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- Effects of decavanadate and insulin enhancing vanadium compounds on glucose uptake in isolated rat adipocytesPublication . Pereira, Maria João; Carvalho, Eugénia; Eriksson, Jan W.; Crans, Debbie C.; Aureliano, M.The effects of different vanadium compounds namely pyridine-2,6-dicarboxylatedioxovanadium(V) (V5-dipic), bis(maltolato) oxovanadium(IV) (BMOV) and amavadine, and oligovanadates namely metavanadate and decavanadate were analysed on basal and insulin stimulated glucose uptake in rat adipocytes. Decavanadate (50 lM), manifest a higher increases (6-fold) on glucose uptake compared with basal, followed by BMOV (1 mM) and metavanadate (1 mM) solutions (3-fold) whereas V5 dipic and amavadine had no effect. Decavanadate (100 lM) also shows the highest insulin like activity when compared with the others compounds studied. In the presence of insulin (10 nM), only decavanadate increases (50%) the glucose uptake when compared with insulin stimulated glucose uptake whereas BMOV and metavanadate, had no effect and V5 dipic and amavadine prevent the stimulation to about half of the basal value. Decavanadate is also able to reduce or eradicate the suppressor effect caused by dexamethasone on glucose uptake at the level of the adipocytes. Altogether, vanadium compounds and oligovanadates with several structures and coordination spheres reveal different effects on glucose uptake in rat primary adipocytes.
- Os semimetais na origem e evolução da vidaPublication . Aureliano, M.; Nolasco, Pedro A.; Silva, João J. R. Fraústo da; Silva, José Armando L.Metalloids in origin and evolution of life. Metalloids have characteristics between metals and non-metals which give them, in some cases, specific properties. At least two of this chemical elements, boron and silicon, are essential to a significant number of living organisms and since some years ago it has been observed that the same metalloids may be involved in the synthesis and stabilization of some molecules relevant to the origin of life.
- Decavanadate and metformin-decavanadate effects in human melanoma cellsPublication . de Sousa-Coelho, Ana Luísa; Aureliano, Manuel; Fraqueza, Gil; Serrão, Gisela; Gonçalves, João; Sánchez-Lombardo, Irma; Link, Wolfgang; Ferreira, BibianaDecavanadate is a polyoxometalate (POMs) that has shown extensive biological activities, including antidiabetic and anticancer activity. Importantly, vanadium-based compounds as well as antidiabetic biguanide drugs, such as metformin, have shown to exert therapeutic effects in melanoma. A combination of these agents, the metformin-decavanadate complex, was also recognized for its antidiabetic effects and recently described as a better treatment than the monotherapy with metformin enabling lower dosage in rodent models of diabetes. Herein, we compare the effects of decavanadate and metformin-decavanadate on Ca2+-ATPase activity in sarcoplasmic reticulum vesicles from rabbit skeletal muscles and on cell signaling events and viability in human melanoma cells. We show that unlike the decavanadate-mediated non-competitive mechanism, metformin-decavanadate inhibits Ca2+-ATPase by a mixed-type competitive-non-competitive inhibition with an IC50 value about 6 times higher (87 mu M) than the previously described for decavanadate (15 mu M). We also found that both decavanadate and metformin-decavanadate exert antiproliferative effects on melanoma cells at 10 times lower concentrations than monomeric vanadate. Western blot analysis revealed that both, decavanadate and metformin-decavanadate increased phosphorylation of extracellular signal-regulated kinase (ERK) and serine/ threonine protein kinase AKT signaling proteins upon 24 h drug exposure, suggesting that the anti-proliferative activities of these compounds act independent of growth-factor signaling pathways.
- Gold compounds inhibit the Ca2+-ATPase activity of brain PMCA and human neuroblastoma SH-SY5Y cells and decrease cell viabilityPublication . Berrocal, Maria; Cordoba-Granados, Juan J.; Carabineiro, Sónia A. C.; Gutierrez-Merino, Carlos; Aureliano, Manuel; Mata, Ana M.Plasma membrane calcium ATPases (PMCA) are key proteins in the maintenance of calcium (Ca2+) homeostasis. Dysregulation of PMCA function is associated with several human pathologies, including neurodegenerative diseases, and, therefore, these proteins are potential drug targets to counteract those diseases. Gold compounds, namely of Au(I), are well-known for their therapeutic use in rheumatoid arthritis and other diseases for centuries. Herein, we report the ability of dichloro(2-pyridinecarboxylate)gold(III) (1), chlorotrimethylphosphinegold(I) (2), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidenegold(I) chloride (3), and chlorotriphenylphosphinegold(I) (4) compounds to interfere with the Ca2+-ATPase activity of pig brain purified PMCA and with membranes from SH-SY5Y neuroblastoma cell cultures. The Au(III) compound (1) inhibits PMCA activity with the IC50 value of 4.9 µM, while Au(I) compounds (2, 3, and 4) inhibit the protein activity with IC50 values of 2.8, 21, and 0.9 µM, respectively. Regarding the native substrate MgATP, gold compounds 1 and 4 showed a non-competitive type of inhibition, whereas compounds 2 and 3 showed a mixed type of inhibition. All gold complexes showed cytotoxic effects on human neuroblastoma SH-SY5Y cells, although compounds 1 and 3 were more cytotoxic than compounds 2 and 4. In summary, this work shows that both Au (I and III) compounds are high-affinity inhibitors of the Ca2+-ATPase activity in purified PMCA fractions and in membranes from SH-SY5Y human neuroblastoma cells. Additionally, they exert strong cytotoxic effects.
- Quenching of myosin intrinsic fluorescence unravels the existence of a high affinity binding site for decavanadatePublication . Aureliano, M.Decavanadate, one of the aggregated species of vanadate, is a potent inhibitor of several enzymes, includingskeletalmusclemyosin.However,itsputativebindingsitesinmyosinarelargelyunknown. Titration of the intrinsic fluorescence of myosin, purified from rabbit skeletal muscle, have been carried out in 0.3 M KCl, 5 mM CaCl2 and 25 mM Tris-HCl (pH 7.0), with 0.1 mg/ml myosin. In the 0–200M total vanadate concentration range, decavanadate produced approximately 25% quenching of the intrinsic fluorescence of myosin, with an apparent dissociation constant in the micromolar range. This effect was found to be specific of decavanadate, because titration with metavanadate up to 200M did not produce a significant quenching of the intrinsic fluorescence of myosin. This quenching was accompanied by a parallel decrease of the accessibility of myosin tryptophans to the water-soluble collisional quencher KI, with an apparent dissociation constant also in the micromolar range. It is concluded that the binding of decavanadate to high-affinity sites in myosin produces local conformational change(s) near the tryptophans more accessible to water in the three-dimensional structure of this protein.
- Ion pumps as biological targets for decavanadatePublication . Aureliano, M.The putative applications of poly-, oligo- and mono-oxometalates in biochemistry, biology, pharmacology and medicine are rapidly attracting interest. In particular, these compounds may act as potent ion pump inhibitors and have the potential to play a role in the treatment of e.g. ulcers, cancer and ischemic heart disease. However, the mechanism of action is not completely understood in most cases, and even remains largely unknown in other cases. In the present review we discuss the most recent insights into the interaction between mono- and polyoxometalate ions with ion pumps, with a particular focus on the interaction of decavanadate with Ca2+- ATPase. We also compare the proposed mode of action with those of established ion pump inhibitors which are currently in therapeutic use. Of the 18 classes of compounds which are known to act as ion pump inhibitors, the complete mechanism of inhibition is only known for a handful. It has, however, been established that most ion pump inhibitors bind mainly to the E2 ion pump conformation within the membrane domain from the extracellular side and block the cation release. Polyoxometalates such as decavanadate, in contrast, interact with Ca2+- ATPase near the nucleotide binding site domain or at a pocket involving several cytoplasmic domains, and therefore needs to cross through the membrane bilayer. In contrast to monomeric vanadate, which only binds to the E2 conformation, decavanadate binds to all protein conformations, i.e. E1, E1P, E2 and E2P. Moreover, the specific interaction of decavanadate with sarcoplasmic reticulum Ca2+- ATPase has been shown to be non-competitive with respect to ATP and induces protein cysteine oxidation with concomitant vanadium reduction which might explain the high inhibitory capacity of V10, (IC50=15 µM) which is quite similar to the majority of the established therapeutic drugs.
- Actin as a potential target for decavanadatePublication . Ramos, Susana; Moura, José J. G.; Aureliano, M.ATP prevents G-actin cysteine oxidation and vanadyl formation specifically induced by decavanadate, suggesting that the oxometalate–protein interaction is affected by the nucleotide. The ATP exchange rate is increased by 2-fold due to the presence of decavanadate when compared with control actin (3.1×10−3 s−1), and an apparent dissociation constant (kdapp) of 227.4±25.7 μM and 112.3±8.7 μM was obtained in absence or presence of 20 μM V10, respectively. Moreover, concentrations as low as 50 μM of decameric vanadate species (V10) increases the relative G-actin intrinsic fluorescence intensity by approximately 80% whereas for a 10-fold concentration of monomeric vanadate (V1) no effects were observed. Upon decavanadate titration, it was observed a linear increase in G-actin hydrophobic surface (2.6-fold), while no changes were detected for V1 (0–200 μM). Taken together, three major ideas arise: i) ATP prevents decavanadate-induced G-actin cysteine oxidation and vanadate reduction; ii) decavanadate promotes actin conformational changes resulting on its inactivation, iii) decavanadate has an effect on actin ATP binding site. Once it is demonstrated that actin is a new potential target for decavanadate, being the ATP binding site a suitable site for decavanadate binding, it is proposed that some of the biological effects of vanadate can be, at least in part, explained by decavanadate interactions with actin.
- Nitração de tirosinas na miosina: consequências funcionaisPublication . Palma, Pedro; Aureliano, M.Tem sido demonstrado que o biomarcador 3-nitrotirosina (3-NT), frequentemente utilizado na reactividade do peroxinitrito (ONOO-) com as proteínas, aumenta na miosina após fibrilação atrial [Mihm et al, 2001b, 2003; Kooy et al, 1997] e durante o envelhecimento [Kansky et al, 2005a, 2005b; Hong et al, 2007].
- Decavavanadate (V10 O6-28) and oxovanadates: oxometalates with many biological activitiesPublication . Aureliano, M.; Crans, Debbie C.The decameric vanadate species V10O6 28 , also referred to as decavanadate, impact proteins, lipid structures and cellular function, and show some effects in vivo on oxidative stress processes and other biological properties. The mode of action of decavanadate in many biochemical systems depends, at least in part, on the charge and size of the species and in some cases competes with the simpler oxovanadate species. The orange decavanadate that contains 10 vanadium atoms is a stable species for several days at neutral pH, but at higher pH immediately converts to the structurally and functionally distinct lower oxovanadates such as the monomer, dimer or tetramer. Although the biological effects of vanadium are generally assumed to derive from monomeric vanadate or the vanadyl cation, we show in this review that not all effects can be attributed to these simple oxovanadate forms. This topic has not previously been reviewed although background information is available [D.C. Crans, Comments Inorg. Chem. 16 (1994) 35–76; M. Aureliano (Ed.), Vanadium Biochemistry, Research Signpost Publs., Kerala, India, 2007]. In addition to pumps, channels and metabotropic receptors, lipid structures represent potential biological targets for decavanadate and some examples have been reported. Decavanadate interact with enzymes, polyphosphate, nucleotide and inositol 3-phosphate binding sites in the substrate domain or in an allosteric site, in a complex manner. In mitochondria, where vanadium was shown to accumulate following decavanadate in vivo administration, nM concentration of decavanadate induces membrane depolarization in addition to inhibiting oxygen consumption, suggesting that mitochondria may be potential targets for decameric toxicity. In vivo effects of decavanadate in piscine models demonstrated that antioxidant stress markers, lipid peroxidation and vanadium subcellular distribution is dependent upon whether or not the solutions administered contain decavanadate. The present review summarizes the reports on biological effects of decavanadate and highlights the importance of considering decavanadate in evaluations of the biological effects of vanadium.
- Vanadium biochemistryPublication . Aureliano, M.Vanadium has long been known to mimic or to enhance insulin activity. It was estimated that by the year 2025 about 300 million people would suffer from diabetes mellitus. Diabetic patients are also subject to other pathologies such as nephropathy, arterial and neurodegenerative diseases. Behind the purpose to produce a special review book in inorganic biochemistry in the area of vanadium compounds/vanadate species, is the increase interest of vanadium knowledge, not only in chemistry but also in biochemistry, biology, toxicology, pharmacology and medicine. It was a wonderful opportunity to bring together remarkable contributions from many people that are responsible, at least in part, for the actual knowledge of vanadium in biological systems, as well for many papers highly cited and for an entire generation of scientists in the field. Personally, I consider myself a beginner in the Biochemistry of Vanadium, (I obtained my first decavanadate solution 51V-NMR spectra by 1985, at the University of Coimbra), and a product of the outstanding group of scientists and teachers that lead the way about 25 years ago, at the late 70´s and early 80´s. They are truly responsible for the actual interest of vanadium in fascinating and different scientific fields of research. The present book can be divided in two main parts: vanadium chemistry/biochemistry and biology/pharmacology/medicine, within the 16 chapters that wipe away the frontiers of 10 different countries. A special attention is given to decavanadate structure and chemistry, biochemistry (effects in muscle contraction/regulation) and in vivo biological studies. Also noteworthy are the chapters describing studies in aquatic organisms such as the ecophysiology perspectives of vanadium accumulation by ascidians, the use of fishes and fish cells lines for understanding the processes of vanadium in biology, as an alternative to mammalian systems, pointing out to a different interface of research. Medicinal applications of vanadium are push forward in chapters focusing structure-activity relationship of anti-diabetic vanadium complexes, vanadium compounds as anti-tumour drugs and anti-parasitic agents, improving bioactive ligands activity through complexation with vanadium, osteogenic action of vanadium compounds and cytotoxicity, in order to make vanadium available and safe for clinical use. Milestones in the history of vanadium biochemistry are also the chapters about the redox profile of vanadium, the role of vanadium in bromoperoxidases, the vanadium binding proteins in ascidians and more recently decavanadate interactions with lipidic structures. Putting it all together, this special Vanadium Biochemistry book would not be so special without the contributions of eminent scientists around the world, although some have been recently retire, such as the esteemed Professor Ramasarma and the esteemed Professor Sakurai. Thanking to all the contributors of the Vanadium Biochemistry book, clearly a wide-ranging and in many aspects an educational book that reflects, at least in part, the versatile and fascinating biochemistry of vanadium.