Mechanism of the antimicrobial activity induced by phosphatase inhibitor sodium ortho-vanadate.

The present study describes a novel antimicrobial mechanism based on Sodium Orthovanadate (SOV), an alkaline phosphatase inhibitor. Scanning electron microscopy (SEM), transmission electron microscopy (TEM) and atomic force microscopy (AFM) were employed to examine the surface morphologies of the test organism, Escherichia coli (E. coli), during various antibacterial phases. Our results indicated that SOV kills bacteria by attacking cell wall growth and development, leaving E. coli's outer membrane intact. Our antimicrobial test indicated that the MIC of SOV for both E. coli and Lactococcus lactis (L. lactis) is 40 µM. A combination of quantum mechanical calculations and vibrational spectroscopy revealed that divanadate from SOV strongly coordinates with Ca2+ and Mg2+, which are the activity centers for the phosphatase that regulates bacterial cell wall synthesis. The current study is the first to propose the antibacterial mechanism caused by SOV attacking cell wall.

Sodium orthovanadate exhibits anti-angiogenic, antiapoptotic and blood glucose-lowering effect on colon cancer associated with diabetes.

BACKGROUND: The presence of type 2 diabetes mellitus increases the risk of developing the colon cancer. The main objective of this study was to determine the role of sodium orthovanadate (SOV) in colon cancer associated with diabetes mellitus by targeting the competitive inhibition of PTP1B. METHODS: For in vivo study, high fat diet with low dose streptozotocin model was used for inducing the diabetes mellitus. Colon cancer was induced by injecting 1,2-dimethylhydrazine (25 mg/kg, sc) twice a week. TNM staging and immunohistochemistry (IHC) was carried out for colon cancer tissues. In vitro studies like MTT assay, clonogenic assay, rhodamine-123 dye assay and annexin V-FITC assay using flow cytometry were performed on HCT-116 cell line. CAM assay was performed to examine the anti-angiogenic effect of the drug. RESULTS: Sodium orthovanadate reduces the blood glucose level and tumor parameters in the animals. In vitro studies revealed that SOV decreased cell proliferation dose dependently. In addition, SOV induced apoptosis as depicted from rhodamine-123 dye assay and annexin V-FITC assay using flow cytometry as well as p53 IHC staining. SOV showed reduced angiogenesis effect on eggs which was depicted from CAM assay and also from CD34 and E-cadherin IHC staining. CONCLUSIONS: Our data suggest that SOV exhibits protective role in colon cancer associated with diabetes mellitus. SOV exhibits anti-proliferative, anti-angiogenic and apoptotic inducing effects hence can be considered for therapeutic switching in diabetic colon cancer.

Lupenone attenuates thapsigargin-induced endoplasmic reticulum stress and apoptosis in pancreatic beta cells possibly through inhibition of protein tyrosine kinase 2 activity.

AIMS: Prolonged high levels of cytokines, glucose, or free fatty acids are associated with diabetes, elevation of cytosolic Ca2+ concentration ([Ca2+]C), and depletion of Ca2+ concentration in the endoplasmic reticulum (ER) of pancreatic beta cells. This Ca2+ imbalance induces ER stress and apoptosis. Lupenone, a lupan-type triterpenoid, is beneficial in diabetes; however, its mechanism of action is yet to be clarified. This study evaluated the protective mechanism of lupenone against thapsigargin-induced ER stress and apoptosis in pancreatic beta cells. MATERIALS AND METHODS: MIN6, INS-1, and native mouse islet cells were used. Western blot for protein expressions, measurement of [Ca2+]C, and in vivo glucose tolerance test were mainly performed. KEY FINDINGS: Thapsigargin increased the protein levels of cleaved caspase 3, cleaved PARP, and the phosphorylated form of JNK, ATF4, and CHOP. Thapsigargin increased the interaction between stromal interaction molecule1 (Stim1) and Orai1, enhancing store-operated calcium entry (SOCE). SOCE is further activated by protein tyrosine kinase 2 (Pyk2), which is Ca2+-dependent and phosphorylates the tyrosine residue at Y361 in Stim1. Lupenone inhibited thapsigargin-mediated Pyk2 activation, suppressed [Ca2+]C, ER stress, and apoptosis. Lupenone restored impaired glucose-stimulated insulin secretion effectuated by thapsigargin and glucose intolerance in a low-dose streptozotocin-induced diabetic mouse model. SIGNIFICANCE: These results suggested that lupenone attenuated thapsigargin-induced ER stress and apoptosis by inhibiting SOCE; this may be due to the hindrance of Pyk2-mediated Stim1 tyrosine phosphorylation. In beta cells that are inevitably exposed to frequent [Ca2+]C elevation, the attenuation of abnormally high SOCE would be beneficial for their survival.

Phosphatase inhibition by sodium orthovanadate displays anti-inflammatory action by suppressing AKT-IKKß signaling in RAW264.7 cells.

Sodium orthovanadate (Na3VO4) is an inhibitor of phosphatases that acts as a phosphate analog and is being developed as an anti-diabetes drug. Phosphatases play important roles in inflammatory signal pathways by modulating the removal of phosphate moieties of key signaling proteins. However, the role of protein phosphatases on the inflammatory response has not been fully established. In this study, we investigated how phosphatases can control the inflammatory response using Na3VO4 in LPS-stimulated RAW264.7 cells and explored the molecular mechanisms by NO assay, mRNA analysis, immunoblotting analysis, kinase assay, luciferase reporter gene assay, and mutation strategy. Na3VO4 decreased the release of nitric oxide (NO) and suppressed the expression of pro-inflammatory genes at the transcriptional level, without cytotoxicity. The translocation of nuclear factor (NF)-κB subunits into the nucleus and the level of p-IκBα were reduced by Na3VO4, as was IKKß activity. Na3VO4 inhibited NF-κB-Luc activity under AKT1/2 and IKKß overexpression. However, the inhibitory effect of Na3VO4 against NF-κB-Luc was not observed in the group overexpressing both AKT2 and IKKß-M10, a mutant in which the 10 serine residues in the autophosphorylated region of the C-terminal were replaced with alanine. Na3VO4 directly decreased the activity of protein phosphatase 1α (PP1α) and protein phosphatase 2 A (PP2A) by 95%. Phosphatase inhibition by Na3VO4 also selectively suppressed AKT-IKKß signaling by directly blocking the phosphatase activity of PP1 and PP2A, consequently down-regulating NF-κB and inflammatory gene expression. Therefore, these results suggest that vanadium compounds including Na3VO4 can be developed as anti-inflammatory drugs.

Antidepressant-like effect of sodium orthovanadate in a mouse model of chronic unpredictable mild stress.

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 (5 & 10 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 (5 & 10 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.

Vanadium Toxicity Monitored by Fertilization Outcomes and Metal Related Proteolytic Activities in Paracentrotus lividus Embryos.

Metal pharmaceutical residues often represent emerging toxic pollutants of the aquatic environment, as wastewater treatment plants do not sufficiently remove these compounds. Recently, vanadium (V) derivatives have been considered as potential therapeutic factors in several diseases, however, only limited information is available about their impact on aquatic environments. This study used sea urchin embryos (Paracentrotus lividus) to test V toxicity, as it is known they are sensitive to V doses from environmentally relevant to very cytotoxic levels (50 nM; 100 nM; 500 nM; 1 µM; 50 µM; 100 µM; 500 µM; and 1 mM). We used two approaches: The fertilization test (FT) and a protease detection assay after 36 h of exposure. V affected the fertilization percentage and increased morphological abnormalities of both egg and fertilization envelope, in a dose-dependent manner. Moreover, a total of nine gelatinases (with apparent molecular masses ranging from 309 to 22 kDa) were detected, and their proteolytic activity depended on the V concentration. Biochemical characterization shows that some of them could be aspartate proteases, whereas substrate specificity and the Ca2+/Zn2+ requirement suggest that others are similar to mammalian matrix metalloproteinases (MMPs).

Ameliorative Effect of Acetyl L-carnitine in Alzheimer's Disease via Downregulating of Homocysteine Levels in Hyperhomocysteinemia Induced Cognitive Deficit in Mouse Model.

AIMS: The study was aimed at exploring the role of Acetyl L-Carnitine supplementation attenuating dementia and degradation of cognitive abilities in Hyperhomocysteinemia induced AD manifestations in the mouse model. BACKGROUND: Alzheimer's disease (AD) is a neurological disorder that is marked by dementia, and degradation of cognitive abilities. There is great popularity gained by natural supplements as the treatment for AD, due to the higher toxicities of synthetic drugs. Hyperhomocysteinemia causes excitotoxicity to the cortical neurons, which brought us to the point that amino acids possibly have a role in causing cholinergic deformities, which are an important etiological parameter in AD. Acetyl L-Carnitine a methyl donor with the presence of three chemically reactive methyl groups linked to a nitrogen atom was found to possess neuroprotective activity against experimental models of AD. OBJECTIVE: The objective of the present investigation was to investigate and evaluate the pharmacological effect of Acetyl L-Carnitine against hyperhomocysteinemia induced Alzheimer's disease (AD) in the mouse model. MATERIALS AND METHODS: The animals were divided into normal control (vehicle-treated), HHcy (dl-Homocysteine thiolactone treated) negative control, test group i.e., low dose (50mg/kg, p.o) of acetyl L-carnitine (L-ALC), high dose (100mg/kg,p.o) of acetyl L-carnitine (H-ALC), L-ALC+ SOV (Sodium orthovanadate) and H-ALC+SOV. HHcy was induced by administration of dl-Homocysteine thiolactone (dl-HCT; 1 g/kg, p.o.) on day-1 to day-15 of experimental schedule to all animals except normal control. The changes in the behaviour pattern of the animals due to neuroinflammation, and cholinergic dysfunction were examined in rotarod, novel objective recognition, passive avoidance, elevated plus maze, and morris water maze analysis. Biochemical investigation includes the estimation of total homocysteine (tHcy), Creatinine Kinase (CK), Acetylcholinesterase (AChE), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and IL-6 and TNF-α. RESULTS: Supplementation of ALC in mouse considerably lowered the HHcy-induced AD manifestations in the experimental animals. It was found that ALC and SOV successfully diminished the behaviour abnormalities and lessened the Hcy-induced alteration in systemic Hcy levels, CK activity, and cholinergic dysfunction with improved bioenergetics in the Prefrontal cortex of the mice. CONCLUSION: ALC was found to improve the HHcy-induced cognitive disabilities which was found to be associated with the decreased systemic levels of Hcy, CK, and cholinergic abnormalities. It also combats the oxidative stress-induced neuroinflammation with diminished pro-inflammatory markers in the pre frontal cortex. The outcomes collectively indicate ALC's potential to be used as a supplementation in the pharmacotherapy of AD.

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.

Sodium orthovanadate inhibits growth of acute leukemia HL60 cells and HL60/A cells in vitro.

Vanadium is an ultratrace element. The transition metal vanadium, widely exists in the environment and exhibits various biological and physiological effects in the human body, yet with no presently known specific physiological function in mammals. Sodium orthovanadate (SOV) is a kind of vanadium compound. SOV has shown promising antineoplastic activity in several human cancers. But the effects of SOV on acute promyelocytic leukemia (APL) are still unknown. In the present study, for the first time, we found that SOV could inhibit proliferation, induce G2/M cell cycle arrest and apoptosis, and could inhibit autophagy of acute leukemia cell lines in vitro. Thus, our findings suggest that SOV could effectively suppress the growth of acute leukemia HL60 cells and HL60/A cells through the regulations of proliferation, cell cycle, apoptosis and autophagy, and thus may act as a potential therapeutic agent in APL treatment.

Sodium orthovanadate improves learning and memory in intracerebroventricular-streptozotocin rat model of Alzheimer's disease through modulation of brain insulin resistance induced tau pathology.

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-3ß 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-3ß. 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-3ß 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.

Pentavalent Vanadium Species as Potential Corrosion Inhibitors of Al2Cu Intermetallic Phase in the Sulfuric(VI) Acid Solutions.

The objective of this work was to test vanadium isopolyoxoanions as potential corrosion inhibitors of the intermetallic phase Al2Cu in sulfuric acid solutions at pH = 1.3 and 2.5. The intermetallic was melted in an electric arc furnace. Its phase composition was confirmed using X-ray diffraction, light microscopy, and differential scanning calorimetry. Then Al2Cu corrosion kinetics was studied. Chemical composition of the solution after corrosion was determined using inductively coupled plasma-optical emission spectroscopy. The surface of corroded specimens was analyzed using scanning electron microscopy and X-ray photoelectron spectroscopy. Subsequent electrochemical studies involved determination of open-circuit potential, electrochemical impedance spectra, and polarization curves. It was found that the Al2Cu phase corrodes selectively and vanadium isopolyoxoanions increase this process both at pH = 1.3 and 2.5 with two exceptions. Corrosion inhibition was observed for 100 and 200 mM of Na3VO4 at pH 1.3, with inhibition efficiency 78% and 62% respectively, due to precipitation of V2O5.

Oleic acid and hydroxytyrosol present in olive oil promote ROS and inflammatory response in normal cultures of murine dermal fibroblasts through the NF-κB and NRF2 pathways.

Few studies have evaluated the effects of olive oil on normal tissues like skin and its components. Hence, we investigated whether olive oil could increase the production of ROS and oxidative damage in murine dermal fibroblast cultures in a short-term exposition. In addition, we evaluated the role of oleic acid and hydroxytyrosol, which are the two most important components of olive oil, in the associated mechanisms of action, and the metabolism of long-chain fatty acids from olive oil. To study this, neonatal murine dermal fibroblasts (NMDF) were incubated with olive oil, oleic acid, or hydroxytyrosol for 24 or 72 h. The NMDF incubated with olive oil or oleic acid showed an increase in the production of ROS after 24 h, lipid peroxidation, and protein carbonylation after 72 h, as well as increased expression of nuclear factor-kappa B (NF-κB) p65 and cyclooxygenase-2 (COX-2) after 72 h. However, NMDF treated with olive oil or hydroxytyrosol demonstrated an increase in the expression of nuclear factor-erythroid2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) after 72 h. In addition, NMDF treated with olive oil also showed an increase in the protein expression of diacylglycerol acyltransferase1 (DGAT1), which promotes triacylglycerol synthesis, and in the levels of triacylglycerols. The microscopic analysis showed Nile red-positive lipid droplets inside olive oil-treated NMDF after 72 h. Moreover, gas chromatography-mass spectrometry demonstrated high levels of oleic acid in the olive oil-treated NMDF after 72 h. In conclusion, oleic acid present in the olive oil promotes the production of ROS and oxidative damage in murine dermal fibroblasts, which leads to NF-κB p65 and COX-2 expression, while hydroxytyrosol promotes NRF2 and HO-1 expression. In addition, NMDF area capable of absorbing long-chain fatty acids derived from olive oil, which promotes the synthesis and the accumulation of triacylglycerols into cytoplasm of NMDF through DGAT1 activation.

Sodium Orthovanadate Changes Fatty Acid Composition and Increased Expression of Stearoyl-Coenzyme A Desaturase in THP-1 Macrophages.

Vanadium compounds are promising antidiabetic agents. In addition to regulating glucose metabolism, they also alter lipid metabolism. Due to the clear association between diabetes and atherosclerosis, the purpose of the present study was to assess the effect of sodium orthovanadate on the amount of individual fatty acids and the expression of stearoyl-coenzyme A desaturase (SCD or Δ9-desaturase), Δ5-desaturase, and Δ6-desaturase in macrophages. THP-1 macrophages differentiated with phorbol 12-myristate 13-acetate (PMA) were incubated in vitro for 48 h with 1 µM or 10 µM sodium orthovanadate (Na3VO4). The estimation of fatty acid composition was performed by gas chromatography. Expressions of the genes SCD, fatty acid desaturase 1 (FADS1), and fatty acid desaturase 2 (FADS2) were tested by qRT-PCR. Sodium orthovanadate in THP-1 macrophages increased the amount of saturated fatty acids (SFA) such as palmitic acid and stearic acid, as well as monounsaturated fatty acids (MUFA)-oleic acid and palmitoleic acid. Sodium orthovanadate caused an upregulation of SCD expression. Sodium orthovanadate at the given concentrations did not affect the amount of polyunsaturated fatty acids (PUFA) such as linoleic acid, arachidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). In conclusion, sodium orthovanadate changed SFA and MUFA composition in THP-1 macrophages and increased expression of SCD. Sodium orthovanadate did not affect the amount of any PUFA. This was associated with a lack of influence on the expression of FADS1 and FADS2.

Neuroprotective effects of a protein tyrosine phosphatase inhibitor against hippocampal excitotoxic injury.

Neuronal excitotoxicity is the neuronal cell death arising from prolonged exposure to glutamate and the associated excessive influx of ions into the cell. Sodium orthovanadate (Na3VO4,) competitively inhibits the protein tyrosine phosphatases that affect intracellular protein phosphorylation. No study has examined the role of protein tyrosine phosphatases in kainic acid (KA)-induced excitotoxic injury using sodium orthovanadate. Thus, the present study was conducted to determine the neuroprotective effects of sodium orthovanadate on KA-induced neuronal death in organotypic hippocampal slice culture. We also performed an in vivo electrophysiology study in Sprague-Dawley rats to observe the function of surviving cells after sodium orthovanadate treatment in KA-induced excitotoxicity. Rats were anaesthetized with sodium pentobarbital and KA was injected unilaterally in CA3 of the hippocampus by microinjection-cannula. Neuronal cell death, as assessed by propidium iodide uptake, was reduced by 10 and 25 µM sodium orthovanadate treatment (24 and 48 h) compared with the KA-only group. Sodium orthovanadate enhanced survival signals by increasing levels of phospho-Akt and superoxide dismutase. In addition, sodium orthovanadate treatment reduced calcineurin level for neuronal protection, which regulates activation of cellular calcium caused by KA-induced injury. In vivo results showed that sodium orthovanadate treatment elicited resistance to KA-induced behavior seizures and significantly reduced the duration of epileptiform discharges. In addition, sodium orthovanadate treatment (25 mM) significantly prevented the increase in power spectra induced by KA injection. These results suggest that sodium orthovanadate decreases the acute effects of KA, thereby inducing neuroprotective effects with reduced reactive oxygen species and cellular Ca2+. Thus, sodium orthovanadate may protect hippocampal neurons against excitotoxicity, and surviving neurons may function to reduce seizures.

Sodium orthovanadate inhibits growth and triggers apoptosis of human anaplastic thyroid carcinoma cells in vitro and in vivo.

Vanadium and its compounds exhibit concentration- and time-dependent anticancer effects on various types of tumor; however, the effects of sodium orthovanadate (SOV) on anaplastic thyroid carcinoma (ATC) have not yet been reported. In the present study, the anticancer effects of SOV on ATC were evaluated. In vitro experiments, including cell viability assays, plate colony formation assays, cell cycle analysis and apoptosis analysis were used to study the role of SOV in ATC. Using in vivo experiments, the effects of SOV on the growth and apoptosis of an ATC-xenograft tumor were studied by comparing the SOV-treatment with the control group. The results revealed that treatment of the human ATC cell line 8505C with SOV inhibited cell viability, induced G2/M phase cell cycle arrest, stimulated apoptosis and reduced mitochondrial membrane potential in a concentration-dependent manner. These findings were confirmed in vivo in a nude mouse ATC xenograft model. In conclusion, the present study demonstrated that SOV inhibited human ATC by regulating proliferation, cell cycle progression and apoptosis, thus suggesting that SOV may be considered a novel option for the treatment of ATC.

Attenuation of hyperhomocysteinemia induced vascular dementia by sodium orthovanadate perhaps via PTP1B: Pertinent downstream outcomes.

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's disease, but drug regulatory authorities have not approved any effective medication for this indication. Researchers are keenly aware of the need to uncover precise and druggable targets for VaD. However, finding such a target is an experimentally impractical and challenging task, owing to the highly complex interplay between cognitive and functional abilities of the brain with a diversity of vascular diseases that usually results from various underlying risk factors. Network pharmacology, may, therefore be an alternative and rational choice because a network of disease targets let researchers select the best target from a disease module. According to this approach, inhibition of protein tyrosine phosphatase 1B (PTP1B) may trigger downstream effects of VaD relevance, but specific inhibitors of this enzyme are currently not in medical use. To assess whether PTP1B mediated actions are possible and are relevant to VaD or not, the impact of sodium orthovanadate on homocysteine-induced endothelial dysfunction, oxidative stress, cholinergic dysfunction learning and memory impairments investigated. The visual, spatial, emotional and fear-motivated learning, and memory impairment assessed by object recognition, water maze, step-through and elevated plus maze task, respectively. These impairments significantly attenuated by sodium orthovanadate, therefore, downstream effects seems to be relevant, and the role of PTP1B is suspected. However, sodium orthovanadate is a non-specific inhibitor of PTP1B; therefore, further in-vivo validation warranted, and it is possible in future because specific PTP1B inhibitors are in development phase.

Fluorometric determination of the activity of alkaline phosphatase and its inhibitors based on ascorbic acid-induced aggregation of carbon dots.

The authors describe a fluorometric method for determination of the activity of alkaline phosphatase (ALP) and its inhibitors. Nitrogen and boron co-doped carbon dots (C-dots) with excitation/emission peaks at 490/540 nm act as the fluorescent probe. The C-dots were prepared by hydrothermal carbonization starting from 3-aminophenylboronic acid as the sole precursor. On the basis of the boronic acid-triggered specific reaction with cis-diols, the boronic acid modified C-dots can bind to ascorbic acid that is generated by ALP-catalyzed hydrolysis of ascorbic acid 2-phosphate. This results in particle aggregation and quenching of fluorescence. If the ALP inhibitor Na3VO4 is introduced into the system, the activity of ALP is reduced and the fluorescence of C-dots recovers. This fluorometric method allows for the determination of ALP activity in the range from 0.2 to 6.0 mU mL-1 with a detection limit of 0.16 mU mL-1. The IC50 value for the inhibitor Na3VO4 is 3.6 µM. The method is convenient and cost-effective. It does not require complicated operations and in our perception widens the scope of applications of C-dots in bioanalytical sciences. Graphical abstract Schematic presentation of the nitrogen and boron co-doped carbon dot-based fluorometric method for determination of alkaline phosphatase (ALP) activity.

Is there a Role for Sodium Orthovanadate in the Treatment of Diabetes?

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.

Downregulation of PTEN by sodium orthovanadate protects the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment.

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.

Magnetic iron oxide nanoparticles modified with vanadate and phosphate salts for purification of alkaline phosphatase from the bovine skim milk.

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.