Orthovanadate Research Articles

Acute Toxicity Evaluation of Non-Innocent Oxidovanadium(V) Schiff Base Complex

The vanadium(V) complexes have been investigated as potential anticancer agents which makes it essential to evaluate their toxicity for safe use in the clinic. The large-scale synthesis and the acute oral toxicity in mice of the oxidovanadium(V) Schiff base catecholate complex, abbreviated as [VO(HSHED)dtb] containing a redox-active ligand with tridentate Schiff base (HSHED = N-(salicylideneaminato)-N’-(2-hydroxyethyl)-1,2-ethylenediamine) and dtb = 3,5-di-(t-butyl)catechol ligands were carried out. The body weight, food consumption, water intake as well biomarkers of liver and kidney toxicity of the [VO(HSHED)dtb] were compared to the precursors, sodium orthovanadate, and free ligand. The 10-fold scale-up synthesis of the oxidovanadium(V) complex resulting in the preparation of material in improved yield leading to 2–3 g (79%) material suitable for investigating the toxicity of vanadium complex. No evidence of toxicity was observed in animals when acutely exposed to a single dose of 300 mg/kg for 14 days. The toxicological results obtained with biochemical and hematological analyses did not show significant changes in kidney and liver parameters when compared with reference values. The low oral acute toxicity of the [VO(HSHED)dtb] is attributed to redox chemistry taking place under biological conditions combined with the hydrolytic stability of the oxidovanadium(V) complex. These results document the design of oxidovanadium(V) complexes that have low toxicity but still are antioxidant and anticancer agents.

Exogenous Potassium (K+) Positively Regulates Na+/H+ Antiport System, Carbohydrate Metabolism, and Ascorbate-Glutathione Cycle in H2S-Dependent Manner in NaCl-Stressed Tomato Seedling Roots.

Potassium (K+) is one of the vital macronutrients required by plants for proper growth and blossoming harvest. In addition, K+ also plays a decisive role in promoting tolerance to various stresses. Under stressful conditions, plants deploy their defense system through various signaling molecules, including hydrogen sulfide (H2S). The present investigation was carried out to unravel the role of K+ and H2S in plants under NaCl stress. The results of the study show that NaCl stress caused a reduction in K+ and an increase in Na+ content in the tomato seedling roots which coincided with a lower H+-ATPase activity and K+/Na+ ratio. However, application of 5 mM K+, in association with endogenous H2S, positively regulated the Na+/H+ antiport system that accelerated K+ influx and Na+ efflux, resulting in the maintenance of a higher K+/Na+ ratio. The role of K+ and H2S in the regulation of the Na+/H+ antiport system was validated by applying sodium orthovanadate (plasma membrane H+-ATPase inhibitor), tetraethylammonium chloride (K+ channel blocker), amiloride (Na+/H+ antiporter inhibitor), and hypotaurine (HT, H2S scavenger). Application of 5 mM K+ positively regulated the ascorbate–glutathione cycle and activity of antioxidant enzymes that resulted in a reduction in reactive oxygen species generation and associated damage. Under NaCl stress, K+ also activated carbohydrate metabolism and proline accumulation that caused improvement in osmotic tolerance and enhanced the hydration level of the stressed seedlings. However, inclusion of the H2S scavenger HT reversed the effect of K+, suggesting H2S-dependent functioning of K+ under NaCl stress. Therefore, the present findings report that K+, in association with H2S, alleviates NaCl-induced impairments by regulating the Na+/H+ antiport system, carbohydrate metabolism, and antioxidative defense system.

Diarylheptanoid-chalcone hybrids with PTP1B and α-glucosidase dual inhibition from Alpinia katsumadai

The EtOH extracts of the dried seeds of Alpinia katsumadai were revealed with hypoglycemic effects on db/db mice at the concentration of 200 mg/kg. In order to clarify the antidiabetic constituents, 16 new diarylheptanoid-chalcone hybrids, katsumadainols A1−A16 (1–16), together with 13 known analogues (17–29), were isolated from A. katsumadai under the guidance of bioassay. Most of the compounds showed α-glucosidase and PTP1B dual inhibition, among which compounds 1–3, 5–7, 11–14, 21–25, and 27 showed PTP1B/TCPTP selective inhibition with IC50 values ranging from 22.0 to 96.7 μM, which were 2–10 times more active than sodium orthovanadate (IC50, 215.7 μM). All compounds exhibited obvious inhibition against α-glucosidase with IC50 values of 2.9–29.5 μM, indicating 6–59 times more active than acarbose (IC50, 170.9 μM). Study of enzyme kinetics indicated compounds 1, 3, and 12 were PTP1B and α-glucosidase mixed-type inhibitors with Ki values of 13.1, 12.9, 21.6 μM, and 4.9, 7.4, 3.4 μM, respectively.

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.

ВЛИЯНИЕ СОЛЕЙ АЗИДА, ФТОРИДА, ОРТОВАНАДАТА И ЭДТА НАТРИЯ НА ЭКТО-АТФАЗНУЮ АКТИВНОСТЬ ЭРИТРОЦИТОВ СКОРПЕНЫ (SCORPAENA PORCUS L .) И МОРСКОЙ ЛИСИЦЫ (RAJA CLAVATA L .)

The effect of azide, fluoride, orthovanadate and EDTA sodium salts on the ecto-ATPase activity in red blood cells (RBCs) of a scorpionfish (Scorpaena porcus L.) and thornback ray (Raja clavata L.) was studied. It was shown that under the influence of millimolar (mM) concentrations of the selected biochemical agents, significant differences in the hydrolytic activity of RBC plasma membrane ecto-ATPases were revealed in cartilaginous vs. teleost fish. For example, thronback ray RBC ecto-ATPase was practically insensitive to sodium azide. In contrast, scorpionfish RBC ecto-ATPase was sensitive to sodium azide, which blocked the enzyme activity by 65% at a concentration of 20 mM. Thornback ray RBC ecto-ATPase retained a significant activity (37%) at high (60 mM) concentrations of sodium fluoride, while scorpionfish RBC ecto-ATPase was almost completely blocked at this concentration. EDTA acted as a modifier of thornback ray ecto-ATPase activity: at concentrations of up to 6 mM, ATP hydrolysis was actively blocked (by 58%), and at higher concentrations, ecto-ATPase activity was stimulated (up to 20%). An increase in the EDTA concentration (up to 12 mM) in suspensions of scorpionfish RBCs constantly stimulated the inhibitory effect of the chelator (up to 52% vs. control). The activity of ecto-ATPases in RBCs of the studied fish species was weakly blocked by sodium orthovanadate. These differences may reflect a higher tolerance of thornback ray RBC ecto-ATPase to the effect of the above chemical reagents compared to a scorpionfish. The absence of the sodium azide inhibitory effect on thornback ray RBC ecto-ATPase suggests that this ecto-ATPase may be referred to a family of type 2 ecto-NTPDases (ENTPD2), while scorpionfish ecto-ATPase may belong to type 1 ecto-NTPDases (ENTPD1).

Effect of sodium orthovanadate on ovulation isolated ovarian follicles in Siberian Sturgeon (Acipenser baerii) In Vitro

Effects of sodium orthovanadate on oocyte ovulation were examined during in vitro culture of Siberian sturgeon ovarian follicles from hibernating fish. It was shown that sodium orthovanadate stimulates ovulation of Siberian sturgeon oocytes in a dose-dependent manner. The stimulating or inhibitory effect of vanadate depends on the time of addition to the incubation medium. It was also shown that the stimulating effects of orthovanadate depend on the physiological status of hibernating females whose oocytes were isolated

Vanadium-dependent activation of glucose transport in adipocytes by catecholamines is not mediated via adrenoceptor stimulation or monoamine oxidase activity.

BACKGROUNDBenzylamine and methylamine activate glucose uptake in adipocytes. For tyramine, this effect has even been extended to cardiomyocytes.AIMTo investigate the effects of catecholamines and other amines on glucose uptake.METHODSA screening compared 25 biogenic amines on 2-deoxyglucose (2-DG) uptake activation in rat adipocytes. Pharmacological approaches and transgenic mouse models were then used to decipher the mode of action of several hits.RESULTSIn rat adipocytes, insulin stimulation of 2-DG uptake was reproduced with catecholamines. 100 µmol/L or 1 mmol/L adrenaline, noradrenaline, dopamine and deoxyepinephrine, maximally activated hexose transport only when sodium orthovanadate was added at 100 µmol/L. Such activation was similar to that already reported for benzylamine, methylamine and tyramine, well-recognized substrates of semicarbazide-sensitive amine oxidase (SSAO) and monoamine oxidase (MAO). Several, but not all, tested agonists of β-adrenoreceptors (β-ARs) also activated glucose transport while α-AR agonists were inactive. Lack of blockade by α- and β-AR antagonists indicated that catecholamine-induced 2-DG uptake was not mediated by AR stimulation. Adipocytes from mice lacking β1-, β2- and β3-ARs (triple KO) also responded to millimolar doses of adrenaline or noradrenaline by activating hexose transport in the presence of 100 µmol/L vanadate. The MAO blocker pargyline, and SSAO inhibitors did not block the effects of adrenaline or noradrenaline plus vanadate, which were blunted by antioxidants.CONCLUSIONCatecholamines exert unexpected insulin-like actions in adipocytes when combined with vanadium. For limiting insulin resistance by activating glucose consumption at least in fat stores, we propose that catecholamine derivatives combined with vanadium can generate novel complexes that may have low toxicity and promising anti-diabetic properties.

Kinetic Studies of Sodium and Metforminium Decavanadates Decomposition and In Vitro Cytotoxicity and Insulin- Like Activity

The kinetics of the decomposition of 0.5 and 1.0 mM sodium decavanadate (NaDeca) and metforminium decavanadate (MetfDeca) solutions were studied by 51V NMR in Dulbecco’s modified Eagle’s medium (DMEM) medium (pH 7.4) at 25 °C. The results showed that decomposition products are orthovanadate [H2VO4]− (V1) and metavanadate species like [H2V2O7]2− (V2), [V4O12]4− (V4) and [V5O15]5− (V5) for both compounds. The calculated half-life times of the decomposition reaction were 9 and 11 h for NaDeca and MetfDeca, respectively, at 1 mM concentration. The hydrolysis products that presented the highest rate constants were V1 and V4 for both compounds. Cytotoxic activity studies using non-tumorigenic HEK293 cell line and human liver cancer HEPG2 cells showed that decavanadates compounds exhibit selectivity action toward HEPG2 cells after 24 h. The effect of vanadium compounds (8–30 μM concentration) on the protein expression of AKT and AMPK were investigated in HEPG2 cell lines, showing that NaDeca and MetfDeca compounds exhibit a dose-dependence increase in phosphorylated AKT. Additionally, NaDeca at 30 µM concentration stimulated the glucose cell uptake moderately (62%) in 3T3-L1 adipocytes. Finally, an insulin release assay in βTC-6 cells (30 µM concentration) showed that sodium orthovanadate (MetV) and MetfDeca enhanced insulin release by 0.7 and 1-fold, respectively.

Calcium-hydrogen sulfide crosstalk during K+-deficient NaCl stress operates through regulation of Na+/H+ antiport and antioxidative defense system in mung bean roots

Present investigation reports the role of calcium (Ca2+) and hydrogen sulfide (H2S) crosstalk associated with Vigna radiata seedlings subjected to K+ deficient conditions under short-term (24 h) and long-term (72 h) NaCl stress. Perusal of the data reveals that under short-term NaCl stress an initial decline in K+ level led to the elevation in Ca2+ and H2S levels along with improvement in antioxidant system and reduction in reactive oxygen species (ROS) production. Under long-term NaCl stress a further decline in K+ content was deleterious that led to a lower K+/Na+ ratio. This was followed by reduction in antioxidant system along with excessive accumulation of ROS and methylglyoxal content, and increased membrane damage. However, supplementation of the seedling roots with Ca2+ enhanced biosynthesis of H2S through enhancing cysteine pool. The present findings suggest that synergistic action of Ca2+ and H2S induced the activity of H+-ATPase that created H+ gradient which in turn induced Na+/H+ antiport system that accelerated K+ influx and Na+ efflux. All of these together contributed to a higher K+/Na+ ratio, activation of antioxidative defense system, and maintenance of redox homeostasis and membrane integrity in Ca2+-supplemented stressed seedlings. Role of Ca2+ and H2S in the regulation of Na+/H+ antiport system was validated by the use of sodium orthovanadate (plasma membrane H+-ATPase inhibitor), tetraethylammonium chloride (K+ channel blocker), and amiloride (Na+/H+ antiporter inhibitor). Application of Ca2+-chelator EGTA (ethylene glycol-bis(b-aminoethylether)-N,N,Nʹ,Nʹ-tetraacetic acid) and H2S scavenger hypotaurine abolished the effect of Ca2+, suggesting the involvement of Ca2+ and H2S in the alleviation of NaCl stress. Moreover, use of EGTA and HT also substantiates the downstream functioning of H2S during Ca2+-mediated regulation of plant adaptive responses to NaCl stress. To sum up, present findings reveal the association of Ca2+ and H2S signaling in the regulation of ion homeostasis and antioxidant defense during K+-deficient NaCl stress.

Electrosynthesis of Crystalline and Phase Pure Silver Orthovanadate (Ag3VO4)-a Visible Light-Active P-Type Semiconductor

Silver-based ternary oxides are promising candidates for use as a visible light active semiconductor since their band gaps are lowered to the visible wavelength range due to the mixing of Ag 4d and O 2p orbitals in the valence band. In particular, Ag3VO4 with the highest ratio of Ag2O: V2O5 stoichiometry (3:1) among Ag-V-O ternary compounds generated from the two binary oxides (Ag2O and V2O5), is a visible light active semiconductor with a low band gap (2.18 eV).1 This paper describes the electrodeposition of Ag3VO4 film and its subsequent characterization. Electrodeposition is a fast and low temperature method which can be deployed to prepare thin films of a given semiconductor. In addition, the optoelectronic parameters (e.g., photocurrent, flat band potential) of the thin film semiconductors prepared by electrodeposition can be measured easily without any more processing steps.A two-step electrodeposition strategy previously developed in this laboratory, for ternary oxides2 was applied in this study, to prepare Ag3VO4 thin films on fluorine doped tin oxide (FTO) substrate. In the first step, a silver thin film was deposited cathodically from silver nitrate in a non-aqueous medium (to preclude silver oxide formation). In the second step, the silver thin film was stripped anodically in sodium orthovanadate (Na3VO4) solution to generate Ag+ and subsequent in situ precipitation with VO4 3- to yield Ag3VO4 thin film on the substrate. Electrochemical crystal microgravimetry confirmed one and three electron stoichiometry for the first and second steps respectively.Rather surprisingly, X-ray diffraction analyses of the as-prepared film showed that it was crystalline even without thermal anneal in phase-pure α-Ag3VO4 form . Compositional assays using energy-dispersive X-ray analysis (EDX) averaged from different spots of the as-prepared sample were consistent with the Ag/V ratio: 2.92 ± 0.02. The direct and indirect energy band gaps of α-Ag3VO4 thin films were measured by diffuse reflectance spectroscopy (DRS) and found to be 2.58 ± 0.04 and 2.37 ± 0.02 eV respectively. The surface band gap of as-prepared α-Ag3VO4 was measured by surface photovoltage spectroscopy (SPS) and found to be 2.16 ± 0.03 eV. The positive polarity of the photovoltage at excitation energies higher than the valence band threshold was diagnostic of p-type semiconductor behavior for α-Ag3VO4. Atmospheric photoemission spectroscopy (APS) showed the valence band position of α-Ag3VO4 to be -4.82 ± 0.03 eV on the vacuum energy scale. By combining the SPS and APS results, the calculated conduction band edge position of α-Ag3VO4 was determined to be -2.66 eV on the vacuum energy scale. These results will be discussed in the context of the application of this semiconductor for photoelectrochemical reduction processes such as hydrogen evolution or CO2 reduction. References W. D. Chemelewski, O. Mabayoje, C. B. Mullins, SILAR Growth of Ag3VO4 and Characterization for Photoelectrochemical Water Oxidation, J. Phys. Chem. C , 2015, 119, 26803−26808.L. H. Dall’Antonia, N. R. Tacconi, W. Chanmanee, H. Timmaji, N. Myung, K. Rajeshwar, Electrochem. Solid-State Lett. 2010, 13, D29-D32.

17-Allylamino-demethoxygeldanamycin Used Alone or in Combination with Sodium Orthovanadate Promotes Apoptosis and Inhibits Invasion of SH-SY5Y Cells by Modulating PIWIL2

Neuroblastoma (NB) is one of the most common extracranial solid tumors of childhood and accounts for 15% of cancer deaths. Even with the multimodality treatment protocols, the advanced-stage tumor overall 5-year survival rate is less than 50%. Therefore, novel drug therapy targeting cellular signal transduction pathways regulating the apoptotic cascade may be important for the treatment of drug-resistant NB. In our previous studies, we have demonstrated that 5 μM sodium orthovanadate (SOV) induced the apoptosis of SH-SY5Y cells. 17-Allylamino-demethoxygeldanamycin (17-AAG) is a geldanamycin- (GA-) derived heat shock protein 90 (Hsp90) inhibitor, and it has been shown to have potent antitumor activity in head and neck cancers. However, the effect of 17-AAG on the apoptosis of NB cells has not been reported. Therefore, the purpose of this study was to determine the effects of 17-AAG and SOV on the growth and invasion of SH-SY5Y cells in vitro and explore the related mechanism. In this study, we first investigated the antiviability effect of 17-AAG on SH-SY5Y cells, then studied the cell apoptosis and invasion influenced by 17-AAG and SOV, and assessed the role of PIWI-Like2 (PIWIL2) and piRNA-PIWI signaling in it. The results showed that 5 μM 17-AAG inhibited cell growth and viability and induced apoptosis in SH-SY5Y cells. Both 17-AAG and SOV reduced the level of PIWIL2 and Bcl-xl proteins and inhibited the invasion of SH-SY5Y cells. In addition, the combined use of the two drugs had greater effect than the single use of any drug.

Inactivation of H+-ATPase Participates in the Influence of Variation Potential on Photosynthesis and Respiration in Peas.

Local damage (e.g., burning, heating, or crushing) causes the generation and propagation of a variation potential (VP), which is a unique electrical signal in higher plants. A VP influences numerous physiological processes, with photosynthesis and respiration being important targets. VP generation is based on transient inactivation of H+-ATPase in plasma membrane. In this work, we investigated the participation of this inactivation in the development of VP-induced photosynthetic and respiratory responses. Two- to three-week-old pea seedlings (Pisum sativum L.) and their protoplasts were investigated. Photosynthesis and respiration in intact seedlings were measured using a GFS-3000 gas analyzer, Dual-PAM-100 Pulse-Amplitude-Modulation (PAM)-fluorometer, and a Dual-PAM gas-exchange Cuvette 3010-Dual. Electrical activity was measured using extracellular electrodes. The parameters of photosynthetic light reactions in protoplasts were measured using the Dual-PAM-100; photosynthesis- and respiration-related changes in O2 exchange rate were measured using an Oxygraph Plus System. We found that preliminary changes in the activity of H+-ATPase in the plasma membrane (its inactivation by sodium orthovanadate or activation by fusicoccin) influenced the amplitudes and magnitudes of VP-induced photosynthetic and respiratory responses in intact seedlings. Decreases in H+-ATPase activity (sodium orthovanadate treatment) induced fast decreases in photosynthetic activity and increases in respiration in protoplasts. Thus, our results support the effect of H+-ATPase inactivation on VP-induced photosynthetic and respiratory responses.

Ectophosphatase activity in the triple-negative breast cancer cell line MDA-MB-231.

Breast cancer is one of the most common cancers in the female population worldwide, and its development is thought to be associated with genetic mutations that lead to uncontrolled and accelerated growth of breast cells. This abnormal behavior requires extra energy, and indeed, tumor cells display a rewired energy metabolism compared to normal breast cells. Inorganic phosphate (Pi) is a glycolytic substrate of glyceraldehyde-3-phosphate dehydrogenase and has an important role in cancer cell proliferation. For cells to obtain Pi, ectoenzymes in the plasma membrane with their catalytic site facing the extracellular environment can hydrolyze phosphorylated molecules, and this is an initial and possibly limiting step for the uptake of Pi by carriers that behave as adjuvants in the process of energy harvesting and thus partially contributes to tumor energy requirements. In this study, the activity of an ectophosphatase in MDA-MB-231 cells was biochemically characterized, and the results showed that the activity of this enzyme was higher in the acidic pH range and that the enzyme had a Km = 4.5 ± 0.5 mM para-nitrophenylphosphate and a Vmax = 2280 ± 158 nM × h-1 × mg protein-1 . In addition, classical acid phosphatase inhibitors, including sodium orthovanadate, decreased enzymatic activity. Sodium orthovanadate was able to inhibit ectophosphatase activity while also inhibiting cell proliferation, adhesion, and migration, which are important processes in tumor progression, especially in metastatic breast cancer MDA-MB-231 cells that have higher ectophosphatase activity than MCF-7 and MCF-10 breast cells.

Exogenous Abscisic Acid Can Influence Photosynthetic Processes in Peas through a Decrease in Activity of H+-ATP-ase in the Plasma Membrane.

Simple SummaryNumerous stressors (drought, low and high temperatures, mechanical damages, etc.) act on plants under environmental conditions, suppressing their physiological processes (in particular, photosynthesis). Abscisic acid (ABA) is an important hormone, which participates in increasing plant tolerance to the action of stressors; as a result, treatment by exogenous ABA is a perspective way of regulating the tolerance in agriculture. We investigated the influence of ABA spraying on photosynthetic processes, as well as on their heat tolerance and their regulation by electrical signals propagating after local burning and modifying photosynthesis. It was shown that ABA spraying decreased photosynthetic activity and increased photosynthetic heat tolerance; additionally, the ABA treatment weakened the influence of electrical signals on photosynthesis. We revealed that these responses could be caused by a decrease in activity of H+-ATP-ase, which is an important ion transporter in plant cell plasma membrane that supports efflux of H+ from cytoplasm. As a whole, our results show the potential influence of the ABA treatment on photosynthetic processes, which is related to a decrease in activity of H+-ATP-ase. The result can be potentially useful for development of new methods of management of plant tolerance in agriculture.Abscisic acid (ABA) is an important hormone in plants that participates in their acclimation to the action of stressors. Treatment by exogenous ABA and its synthetic analogs are a potential way of controlling the tolerance of agricultural plants; however, the mechanisms of influence of the ABA treatment on photosynthetic processes require further investigations. The aim of our work was to investigate the participation of inactivation of the plasma membrane H+-ATP-ase on the influence of ABA treatment on photosynthetic processes and their regulation by electrical signals in peas. The ABA treatment of seedlings was performed by spraying them with aqueous solutions (10−5 M). The combination of a Dual-PAM-100 PAM fluorometer and GFS-3000 infrared gas analyzer was used for photosynthetic measurements; the patch clamp system on the basis of a SliceScope Pro 2000 microscope was used for measurements of electrical activity. It was shown that the ABA treatment stimulated the cyclic electron flow around photosystem I and decreased the photosynthetic CO2 assimilation, the amplitude of burning-induced electrical signals (variation potentials), and the magnitude of photosynthetic responses relating to these signals; in contrast, treatment with exogenous ABA increased the heat tolerance of photosynthesis. An investigation of the influence of ABA treatment on the metabolic component of the resting potential showed that this treatment decreased the activity of the H+-ATP-ase in the plasma membrane. Inhibitor analysis using sodium orthovanadate demonstrated that this decrease may be a mechanism of the ABA treatment-induced changes in photosynthetic processes, their heat tolerance, and regulation by electrical signals.

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.

Inhibition of PTP1B by farnesylated 2-arylbenzofurans isolated from Morus alba root bark: unraveling the mechanism of inhibition based on in vitro and in silico studies.

Among the 2-arylbenzofuran derivatives isolated from Morus alba, the farnesylated 2-arylbenzofuran is a rarer constituent. The derivative has been reported to exert anti-obesity effect; however, its inhibitory effect on protein tyrosine phosphatase 1B (PTP1B) has not been investigated. In the previous study, the presence of the farnesyl group in the structure of 2-arylbenzofurans was found to have positive influences on their pancreatic lipase inhibitory activity. In the present study, we have confirmed the authenticity of the notation based on the PTP1B inhibitory activity of farnesylated 2-arylbenzofurans. Specifically, two farnesylated 2-arylbenzofurans [morusalfurans B (2) and C (3)] showed strong inhibitory effects on PTP1B with IC50 values of 8.92 and 7.26 µM, respectively, which was significantly higher than that of the positive controls [sodium orthovanadate (IC50 = 15.10 µM) and ursolic acid (IC50 = 11.34 µM)]. Besides, two 2-arylbenzofurans [morusalfurans A (1) and F (6)], one flavonoid [morusalnol B (9)], and one geranylated stilbene [morusibene A (11)] exhibited PTP1B inhibition with IC50 values ranging from 11.02 to 26.56 µM. Kinetic studies revealed compounds 2, 3, 6, and 11 as mixed type PTP1B inhibitors, while 1 and 9 are known as noncompetitive. Molecular docking simulations demonstrated that these active compounds can bind with the respective catalytic or/and allosteric sites of PTP1B with negative binding energies and the results are in accordance with that of the kinetic studies. To the best of our knowledge, this is the first time, the PTP1B inhibitory activity of eleven compounds (1–11), as well as the mechanism of action underlying the effects on PTP1B enzyme of the active compounds, were investigated. In vitro and in silico results suggest that the farnesylated 2-arylbenzofurans from M. alba may potentially be utilized as an effective treatment therapy for type 2 diabetes mellitus and its associated complications.

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-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.

Anti-Bronchospasmodic Effect of JME-173, a Novel Mexiletine Analog Endowed With Highly Attenuated Anesthetic Activity.

Local anesthetics (LAs), such as lidocaine and mexiletine, inhibit bronchoconstriction in asthmatics, but adverse effects limit their use for this specific clinical application. In this study, we describe the anti-spasmodic properties of the mexiletine analog 2-(2-aminopropoxy)-3,5-dimethyl, 4-Br-benzene (JME-173), which was synthesized and screened for inducing reduced activity on Na+ channels. The effectiveness of JME-173 was assessed using rat tracheal rings, a GH3 cell line and mouse cardiomyocytes to access changes in smooth muscle contraction, and Na+, and Ca++ionic currents, respectively. Bronchospasm and airway hyper-reactivity (AHR) were studied using whole-body barometric plethysmography in A/J mice. We observed that the potency of JME-173 was 653-fold lower than mexiletine in inhibiting Na+ currents, but 12-fold higher in inhibiting L-type Ca++ currents. JME-173 was also more potent than mexiletine in inhibiting tracheal contraction by carbachol, allergen, extracellular Ca++, or sodium orthovanadate provocations. The effect of JME-173 on carbachol-induced tracheal contraction remained unaltered under conditions of de-epithelized rings, β2-receptor blockade or adenylate cyclase inhibition. When orally administered, JME-173 and theophylline inhibited methacholine-induced bronchospasm at time points of 1 and 3 h post-treatment, while only JME-173 remained active for at least 6 h. In addition, JME-173 also inhibited AHR in a mouse model of lipopolysaccharide (LPS)-induced lung inflammation. Thus, the mexiletine analog JME-173 shows highly attenuated activity on Na+ channels and optimized anti-spasmodic properties, in a mechanism that is at least in part mediated by regulation of Ca++ inflow toward the cytosol. Thus, JME-173 is a promising alternative for the treatment of clinical conditions marked by life-threatening bronchoconstriction.

Orthovanadate nanoparticles delay the accelerated aging in rats via the prevention of oxidative disturbances

Orthovanadate nanoparticles delay the accelerated aging in rats via the prevention of oxidative disturbances

Retracted: P0991EFFECTS OF TRIGONELLA FOENUM GRAECUM AND SODIUM ORTHOVANADATE ON ALTERED RENAL MEMBRANE FUNCTIONS IN ALLOXAN DIABETIC RATS.

Abstract Background and Aims The present study was carried out to observe, the antihyperglycemic and renoprotective effect of sodium orthovanadate (SOV) and Trigonella foenum graecum seed powder (TSP) administration on blood glucose, renal functions, expression of glucose transporter, DNA fragmentation, inflammatory cytokines and oxidative stress markers in kidney tissues and to see whether the treatment with SOV and TSP was capable of reversing the diabetic effects. Method Diabetes was induced by administration of alloxan monohydrate (15 mg/100 g body weight.) and rats were treated with 2 IU insulin, 0.6mg/ml SOV, 5% TSP in the diet and a combination of 0.2 mg/ml SOV and 5% TSP separately for three weeks. Renal damage was assessed by measuring proteinuria, enzymuria, expression of glucose transporters, renin-angiotensin system, and activities of polyol pathway enzymes. Results Diabetic rats showed hyperglycemia with almost four fold high blood glucose levels. Activity of Na+K+ATPase decreased in diabetic kidney. Diabetic rats exhibited an increased level of lipid peroxidation, intracellular Ca2+ levels, and decreased membrane fluidity. Combined therapy of lower dose of SOV with TSP significantly reduced metabolites of polyol pathway, oxidative stress, nitric oxide, and N-acetyl-β-d-glucosaminidase activity with glucose transporter in kidney of alloxan diabetic rats. Markers of podocyte damage in kidney (nephrin, podocin, and podocalyxin) and their urinary excretion were normalized along with downregulation of the expression of kidney injury molecule-1 by SOV and TSP treatment. TSP treatment alone is partially effective in restoring the above diabetes induced alterations. Dietary combined SOV and TSP effectively countered the diabetes-induced structural abnormalities of renal tissue. Conclusion Our results showed that lower doses of SOV (0.2mg/ml) could be used in combination with TSP to effectively in normalization of altered metabolic parameters and membrane linked enzymes without any harmful side effect and renoprotective actions.