibited effective inhibitory effects in NSCLC both in cultured cells and in a xenograft mouse model. VAOS was further identified to induce NSCLC cell apoptosis through activating protein kinase B (AKT) to elevate intracellular reactive oxygen species (ROS) levels by increasing in oxygen consumption and impairing the ROS-scavenging system. Neither silencing of PTP1B by siRNA nor transient overexpression of PTP1B had an effect on the AKT phosphorylation triggered by VAOS, indicating that PTP1B inhibition was not involved in VAOS-induced apoptosis. Through phosphorus colorimetric assay, we demonstrated that VAOS notably inhibited phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylation activity, another member of the protein tyrosine phosphatases (PTPases)-upstream factor of AKT. Interestingly, PTEN knockdown sensitized cells to VAOS, whereas ectopic expression of PTEN markedly rescued VAOS-mediated lethality. In vivo, VAOS treatment markedly reduced PTEN activity and tumour cell burden with low systemic toxicity. Thus, our data not only provided a new therapeutic drug candidate for NSCLC, but presented new understanding into the pharmacological research of VAOS.

Acute statin treatment has been reported to be critical in protecting the cardiac cells against ischemia/reperfusion injury by activating PI3K/Akt signal pathway. In vitro rat myocardial ischemia/reperfusion model, chronic statin treatment led to upregulation of phosphatase and tensin homolog (PTEN). This has been potentially indicated the correlation in PTEN and protective effect of statin on myocardium. In this current study, we evaluated the role of sodium orthovanadate a nonspecific inhibitor to PTEN and its correlation with atorvastatin on protecting myocardium against ischemia/reperfusion injury. We found a long-term statin treatment could increase the PTEN level, and this process was counteracted in the presence of sodium orthovanadate. However, the phosphotyrosine level was not affected by this statin. Besides, this process was mediated by Akt signaling since phosphorylated Akt level was altered by statin and sodium orthovanadate treatment. In a conclusion, this study showed a potential mechanism underlying PTEN-induced attenuation in long-term statin's therapeutic effect, which provided the new insight into the synergic role of PTEN and atorvastatin in protecting cardiac cells against ischemia/reperfusion injury.

Decavanadate salts with nicotinamide (3-pyridinecarboxamide, 3-pca) and isonicotinamide (4-pyridinecarboxamide, 4-pca) in both neutral and protonated forms, (3-Hpca)4[H2V10O28]·2H2O·2(3-pca) (complex I) and (4-Hpca)4[H2V10O28]·2(4-pca) (complex II), have been synthesized and characterized by vibrational spectroscopy (infrared and Raman), thermogravimetric analysis (TGA), 51V NMR, and single-crystal X-ray diffraction analysis. The effects of sodium decavanadate (henceforth called NaV10) and compounds I and II on Escherichia coli, Giardia intestinalis, and Vero (African green monkey epithelial kidney) cells were evaluated. Enhanced growth inhibitory activity against E. coli cultures was observed upon treatment with products I and II when compared to that with NaV10 (GI50 values of 2.8, 4.0, and 11 mmol L–1, respectively), as well as lower cell viability as measured by the intake of propidium iodide (PI). Exposure of Giardia trophozoites to NaV10 and II revealed reduction in trophozoite viability (GI50 value...

Association of Alzheimer’s disease (AD) with cerebral glucose hypometabolism, likely due to impairments of insulin signaling, has been reported recently, with encouraging results when additional insulin is provided to AD patients. Here, we tested the potential effects of the anti-diabetic vanadium, vanadyl (IV) acetylacetonate (VAC), on AD in vitro and in vivo models. The experimental results showed that VAC at sub-micromolar concentrations improved the viability of neural cells with or without increased β-amyloid (Aβ) burden; and in APP/PS1 transgenic mice, VAC treatment (0.1 mmol kg−1 d−1) preserved cognitive function and attenuated neuron loss, but did not reduce brain Aβ plaques. Further studies revealed that VAC attenuated Aβ pathogenesis by (i) activation of the PPARγ-AMPK signal transduction pathway, leading to improved glucose and energy metabolism; (ii) up-regulation of the expression of glucose-regulated protein 75 (Grp75), thus suppressing p53-mediated neuronal apoptosis under Aβ-related stresses; and (iii) decreasing toxic soluble Aβ peptides. Overall, our work suggested that vanadyl complexes may have great potential for effective therapeutic treatment of AD.

Pollution of environment due to increased exploitation of minerals has been on the rise, and vanadium, a metal in the first transition series essential for mammalian existence, is a major component of air pollution. This study investigated the clinico-pathological, hepato-renal toxicity, and cytogenotoxicity of intraperitoneal exposure of African giant rats (AGRs), a proposed model for ecotoxicological research to sodium metavanadate. A total of 27 adult male African giant rats weighing 975 ± 54.10 g were distributed into two major groups: sodium metavanadate (SMV) treated and control. They were observed daily for clinical signs of toxicity. Four rats from each group were randomly collected and sacrificed after 3, 7, and 14 days of SMV treatment. Liver, kidney, and bone marrow were analyzed for histopathology and micronucleated normochromated and polychromated erythrocytes (MNNCE and MNPCE), respectively. Clinical signs in treated AGR include sluggish and weak movements, un-groomed fur, and labored breathing. Histology of the kidney revealed severe glomerular atrophy, tubular ectasia, and vacuolar degeneration of tubular epithelium, while liver histology showed sinusoidal congestion and severe hepatocellular necrosis after 14 days SMV exposure. Also, MNNCE and MNPCE significantly increased with a decrease in PCE/NCE ratio in SMV-treated AGR, suggestive of alternations in bone marrow cell proliferation. Hence, SMV treatment to AGR resulted to severe clinicopathologic alterations, kidney, and liver dysfunction and cytogenotoxicity evident by somatic mutation induction which could be severe with prolonged exposure. This suggests African giant rat as an ecotoxicological model to measure major health risks to animals and human populations in highly polluted environment.

Accumulation and polarization of anti-inflammatory M2 to proinflammatory M1 macrophage in the adipose tissue of obese diabetic mice is an important pathogenic signature. It worsens lipid induced inflammation and insulin resistance. Here we demonstrate that a small molecule, a peroxyvanadate compound i.e. DmpzH [VO(O2)2 (dmpz)] or dmp, could robustly decrease macrophage infiltration, accumulation and their polarization in high fat diet (HFD) induced obese diabetic mice. In searching the underlying mechanism it was revealed that SIRT1 level was strikingly low in the inflamed adipose tissue of HFD mice as compared to mice fed with standard diet (SD). Administration of dmp markedly increased SIRT1 level by inducing its gene expression with a consequent decrease in macrophage population. Elevation of SIRT1 coincided with the decrease of MCP1, Fetuin-A (FetA) and IFNγ. Since MCP1 and FetA drive macrophage to inflamed adipose tissue and IFNγ promotes M2 to M1 transformation, both recruitment and M1 induced inflammation were found to be significantly repressed by dmp. In addressing the question about how dmp induced excess SIRT1 could reduce MCP1, FetA and IFNγ levels, we found that it was due to the inactivation of NFκB because of its deacetylation by SIRT1. Since NFκB is the transcriptional regulator of these molecules, their expressions were significantly suppressed and that caused sharp decline in macrophage recruitment and their polarity to M1. This effected a marked fall in proinflammatory cytokine level which significantly improved insulin sensitivity. dmp is likely to be the first molecule that rescues inflammatory burden contributed by macrophage in obese diabetic mice adipose tissue which causes significant increase in insulin sensitivity therefore it may be a meaningful choice to treat type 2 diabetes.

Nucleoside diphosphate kinases (NDKs) are implicated in a wide variety of cellular functions owing to their enzymatic conversion of NDP to NTP. NDK fromBorrelia burgdorferi(BbNDK) was selected for functional and structural analysis to determine whether its activity is required for infection and to assess its potential for therapeutic inhibition. The Seattle Structural Genomics Center for Infectious Diseases (SSGCID) expressed recombinantBbNDK protein. The protein was crystallized and structures were solved of both the apoenzyme and a liganded form with ADP and vanadate ligands. This provided two structures and allowed the elucidation of changes between the apo and ligand-bound enzymes. Infectivity studies withndktransposon mutants demonstrated that NDK function was important for establishing a robust infection in mice, and provided a rationale for therapeutic targeting ofBbNDK. The protein structure was compared with other NDK structures found in the Protein Data Bank and was found to have similar primary, secondary, tertiary and quaternary structures, with conserved residues acting as the catalytic pocket, primarily using His132 as the phosphohistidine-transfer residue. Vanadate and ADP complexes model the transition state of this phosphoryl-transfer reaction, demonstrating that the pocket closes when bound to ADP, while allowing the addition or removal of a γ-phosphate. This analysis provides a framework for the design of potential therapeutics targetingBbNDK inhibition.

Oxidative stress caused by an overproduction of reactive oxygen species (ROS) is the key factor in developing a variety of pathological conditions. Recently various nanomaterials have attracted growing interest as nanoantioxidants with ROS-regulating ability. Here, for the first time, we report on high antioxidant behavior (enzyme-like activity) of GdYVO4:Eu3+ nanoparticles (GdYVO NPs) revealed by spectroscopic methods both in cell-free and biological milieu using various ROS sensors. It was revealed that GdYVO NPs (d = 2 nm) effectively scavenge hydroxyl radicals · O H , superoxide anions O 2 · − , hydrogen peroxide H 2 O 2 , peroxyl radicals R O O · , and remarkably reduce the lipopolysaccharide-induced ROS generation in rat leukocytes. The antioxidant activity of GdYVO NPs is ascribed to high amount of V4+ and V3+ ions in the structure of the NPs and the reversible switching V 3 + ↔ V 4 + and V 4 + ↔ V 5 + vanadium oxidation states.

Conventional photothermal therapy (PTT) is insufficient to induce a strong and potent anti-tumor immune response. Herein, we present a vanadyl nanocomplex, which simultaneously serves as a photothermal agent (PTA) and an immunogenic cell death (ICD) inducer to enhance the anti-tumor immunity of PTT. The vanadyl nanocomplex (STVN) is constructed via facile one-step coordination assembly under ambient conditions. STVN not only has a strong and stable photothermal effect under near-infrared (NIR) irradiation, but also can cause severe endoplasmic reticulum (ER) stress by itself, leading to ICD and activating the systemic immune responses. In the absence of any adjuvants, NIR-irradiated STVN almost completely ablates primary tumors and simultaneously inhibits distant tumors in mice bearing bilateral melanoma. Meanwhile, the intratumorally injected STVN combined with NIR effectively suppressed melanoma lung metastasis as well as tumor recurrence, displaying that local STVN-mediated PTT could trigger a systemic anti-tumor immunity. Therefore, STVN, as a novel immunogenicity-enhanced PTA, affords a "one stone two birds" strategy for improved photothermia-induced cancer immunotherapy.

The objective of this study was to investigate the effect of resveratrol (a natural polyphenolic phytostilbene) on tau hyperphosphorylation and oxidative damage induced by sodium orthovanadate (Na3VO4), the prevalent species of vanadium (vanadate), in rat hippocampal slices. Our results showed that resveratrol significantly inhibited Na3VO4-induced hyperphosphorylation of tau at the Ser396 (p-S396-tau) site, which is upregulated in the hippocampus of Alzheimer’s disease (AD) brains and principally linked to AD-associated cognitive dysfunction. Subsequent mechanistic studies revealed that reduction of ERK1/2 activation was involved in the inhibitory effect of resveratrol by inhibiting the ERK1/2 pathway with SL327 mimicking the aforementioned effect of resveratrol. Moreover, resveratrol potently induced GSK-3β Ser9 phosphorylation and reduced Na3VO4-induced p-S396-tau levels, which were markedly replicated by pharmacologic inhibition of GSK-3β with LiCl. These results indicate that resveratrol could suppre...