Vanadium Compounds with Antidiabetic Potential.

Over the last four decades, vanadium compounds have been extensively studied as potential antidiabetic drugs. With the present review, we aim at presenting a general overview of the most promising compounds and the main results obtained with in vivo studies, reported from 1899-2023. The chemistry of vanadium is explored, discussing the importance of the structure and biochemistry of vanadate and the impact of its similarity with phosphate on the antidiabetic effect. The spectroscopic characterization of vanadium compounds is discussed, particularly magnetic resonance methodologies, emphasizing its relevance for understanding species activity, speciation, and interaction with biological membranes. Finally, the most relevant studies regarding the use of vanadium compounds to treat diabetes are summarized, considering both animal models and human clinical trials. An overview of the main hypotheses explaining the biological activity of these compounds is presented, particularly the most accepted pathway involving vanadium interaction with phosphatase and kinase enzymes involved in the insulin signaling cascade. From our point of view, the major discoveries regarding the pharmacological action of this family of compounds are not yet fully understood. Thus, we still believe that vanadium presents the potential to help in metabolic control and the clinical management of diabetes, either as an insulin-like drug or as an insulin adjuvant. We look forward to the next forty years of research in this field, aiming to discover a vanadium compound with the desired therapeutic properties.

Vanadium as potential therapeutic agent for COVID-19: A focus on its antiviral, antiinflamatory, and antihyperglycemic effects.

An increasing evidence suggests that vanadium compounds are novel potential drugs in the treatment of diabetes, atherosclerosis, and cancer. Vanadium has also demonstrated activities against RNA viruses and is a promising candidate for treating acute respiratory diseases. The antidiabetic, antihypertensive, lipid-lowering, cardioprotective, antineoplastic, antiviral, and other potential effects of vanadium are summarized here. Given the beneficial antihyperglycemic and antiinflammatory effects as well as the potential mechanistic link between the COVID-19 and diabetes, vanadium compounds could be considered as a complement to the prescribed treatment of COVID-19. Thus, further clinical trials are warranted to confirm these favorable effects of vanadium treatment in COVID-19 patients, which appear not to be studied yet.

Study on the cytotoxic, antimetastatic and albumin binding properties of the oxidovanadium(IV) chrysin complex. Structural elucidation by computational methodologies.

We have previously synthesized and characterized the chrysin coordination complex with the oxidovanadium(IV) cation (VIVO(chrys)2) and characterized in ethanolic solution and in solid state. Because suitable single crystals for X-ray diffraction determinations could not be obtained, in the present work, we elucidate the geometrical parameters of this complex by computational methodologies. The optimization and vibrational investigation were carried out both in ethanolic solution and in gas phase. The computational results support the experimentally proposed geometries of the VIVO(chrys)2 complex, thus leading to the conclusion that the complex exists as conformers with trans-octahedral geometry in ethanolic solution and as conformers with cis-octahedral geometry in the solid state. The complex also exists as conformers with trans-octahedral geometry in aqueous media. The active species formed after dissolution in DMSO showed anticancer and antimetastatic behavior in human lung cell line A549 with moderate binding (Kaca. 105 M-1) to bovine serum albumin (BSA). The interaction through hydrogen bonding and van der Waals forces resulted in a spontaneous process. Site marker competitive experiments showed binding sites for chrysin mainly located in site II (subdomain IIIA) and in site I (subdomain IIIA) for the complex. FT-IR spectral measurements showed evidences of the alterations of protein secondary structure in the presence of chrysin and VIVO(chrys)2.

Bisperoxovanadium promotes motor neuron survival and neuromuscular innervation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease, with no present cure. The progressive loss of MNs is the hallmark of ALS. We have previously shown the therapeutic effects of the phosphatase and tensin homolog (PTEN) inhibitor, potassium bisperoxo (picolinato) vanadium (bpV[pic]), in models of neurological injury and demonstrated significant neuroprotective effects on MN survival. However, accumulating evidence suggests PTEN is detrimental for MN survival in ALS. Therefore, we hypothesized that treating the mutant superoxide dismutase 1 G93A (mSOD1G93A) mouse model of ALS during motor neuron degeneration and an in vitro model of mSOD1G93A motor neuron injury with bpV(pic) would prevent motor neuron loss. To test our hypothesis, we treated mSOD1G93A mice intraperitoneally daily with 400 µg/kg bpV(pic) from 70 to 90 days of age. Immunolabeled MNs and microglial reactivity were analyzed in lumbar spinal cord tissue, and bpV(pic) treatment significantly ameliorated ventral horn motor neuron loss in mSOD1G93A mice (p = 0.003) while not significantly altering microglial reactivity (p = 0.701). Treatment with bpV(pic) also significantly increased neuromuscular innervation (p = 0.018) but did not affect muscle atrophy. We also cultured motor neuron-like NSC-34 cells transfected with a plasmid to overexpress mutant SOD1G93A and starved them in serum-free medium for 24 h with and without bpV(pic) and downstream inhibitor of Akt signaling, LY294002. In vitro, bpV(pic) improved neuronal viability, and Akt inhibition reversed this protective effect (p < 0.05). In conclusion, our study indicates systemic bpV(pic) treatment could be a valuable neuroprotective therapy for ALS.

Water-Soluble Dioxidovanadium(V) Complexes of Aroylhydrazones: DNA/BSA Interactions, Hydrophobicity, and Cell-Selective Anticancer Potential.

Five new anionic aqueous dioxidovanadium(V) complexes, [{VO2L1,2}A(H2O)n]α (1-5), with the aroylhydrazone ligands pyridine-4-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)hydrazide (H2L1) and furan-2-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)hydrazide (H2L2) incorporating different alkali metals (A = Na+, K+, Cs+) as countercation were synthesized and characterized by various physicochemical techniques. The solution-phase stabilities of 1-5 were determined by time-dependent NMR and UV-vis, and also the octanol/water partition coefficients were obtained by spectroscopic techniques. X-ray crystallography of 2-4 confirmed the presence of vanadium(V) centers coordinated by two cis-oxido-O atoms and the O, N, and O atoms of a dianionic tridentate ligand. To evaluate the biological behavior, all complexes were screened for their DNA/protein binding propensity through spectroscopic experiments. Finally, a cytotoxicity study of 1-5 was performed against colon (HT-29), breast (MCF-7), and cervical (HeLa) cancer cell lines and a noncancerous NIH-3T3 cell line. The cytotoxicity was cell-selective, being more active against HT-29 than against other cells. In addition, the role of hydrophobicity in the cytotoxicity was explained in that an optimal hydrophobicity is essential for high cytotoxicity. Moreover, the results of wound-healing assays indicated antimigration in case of HT-29 cells. Remarkably, 1 with an IC50 value of 5.42 ± 0.15 µM showed greater activity in comparison to cisplatin against the HT-29 cell line.

Effects of Vanadyl Complexes with Acetylacetonate Derivatives on Non-Tumor and Tumor Cell Lines.

Vanadium has a good therapeutic potential, as several biological effects, but few side effects, have been demonstrated. Evidence suggests that vanadium compounds could represent a new class of non-platinum, metal antitumor agents. In the present study, we aimed to characterize the antiproliferative activities of fluorescent vanadyl complexes with acetylacetonate derivates bearing asymmetric substitutions on the ß-dicarbonyl moiety on different cell lines. The effects of fluorescent vanadyl complexes on proliferation and cell cycle modulation in different cell lines were detected by ATP content using the CellTiter-Glo Luminescent Assay and flow cytometry, respectively. Western blotting was performed to assess the modulation of mitogen-activated protein kinases (MAPKs) and relevant proteins. Confocal microscopy revealed that complexes were mainly localized in the cytoplasm, with a diffuse distribution, as in podocyte or a more aggregate conformation, as in the other cell lines. The effects of complexes on cell cycle were studied by cytofluorimetry and Western blot analysis, suggesting that the inhibition of proliferation could be correlated with a block in the G2/M phase of cell cycle and an increase in cdc2 phosphorylation. Complexes modulated mitogen-activated protein kinases (MAPKs) activation in a cell-dependent manner, but MAPK modulation can only partly explain the antiproliferative activity of these complexes. All together our results demonstrate that antiproliferative effects mediated by these compounds are cell type-dependent and involve the cdc2 and MAPKs pathway.

Vanadium-Flavonoid Complexes: A Promising Class of Molecules for Therapeutic Applications.

Several reports have revealed the superior biological activity of metal ion-flavonoid complexes when compared with the parent flavonoid. Among the different metal ions explored, vanadium and its compounds are in the forefront because of their anticancer and antidiabetic properties. However, the toxicity of vanadium-based ions and their inorganic derivatives limits their therapeutic applications. Complexation of vanadium with flavonoids not only reduces its adverse effects but also augments its biological activity. This Review discusses the nature of coordination in vanadium-flavonoid complexes, their structure-activity correlations, with special emphasis on their therapeutic activities. Several investigations suggest that the superior biological activity of vanadium complexes arise because of their ability to regulate metabolic pathways distinct from those acted upon by vanadium alone. These studies serve to decipher the underlying molecular mechanism of vanadium-flavonoid complexes that can be explored further for generating a series of novel compounds with improved pharmacological and therapeutic performance.

Influence of calcium channel modulators on the production of serotonin, gentisic acid, and a few other biosynthetically related phenolic metabolites in seedling leaves of salt tolerant rice variety Nonabokra.

Rice, a most salt-sensitive cereal plant, adopts diverse pathways to withstand sodium chloride-induced salinity-related adversities. During the present study, attempt was made to understand the role of calcium on metabolite profile of the leaves of salt tolerant rice seedlings of variety of Nonabokra under sodium chloride induced salinity, by Gas Chromatography-Mass Spectrometry-based metabolomics approach. Calcium availability in the seedlings was reduced or enhanced applying inhibitors (vanadyl sulfate, lanthanum chloride, and verapamil) or promoters of calcium influx (calcimycin also known as calcium ionophore A23187) in the sodium chloride (100 mM) supplemented growth medium. Growth medium of ten-day-old seedlings was replaced by sodium chloride supplemented hydroponic solution with promotor or inhibitors of calcium channel. Fifteen days old seedlings were harvested. It was observed that depletion of calcium availability increased the level of serotonin and gentisic acid whereas increased calcium level decreased these metabolites. It was concluded from the results that production of the signaling molecules serotonin and gentisic acids was elevated in calcium-deficient seedlings under salt stress the condition that was considered as control during the experiment. The two signaling molecules probably help this tolerant rice variety Nonabokra to withstand the salt-induced adversities.

Vanadocene dichloride induces apoptosis in HeLa cells through depolymerization of microtubules and inhibition of Eg5.

Vanadocene dichloride (VDC), a vanadium containing metallocene dihalide exhibits promising anticancer activity. However, its mechanism of action remains elusive as several diverse targets and pathways have been proposed for its anticancer activity. In this study, we observed that VDC inhibited the proliferation of mammalian cancer cells and induced apoptotic cell death by altering the mitochondrial membrane potential and the expression of bcl2 and bax. Probing further into its anticancer mechanism, we found that VDC caused depolymerization of interphase microtubules and blocked the cells at mitosis with considerable proportion of cells exhibiting monopolar spindles. The reassembly of cold depolymerized microtubules was strongly inhibited in the presence of 10 µM VDC. VDC perturbed the microtubule-kinetochore interactions during mitosis as indicated by the absence of cold stable spindle microtubules in the cells treated with 20 µM VDC. Using goat brain tubulin, we found that VDC inhibited the steady-state polymer mass of microtubules and bound to tubulin at a novel site with a Kd of 9.71 ± 0.19 µM and perturbed the secondary structure of tubulin dimer. In addition, VDC was also found to bind to the mitotic kinesin Eg5 and inhibit its basal as well as microtubule stimulated ATPase activity. The results suggest that disruption of microtubule assembly dynamics and inhibition of the ATPase activity of Eg5 could be a plausible mechanism for the antiproliferative and antimitotic activity of VDC.Graphic abstract.

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

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

Cardio-protective effects of a dioxidovanadium(V) complex in male sprague-dawley rats with streptozotocin-induced diabetes.

Cardiovascular complications are among the leading causes of morbidity and mortality in diabetes mellitus (DM). Despite the anti-hyperglycemic effects of various anti-diabetic therapeutic agents like insulin, some of these drugs are implicated in precipitating cardiovascular dysfunction. There is therefore an imperative need to seek alternative drugs that may ameliorate these complications. Accordingly, the aim of the study was to investigate the effects of a dioxidovanadium (V) complex, cis-[VO2(obz)py]) on selected cardiovascular function markers in STZ-induced diabetic rats. The vanadium complex (40 mg kg) was administered orally twice every 3rd day 5 weeks, non-diabetic and diabetic control groups received distilled water whereas the insulin group received subcutaneous insulin injections twice daily for 5 weeks. Blood glucose concentrations, mean arterial pressure (MAP), heart rate, triglycerides (TG) and total cholesterol concentrations were monitored weekly for 5 weeks. Rats were then euthanised and blood and hearts were collected for biochemical analysis. There was a significant decrease in blood glucose, triglycerides, cholesterol concentrations as well as blood pressure of vanadium treated rats compared to the untreated diabetic animals. Vanadium treatment also attenuated cardiac oxidative stress and decreased the expression of transforming growth factor ß1 (TGFß1) and Smad7. Lastly, the administration of the vanadium complex significantly decreased C reactive protein (CRP) and cardiotropin 1(CT-1) concentrations in the plasma and heart tissues. The administration of the dioxidovanadium(V) complex to diabetic rats culminated into cardio-protective effects. Taken together, these observations suggest that this metal complex exhibit a significant potential as an alternative therapeutic drug for DM management.

Cell Arrest and Apoptosis Induced by the Next Generation of Vanadium Based Drugs: Action Mechanism to Structure Relation and Future Perspectives.

BACKGROUND: Every year, we encounter more projects indicating the promising anticancer activity of vanadium molecules against different types of cancer cells. The new generation of metal-based drugs, targets the energy supplies of the cell through ROS generation leading them to cell arrest and apoptosis. The relatively low toxicity of vanadium metal, the different oxidation states that it can occur and in general, the lipophilicity of transition metals, gave attention to vanadium after the exhausting research in platinum-based drugs. Herein, the latest advances in the apoptotic activity of vanadium complex molecules have been reviewed and revealed the structure to action relationship. Future perspectives of vanadium anticancer drugs are also discussed. METHODS: Data were collected from Web of Science, Scopus, Pubmed, through searching of these keywords: "apoptosis", "anticancer drugs", "vanadium complexes", "synthesis" and "cell arrest". RESULTS: A good amount of vanadium complexes gave promising results over the past few years, showing that a more careful approach of a ligand design could give rise to the next generation of vanadium drugs. CONCLUSION: The low toxicity of vanadium ion in combination with its V(IV) species selectivity gives the vanadium a head starts against other transition metal complexes.

CREB activity is required for mTORC1 signaling-induced primordial follicle activation in mice.

In mammals, progressive activation of primordial follicles is essential for maintenance of the reproductive lifespan. Several reports have demonstrated that mitogen-activated protein kinases 3 and 1 (MAPK3/1)-mammalian target of rapamycin complex 1 (mTORC1) signaling in pre-granulosa cells promotes primordial follicle activation by increasing KIT ligand (KITL) expression and then stimulating phosphatidylinositol 3 kinase signaling in oocytes. However, the mechanism of mTORC1 signaling in the promotion of KITL expression is unclear. Immunofluorescence staining results showed that phosphorylated cyclic AMP response element-binding protein (CREB) was mainly expressed in pre-granulosa cells. The CREB inhibitor KG-501 and CREB knockdown by Creb siRNA significantly suppressed primordial follicle activation, reduced pre-granulosa cell proliferation and dramatically increased oocyte apoptosis. Western blotting results demonstrated that both the MAPK3/1 inhibitor U0126 and mTORC1 inhibitor rapamycin significantly decreased the levels of phosphorylated CREB, indicating that MAPK3/1-mTORC1 signaling is required for CREB activation. Furthermore, CREB could bind to the Kitl promoter region, and KG-501 significantly decreased the expression levels of KITL. In addition, KG-501 and CREB knockdown significantly decreased the levels of phosphorylated Akt, leading to a reduced number of oocytes with Foxo3a nuclear export. KG-501 also inhibited bpV (HOpic)-stimulated primordial follicle activation. Taken together, the results show that CREB is required for MAPK3/1-mTORC1 signaling-promoted KITL expression followed by the activation of primordial follicles.

Molecular and Cellular Mechanisms of Cytotoxic Activity of Vanadium Compounds against Cancer Cells.

Discovering that metals are essential for the structure and function of biomolecules has given a completely new perspective on the role of metal ions in living organisms. Nowadays, the design and synthesis of new metal-based compounds, as well as metal ion binding components, for the treatment of human diseases is one of the main aims of bioinorganic chemistry. One of the areas in vanadium-based compound research is their potential anticancer activity. In this review, we summarize recent molecular and cellular mechanisms in the cytotoxic activity of many different synthetic vanadium complexes as well as inorganic salts. Such mechanisms shall include DNA binding, oxidative stress, cell cycle regulation and programed cell death. We focus mainly on cellular studies involving many type of cancer cell lines trying to highlight some new significant advances.

Trinuclear vanadium(iv) and vanadium(v) complexes derived from 2,4,6-triacetylphloroglucinol and study of their peroxidase mimicking activity.

Novel dibasic Schiff bases with three tridentate sites were obtained from the condensation of the triketone 2,4,6-triacetylphloroglucinol (H3ptk) with four different hydrazides, benzoyl hydrazide (bhz), furoyl hydrazide (fah), isonicotinoyl hydrazide (inh) and nicotinoyl hydrazide (nah): H6ptk(bhz)3I, H6ptk(fah)3II, H6ptk(inh)3III and H6ptk(nah)3IV. These ligand precursors I-IV, each being an ONO donor, are tricompartmental building blocks able to form trinuclear complexes having C3 symmetry. The reaction of I-IV with [VIVO(acac)2] leads to the formation of [{VIVO(H2O)}3(ptk(bhz)3)] 1, [{VIVO(H2O)}3(ptk(fah)3)] 2, [{VIVO(H2O)}3(ptk(inh)3)] 3, and [{VIVO(H2O)}3(ptk(nah)3)] 4. In methanol/aqueous solutions of M2CO3 (M+ = Na+, K+ and Cs+), these complexes are slowly converted into dioxidovanadium(v) compounds, namely, M3[(VVO2)3{ptk(bhz)3}]·6H2O [M+ = K+5, Na+9, Cs+13], M3[(VVO2)3{ptk(fah)3}]·6H2O [M+ = K+6, Na+10, Cs+14], M3[(VVO2)3{ptk(inh)3}]·6H2O [M+ = K+7, Na+11, Cs+15] and M3[(VVO2)3{ptk(nah)3}]·6H2O [M+ = K+8, Na+12, Cs+16]. All ligand precursors and complexes are characterized by various techniques such as FT-IR, UV/Visible, EPR, NMR (1H, 13C and 51V), elemental analysis, thermal studies, cyclic voltammetry (CV) and single-crystal X-ray analysis. X-ray diffraction studies of complexes K2.7[{(VVO2)3ptk(fah)3}]·11.5H2O·MeOH 6a, Cs3[{(VVO2)3ptk(bhz)3}]·7H2O 13a and Cs3[{(VVO2)3ptk(nah)3}]·7.3H2O 16a reveal their distorted square pyramidal geometry by coordinating through phenolate oxygen (of ptk), azomethine nitrogen and enolate oxygen (of hydrazide) atoms. The reactivity of complexes 5-16 and their catalytic potential were screened towards their peroxidase mimetic activity in the oxidation of dopamine to aminochrome driven by H2O2 as an oxidant. The conversion of dopamine to aminochrome with different catalysts was monitored by HPLC showing high activity under mild conditions with good conversions within 1 h. Kinetic studies using compounds 13-16 as catalyst precursors reveal that the reaction follows a Michaelis-Menten-like kinetics.

Antifungal activity and biocompatibility of α-AgVO3 microcrystals: A promising material against oral Candida disease.

The number of studies on microcrystals containing silver has increased in recent decades. Among the silver-containing microcrystals, α-AgVO3 has gained prominence owing to its polymorphism that allows it to exert interesting antimicrobial activity against pathogenic microorganisms. The aim of this study was to evaluate the antifungal activity and cytotoxicity of three different α-AgVO3 microcrystals when in solution. α-AgVO3 microcrystals were synthesized using the co-precipitation method at three different temperatures (10 °C, 20 °C, and 30 °C), and then characterized by X-ray diffraction and scanning electron microscopy. The antifungal activity of α-AgVO3 microcrystals against Candida albicans was determined by estimating the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC). Fluorescence images were obtained to confirm antifungal concentrations. To assess the biocompatibility of microcrystals applied at MIC and MFC on keratinocytes cells (NOK-si), an Alamar Blue assay, scanning electron microscopy, and a DNA gel integrity test were carried out. The quantitative and qualitative results showed that, regardless of the co-precipitation method used to synthetize α-AgVO3 microcrystals, C. albicans growth was visibly inhibited at 3.9 µg/mL (MIC) and completely inhibited at 15.62 µg/mL (MFC). The cytotoxic and genotoxic outcomes revealed that the MIC and MFC concentrations did not affect NOK-si cell morphology, proliferation, or DNA integrity. The search for new antimicrobial materials has been the focus of the research community recently because of increases in microbial resistance. The findings reported herein demonstrate a novel antifungal and non-cytotoxic material that could be used in biomedical and dental applications.

In vitro Studies of Antitumor Activity of Vanadium Complexes with Orotic and Glutamic Acids / Estudos in vitro da Atividade Antitumoral de Complexos de Vanádio com Ácidos Órotico e Glutâmico / Estudios in vitro de la Actividad Antitumoral de Complejos de Vanadio con Ácidos Orótico y Glutámico

Introduction: Three vanadium complexes with orotic and glutamic acids, in their anion forms, were prepared and their in vitro cytotoxicity toward human lung fibroblasts (MRC-5), human hepatocellular carcinoma (HepG2) and human colorectal adenocarcinoma (Caco-2) are reported. Objective: Describe the synthesis and characterization of new vanadium complexes with orotic and glutamic acids, and test its antitumor activity against HepG2 and Caco-2. Method: The complexes were formulated as VO (oro), VO (α-glu) and VO (γ-glu) based on chemical, thermogravimetric analyses and infrared spectra. Results: Resazurin assay demonstrates its cytotoxicity against the HepG2 and Caco-2 cell lines with the IC50 ranging from 7.90 to 44.56 µmol.L-1. The cytotoxicity profiles indicate that the tumoral lines show more activity than the cells MRC-5, with selectivity indexes ranging from 1.58 to 8.96. Conclusion: The three complexes had better in vitro activity than cisplatin for both normal and cancer cell lines. The IC50 values are two to six times better for the cancer cell ines and five to seven times better for the normal cell lines. This study indicates that the complexes obtained are promising candidates for antitumor drugs.

Introdução: Foram preparados três complexos de vanádio com ácidos orótico e glutâmico, em suas formas aniônicas, e foi testada sua citotoxicidade in vitro para fibroblastos pulmonares humanos (MRC-5), carcinoma hepatocelular humano (HepG2) e adenocarcinoma colorretal humano (Caco-2). Objetivo: Descrever a síntese e caracterização de novos complexos de vanádio com ácidos orótico e glutâmico e testar sua atividade antitumoral contra HepG2 e Caco-2. Método: Os complexos foram formulados como VO (oro), VO (α-glu) e VO (γ-glu) com base em análises químicas, termogravimétricas e espectros no infravermelho. Resultados: O ensaio de resazurina demonstrou sua citotoxicidade contra as linhagens celulares HepG2 e Caco-2 com o IC50 variando de 7,90 a 44,56 µmol.L-1. Os perfis de citotoxicidade indicam que as linhas tumorais apresentam maior atividade que as células MRC-5, com índices de seletividade variando de 1,58 a 8,96. Conclusão: Os três complexos tiveram melhor atividade in vitro do que a cisplatina, tanto para linhagens celulares normais como cancerosas. Os valores de IC50 são de duas a seis vezes melhores para as linhagens celulares cancerosas e de cinco a sete vezes melhores para as linhagens celulares normais. Este estudo indica que os complexos obtidos são promissores candidatos a fármacos antitumorais.

Introducción: Tres complejos de vanadio con ácidos orótico y glutámico, en sus formas aniónicas, fueram preparados. Su citotoxicidad in vitro hacia los fibroblastos pulmonares humanos (MRC-5), el carcinoma hepatocelular humano (HepG2) y el adenocarcinoma colorrectal humano (Caco-2) son reportados. Objetivo: Los principales objetivos de este trabajo son describir la síntesis y caracterización de nuevos complejos de vanadio con ácidos orótico y glutámico y probar su actividad antitumoral contra el HepG2 y el Caco-2. Método: Los complejos fueron formulados como VO (oro), VO (α-glu) y VO (γ-glu) basados en análisis químicos, termogravimétricos y espectros infrarrojos. El ensayo de resazurina demuestra su citotoxicidad contra las líneas celulares HepG2 y Caco-2 con el IC50 que van de 7,90 a 44,56 µmol.L-1. Los perfiles de citotoxicidad indican que las líneas tumorales presentan mayor actividad que los MRC-5, con índices de selectividad que van de 1,58 a 8,96. Conclusión: Los tres complejos tuvieron mejor actividad in vitro que el cisplatino, tanto para líneas celulares normales como para líneas celulares cancerosas. Los valores del IC50 son de dos a seis veces mejores para las líneas celulares de cáncer y de cinco a siete veces mejores para las líneas celulares normales. Este estudio indica que los complejos obtenidos son candidatos prometedores para fármacos antitumorales.

[The effect of vanadium compounds on carbohydrate and lipid metabolism disorders].

At this stage in the development of nutriciological science, it has not been established if biologically active substances are essential to the human body; however, an explanation of the physiological role of minor biologically active substances is necessary to clarify the qualitative composition of Nutrioma. Of particular interest is the transition metal, vanadium. Adding vanadium to the diet of animals with induced or genetically determined type 2 diabetes mellitus normalizes glucose and blood insulin levels, reduces insulin resistance, promotes ß-cell regeneration, and has a beneficial effect on lipid metabolism. Clinical studies of the effectiveness of vanadium are not convincing, in most part, because of their insufficient duration. The review briefly discusses the main mechanisms of the action of vanadium compounds. Therapeutic doses of vanadium compounds may overlap with toxic doses. Organic vanadium compounds could be used in significantly lower doses. The main problem with the possible use of vanadium compounds in antidiabetic therapy is the balance between their beneficial effects and the connected risks of side effects.

Three peroxidovanadium(v) compounds mediated by transition metal cations for enhanced anticancer activity.

Three peroxidovanadium(v) compounds with different ligands (L1-L3) {L1 = N-tris(hydroxymethyl)methylglycine; L2 = ethylenediamine-N,N'-diacetic acid; L3 = 2,2-[(2-amino-2-oxoethyl)imino]diacetic acid} were first synthesized, characterized and further investigated for their anticancer activities under the mediation of transition metal cations. Encouragingly, all compounds showed preferentially enhanced cytotoxicity toward cancer cells (MCF-7 and A549) compared to normal cells (BEAS-2B) under the mediation of transition metal cations (Mn2+ or Fe2+), especially for Mn2+. It was noted that cell death was triggered by the transition metal cation-mediated peroxidovanadium(v) compounds through the induction of early apoptosis, inhibition of cell cycles, and boosting the generation of intracellular reactive oxygen species (ROS). Mechanistic studies further elucidated the vital roles of an acidic environment and transition metal cations for the anticancer activity of peroxidovanadium(v) compounds. Therefore, this study will offer precious insight into the development of the transition metal cation-mediated peroxidovanadium(v) compounds for further clinical translation.

Dose optimisation of PTEN inhibitor, bpV (HOpic), and SCF for the in-vitro activation of sheep primordial follicles.

The in-vitro development of primordial follicles is critical for improving mammalian fertility and wildlife conservation. This study aimed to optimise the effective doses of bpV (HOpic) and stem cell factor (SCF) for the in-vitro activation of sheep primordial follicles. To do this, sheep ovarian cortex was treated with bpV (1.5, 15, and 150 µM) and SCF (50 and 100 ng/ml). Follicular count indicated that 15 µM bpV and 100 ng/ml SCF significantly increased normal primary follicles compared to other groups (p < 0.05). Also, a significant downregulation of P53 and PTEN, as well as the increased expression of PI3K was observed. The in-vitro maturation was more pronounced when the fragmented tissues were co-treated with selected doses of bpV and SCF. In conclusion, the combination of 15 µM bpV and 100 ng/ml SCF was the most effective treatment strategy for the activation and survival of primordial follicles in sheep ovarian fragments.