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Objective: To characterize rest-activity rhythm in chronic migraine (CM) and to investigate the relationship between this rhythm and depressive and anxiety symptoms in patients with CM. Methods: This was a study of adults aged 20 to 40 years. The rest-activity rhythm of patients with CM (n=23) and non-headache controls (NH, n=23) was assessed by actigraphy for 15 days, and they completed the following assessments: Visual Analogue Scale for pain intensity; Headache Diary; Headache Impact Test-6; Morningness-Eveningness Questionnaire; Pittsburgh Sleep Quality Index; Epworth Sleepiness Scale; Beck Depression Inventory; and State-Trait Anxiety Inventory. Results: Patients with CM showed less activity over 24 hours and more fragmented sleep. Reduced interdaily stability of the rest-activity rhythm was observed, with less robustness of this rhythm in the CM group. Multiple linear regressions revealed a significant association between the rest-activity rhythm and trait anxiety variables in patients with CM, specifically regarding the relative amplitude of the cycle, activity throughout 24 hours and during sleep, and robustness of the rest-activity rhythm. Conclusions: Our findings provide evidence that the robustness of the rest-activity rhythm, activity throughout 24 hours, and sleep fragmentation are associated with trait anxiety in patients with CM. Clinical trial registration: Brazilian Clinical Trials Registry (registration number: RBR-4M5J4S).
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OBJECTIVE: To characterize rest-activity rhythm in chronic migraine (CM) and to investigate the relationship between this rhythm and depressive and anxiety symptoms in patients with CM. METHODS: This was a study of adults aged 20 to 40 years. The rest-activity rhythm of patients with CM (n=23) and non-headache controls (NH, n=23) was assessed by actigraphy for 15 days, and they completed the following assessments: Visual Analogue Scale for pain intensity; Headache Diary; Headache Impact Test-6; Morningness-Eveningness Questionnaire; Pittsburgh Sleep Quality Index; Epworth Sleepiness Scale; Beck Depression Inventory; and State-Trait Anxiety Inventory. RESULTS: Patients with CM showed less activity over 24 hours and more fragmented sleep. Reduced interdaily stability of the rest-activity rhythm was observed, with less robustness of this rhythm in the CM group. Multiple linear regressions revealed a significant association between the rest-activity rhythm and trait anxiety variables in patients with CM, specifically regarding the relative amplitude of the cycle, activity throughout 24 hours and during sleep, and robustness of the rest-activity rhythm. CONCLUSIONS: Our findings provide evidence that the robustness of the rest-activity rhythm, activity throughout 24 hours, and sleep fragmentation are associated with trait anxiety in patients with CM.
Assuntos
Ritmo Circadiano , Transtornos de Enxaqueca , Adulto , Humanos , Sono , Descanso , AnsiedadeRESUMO
The aim of this work was to study the antitumor effects and the mechanisms of toxic action of a series of 6-methoxyquinoline (6MQ) complexes in vitro. The Cu(II) and Zn(II) complexes (Cu6MQ and Zn6MQ) are formulated as M(6MQ)2Cl2; the Co(II) and Ag(I) compounds (Co6MQ and Ag6MQ) are ionic with formulae [Ag(6MQ)2]+NO3- and H(6MQ)+[Co(6MQ)Cl3]- (where H(6MQ)+ is the protonated ligand). We found that the copper complex, outperformed the Co(II), Zn(II) and Ag(I) complexes with a lower IC50 (57.9 µM) in A549 cells exposed for 24 h. Cu6MQ decreased cell proliferation and induced oxidative stress detected with H2DCFDA at 40 µM, which reduces GSH/GSSG ratio. This redox imbalance induced oxidative DNA damage revealed by the Micronucleus test and the Comet assay, which turned into a cell cycle arrest at G2/M phase and induced apoptosis. In multicellular spheroids, the IC50 values tripled the monolayer model (187.3 µM for 24 h). At this concentration, the proportion of live/dead cells diminished, and the spheroids could not proliferate or invade. Although Zn6MQ also decreased GSH/GSSG ratio from 200 µM and the cytotoxicity is related to oxidative stress, the induction of the hydrogen peroxide levels only doubled the control value. Zn6MQ induced S phase arrest, which relates with the increased micronucleus frequency and with the induction of necrosis. Finally, our results reveal a synergistic activity with a 1:1 ratio of both complexes in the monolayer and multicellular spheroids.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Quinolinas/farmacologia , Esferoides Celulares/efeitos dos fármacos , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Quinolinas/química , Esferoides Celulares/patologia , Relação Estrutura-AtividadeRESUMO
A long-standing problem in quantum mechanics is the minimum number of observables required for the characterization of unknown pure quantum states. The solution to this problem is especially important for the developing field of high-dimensional quantum information processing. In this work we demonstrate that any pure d-dimensional state is unambiguously reconstructed by measuring five observables, that is, via projective measurements onto the states of five orthonormal bases. Thus, in our method the total number of different measurement outcomes (5d) scales linearly with d. The state reconstruction is robust against experimental errors and requires simple postprocessing, regardless of d. We experimentally demonstrate the feasibility of our scheme through the reconstruction of eight-dimensional quantum states, encoded in the momentum of single photons.
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Vanadium compounds were studied during recent years to be considered as a representative of a new class of nonplatinum metal antitumor agents in combination to its low toxicity. On the other hand, flavonoids are a wide family of polyphenolic compounds synthesized by plants that display many interesting biological effects. Since coordination of ligands to metals can improve the pharmacological properties, we report herein, for the first time, a exhaustive study of the mechanisms of action of two oxidovanadium(IV) complexes with the flavonoids: silibinin Na2[VO(silibinin)22]·6H2O (VOsil) and chrysin [VO(chrysin)2EtOH]2(VOchrys) on human colon adenocarcinoma derived cell line HT-29. The complexes inhibited the cell viability of colon adenocarcinoma cells in a dose dependent manner with a greater potency than that the free ligands and free metal, demonstrating the benefit of complexation. The decrease of the ratio of the amount of reduced glutathione to the amount of oxidized glutathione were involved in the deleterious effects of both complexes. Besides, VOchrys caused cell cycle arrest in G2/M phase while VOsil activated caspase 3 and triggering the cells directly to apoptosis. Moreover, VOsil diminished the NF-kB activation via increasing the sensitivity of cells to apoptosis. On the other hand, VOsil inhibited the topoisomerase IB activity concluding that this is important target involved in the anticancer vanadium effects. As a whole, the results presented herein demonstrate that VOsil has a stronger deleterious action than VOchrys on HT-29 cells, whereby suggesting that Vosil is the potentially best candidate for future use in alternative anti-tumor treatments.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Complexos de Coordenação/química , Flavonoides , Silimarina , Vanádio , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Complexos de Coordenação/farmacologia , Flavonoides/química , Humanos , Estrutura Molecular , Silibina , Silimarina/química , Vanádio/químicaRESUMO
Polyoxometalates (POMs) are early transition metal oxygen anion clusters. They display interesting biological effects mainly related to their antiviral and antitumor properties. On the other hand, copper compounds also show different biological and pharmacological effects in cell culture and in animal models. We report herein for the first time, a detailed study of the mechanisms of action of a copper(II) compound of the group of HPOMs with the formula K7Na3[Cu4(H2O)2(PW9034)2]20H2O (PW9Cu), in a model of human osteosarcoma derived cell line, MG-63. The compound inhibited selectively the viability of the osteosarcoma cells in the range of 25-100µM (p<0.01). Besides, we have clearly shown a more deleterious action of PW9Cu on tumor osteoblasts than in normal cells. Cytotoxicity studies also showed deleterious effects for PW9Cu. The increment of reactive oxygen species (ROS) and the decrease of the GSH/GSSG ratio were involved in the antiproliferative effects of PW9Cu. Moreover, the compound caused cell cycle arrest in G2 phase, triggering apoptosis as determined by flow cytometry. As a whole, these results showed the main mechanisms of the deleterious effects of PW9Cu in the osteosarcoma cell line MG-63, demonstrating that this compound is a promissory agent for cancer treatments.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Complexos de Coordenação/farmacologia , Cobre/farmacologia , Osteossarcoma/tratamento farmacológico , Óxidos/farmacologia , Compostos de Tungstênio/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Cobre/química , Fragmentação do DNA , Glutationa/metabolismo , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Estresse Oxidativo/efeitos dos fármacos , Óxidos/química , Fosfatidilserinas/metabolismo , Compostos de Tungstênio/químicaRESUMO
We report herein the antitumor actions of three oxidovanadium(IV) complexes on MG-63 human osteosarcoma cell line. The three complexes: VO(oda), VO(oda)bipy and VO(oda)phen (oda=oxodiacetate), caused a concentration dependent inhibition of cell viability. The antiproliferative action of VO(oda)phen could be observed in the whole range of concentrations (at 2.5 µM), while VO(oda)bipy and VO(oda) showed a decrease of cell viability only at higher concentrations (at 50 and 75 µM, respectively) (p<0.01). Moreover, VO(oda)phen caused a decrease of lysosomal and mitochondrial activities at 2.5 µM, while VO(oda) and VO(oda)bipy affected neutral red uptake and mitochondrial metabolism at 50 µM (p<0.01). On the other hand, no DNA damage studied by the Comet assay could be observed in MG-63 cells treated with VO(oda) at 2.5-10 µM. Nevertheless, VO(oda)phen and VO(oda)bipy induced DNA damage at 2.5 and 10 µM, respectively (p<0.01). The generation of reactive oxygen species increased at 10 µM of VO(oda)phen and only at 100 µM of VO(oda) and VO(oda)bipy (p<0.01). Besides, VO(oda)phen and VO(oda)bipy triggered apoptosis as determined by externalization of the phosphatidylserine. The determination of DNA cleavage by agarose gel electrophoresis showed that the ability of VO(oda)(bipy) is similar to that of VO(oda), while VO(oda)(phen) showed the highest nuclease activity in this series. Overall, our results showed a good relationship between the bioactivity of the complexes and their structures since VO(oda)phen presented the most potent antitumor action in human osteosarcoma cells followed by VO(oda)bipy and then by VO(oda) according to the number of intercalating heterocyclic moieties.
Assuntos
2,2'-Dipiridil/química , Acetatos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fenantrolinas/química , Vanádio/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Complexos de Coordenação/síntese química , Fragmentação do DNA/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Vermelho Neutro/metabolismo , Fosfatidilserinas/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
The secure transfer of information is an important problem in modern telecommunications. Quantum key distribution (QKD) provides a solution to this problem by using individual quantum systems to generate correlated bits between remote parties, that can be used to extract a secret key. QKD with D-dimensional quantum channels provides security advantages that grow with increasing D. However, the vast majority of QKD implementations has been restricted to two dimensions. Here we demonstrate the feasibility of using higher dimensions for real-world quantum cryptography by performing, for the first time, a fully automated QKD session based on the BB84 protocol with 16-dimensional quantum states. Information is encoded in the single-photon transverse momentum and the required states are dynamically generated with programmable spatial light modulators. Our setup paves the way for future developments in the field of experimental high-dimensional QKD.
RESUMO
Flavonoids, a polyphenolic compound family, and the vanadium compounds have interesting biological, pharmacological, and medicinal properties. We report herein the antitumor actions of the complex [VO(chrysin)2EtOH]2 (VOchrys) on the MG-63 human osteosarcoma cell line. Oxovanadium(IV), chrysin and VOchrys caused a concentration-dependent inhibition of cell viability. The complex was the strongest antiproliferative agent (p < 0.05). Cytotoxicity and genotoxicity studies also showed a concentration effect. Reactive oxygen species (ROS) and the alterations in the GSH/GSSG ratio underlie the main mechanisms of action of VOchrys. Additions of ROS scavengers (vitamin C plus vitamin E) or GSH to the viability experiments demonstrated beneficial effects (p < 0.01). Besides, the complex triggered apoptosis, disruption of the mitochondria membrane potential (MMP), increased levels of caspase 3 and DNA fragmentation measured by the sub-G1 peak in cell cycle arrest experiments (p < 0.01). Collectively, VOchrys is a cell death modulator and a promissory complex to be used in cancer treatments.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Flavonoides/química , Compostos Organometálicos/farmacologia , Osteossarcoma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Vanadatos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Osteossarcoma/patologia , Relação Estrutura-AtividadeRESUMO
We report the experimental implementation of a new method for generating multiple dynamical optical tweezers, where each one of them is generated with an independent linear polarization state with arbitrary orientation. This also allows an independent simultaneous polarization-rotation control. The laser beam, both for generating multiple traps and polarization control, has been modulated using a single reflective nematic liquid crystal with parallel alignment. We present experimental results of controlled displacement, orientation and rotation of birefringent particles. In addition, a simple method for estimating and canceling out the primary astigmatism present in the system is presented.
Assuntos
Biofísica/métodos , Birrefringência , Holografia/instrumentação , Pinças Ópticas , Rotação , Algoritmos , DNA/química , Dimerização , Desenho de Equipamento , Holografia/métodos , Cristais Líquidos , Óptica e Fotônica/métodos , Tamanho da Partícula , Estresse Mecânico , Raios UltravioletaRESUMO
Norfloxacin is a fluoroquinolone antibiotic used in the treatment of bacterial infections. In this article, we studied the potential antitumoral action of a complex of Norfloxacin with Cu(II), Cu(Nor)(2)·5H(2)O on osteosarcoma cells (UMR106) and calvaria-derived cells (MC3T3-E1), evaluating its cytotoxicity and genitoxicity. We have also elucidated the more stable conformation of this complex under physiologic conditions by Molecular Dynamic simulations based on the model of the canonical ensemble and PM6 force field. When solvent effect was taken into account, the complex conformation with both carbonyl groups in opposite sides displayed lower energy. Cu(Nor)(2)·5H(2)O caused an inhibitory effect on the proliferation on both cell lines from 300 µM (P < 0.01). Nevertheless, the decline on cell proliferation of UMR106 cells was more pronounced (45 % vs basal) than in MC3T3-E1 cells (20 % vs basal) at 300 µM (P < 0.01). Cu(Nor)(2)·5H(2)O altered lysosomal metabolism (Neutral Red assay) in a dose-dependent manner from 300 µM (P < 0.001). Morphological studies showed important transformations that correlated with a decrease in the number of cells in a dose-dependent manner. Moreover, Cu(Nor)(2)·5H(2)O caused statistically significant genotoxic effects on both osteoblast cell lines in a lower range of concentrations (Micronucleus assay) (P < 0.05 at 10 µM, P < 0.001 from 25 to 50 µM). UMR106 cells displayed a dose-related genotoxic effect between 5 and 25 µM while the MC3T3-E1 cells showed a narrower concentration dependent range. Altogether, these results suggest that Cu(Nor)(2)·5H(2)O is a good candidate to be further evaluated for alternative therapeutics in cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Complexos de Coordenação/farmacologia , Cobre/química , Osteossarcoma/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Neoplasias Ósseas/patologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Lisossomos/efeitos dos fármacos , Camundongos , Testes para Micronúcleos , Simulação de Dinâmica Molecular , Testes de Mutagenicidade , Norfloxacino/síntese química , Norfloxacino/química , Norfloxacino/farmacologia , Osteoblastos/efeitos dos fármacos , Osteossarcoma/patologia , RatosRESUMO
Vanadium is a trace element present in practically all cells in plants and animals. While the essentiality of vanadium for human beings remains to be well established, vanadium has become an increasingly important environmental metal. Vanadium compounds exert a variety of biological activities and responses. At pharmacological doses, vanadium compounds display relevant biological actions such as insulin and growth factor mimetic or enhancing effects, as well as osteogenic and cardioprotective activity. On the other hand, depending on the nature of compounds and their concentrations, toxicological actions and adverse side effects may also be shown. Nevertheless, the toxic effects may be useful to develop new antitumoral drugs. In this review, the authors summarize current knowledge and new advances on in vitro and in vivo effects of inorganic and organically-chelated vanadium compounds. The effects of vanadium derivatives on some cellular signaling pathways related to different diseases are compiled. In particular, the pathways relevant to the insulin mimetic, osteogenic, cadioprotective and antitumoral actions of vanadium compounds have been comprehensively reviewed. The knowledge of these intracellular signaling pathways may facilitate the rational design of new vanadium compounds with promising therapeutic applications as well as the understanding of secondary side effects derived from the use of vanadium as a therapeutic agent.
Assuntos
Hipoglicemiantes/uso terapêutico , Compostos de Vanádio/farmacologia , Compostos de Vanádio/uso terapêutico , Vanádio/farmacologia , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Glicemia/metabolismo , Cardiotônicos/metabolismo , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Quelantes , Feminino , Humanos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Vanádio/fisiologia , Compostos de Vanádio/metabolismoRESUMO
Strong chelating ligands as oxodiacetate (oda) are model systems to study the process of metal trapping by living organisms. Vanadium compounds display interesting biological and pharmacological actions. In vertebrates, vanadium is stored mainly in bones. In the present study we report the effects of the complex of oda with vanadyl(IV) cation, VO(oda), on two osteoblast cell lines, one normal (MC3T3E1) and the other tumoral (UMR106). VO(oda) exerted cytotoxic actions in osteoblasts as it was determined through a dose-dependent decrease in cell proliferation, and morphological and actin alterations. The putative mechanisms underlying VO(oda) deleterious effects were also investigated. The complex increased the level of ROS which correlated with a decreased in GSH/GSSG ratio. Besides, VO(oda) induced a dissipation of the mitochondria membrane potential (MMP) and promoted an increase in ERK cascade phosphorylation, which is involved in the regulation of cellular death and survival. All the effects were more pronounced in MC3T3-E1 than in UMR106 cells. ERK activation was inhibited by PD98059, Wortmanin and the ROS scavenger NAC (N-acetyl cysteine). These results suggest that VO(oda) stimulated ERKs phosphorilation by induction of free radicals involving kinases upstream of ERK pathway. The inhibitory effect of the complex on cell proliferation was partially reversed in both cell lines by NAC. Moreover, PD98059 and Wortmanin also partially reversed the inhibition of cell proliferation in the tumoral osteoblasts. The use of specific inhibitors and ROS scavengers suggested the involvement of oxidative stress, MMP alterations and ERK pathway in the apoptotic actions of this complex.
Assuntos
Citotoxinas/química , Citotoxinas/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Osteoblastos/efeitos dos fármacos , Oxigênio/química , Vanádio/química , Actinas/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Ativação Enzimática/efeitos dos fármacos , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Espaço Intracelular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Vermelho Neutro , Osteoblastos/citologia , Osteoblastos/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
The potassium salt of the carbonato oxodiperoxovanadate(V) complex, obtained by a known synthetic procedure, was thoroughly characterized by infrared, Raman, and electronic spectroscopy. The bioactivity of the complex on the cell proliferation was tested on osteoblast-like cells (MC3T3E1 osteoblastic mouse calvaria-derived cells and UMR106 rat osteosarcoma-derived cells) in culture. At low doses, the complex is more toxic for the nontransformed osteoblasts than for the tumoral ones, whereas at higher doses the deleterious effects are similar for both cell lines. This peroxo complex seems to be the most toxic compound that has so far been tested on osteoblast-like cells in culture.
Assuntos
Compostos de Vanádio/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos , Ratos , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The oxovanadium(IV) complex of oxodiacetic acid (H2oda) of stoichiometry [VO(oda)(H2O)2], which presents an unprecedented tridentate OOO coordination, was thoroughly characterized by infrared, Raman, electronic, and electron paramagnetic resonance spectroscopies. The biological activity of the complex on the cell proliferation and differentiation was tested on osteoblast-like cells (MC3T3E1 osteoblastic mouse calvaria-derived cells and UMR106 rat osteosarcoma-derived cells) in culture. The complex caused inhibition of cellular proliferation in both osteoblast-like cells in culture, but the cytotoxicity was stronger in the normal (MC3T3E1) than in the tumoral (UMR106) osteoblasts. The effect of the complex in cell differentiation was tested through the specific activity of alkaline phosphatase of the UMR106 cells because they expressed a high activity of this enzyme. What occurs with other vanadium compounds [VO(oda)(H2O)2] is an inhibitory agent of osteoblast differentiation.
Assuntos
Acetatos , Osteoblastos/metabolismo , Vanadatos , Acetatos/química , Acetatos/farmacocinética , Animais , Diferenciação Celular , Linhagem Celular , Camundongos , Estrutura Molecular , Osteoblastos/citologia , Ratos , Análise Espectral , Vanadatos/química , Vanadatos/farmacocinéticaRESUMO
Vanadium is a trace element present in practically all cells in plants and animals. It exerts interesting actions in living systems. At pharmacological doses, vanadium compounds display relevant biological actions such as mimicking insulin and growth factors as well as having osteogenic activity. Some vanadium compounds also show antitumoral properties. The importance of vanadium in bone arises from the studies developed to establish the essentiality of this element in animals and humans. Bone tissue, where the element seems to play an important role, accumulates great amounts of vanadium. This paper reviews the physiology of osteoblasts, the involvement of different growth factors on bone development, and the effects of vanadium derivatives on the skeletal system of animal models and bone-related cells. Two cellular lines are discussed in particular; one derived from a rat osteosarcoma (UMR106) and the other is a nontransformed osteoblast cell line (MC3T3-E1). The effects of different growth factors and their mechanisms of action in these cellular lines are reviewed. These models of osteoblasts are especially useful in understanding the intracellular signaling pathways of vanadium derivatives in hard tissues. Vanadium uses an intricate interplay of intracellular mechanisms to exert different biochemical and pharmacological actions. The effects of vanadium derivatives on some cellular signaling pathways related to insulin are compiled in this review. The comprehension of these intracellular signaling pathways may facilitate the design of vanadium compounds with promising therapeutic applications as well as the understanding of secondary side effects derived from the use of vanadium as a therapeutic agent.
Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Compostos de Vanádio/farmacologia , Animais , Desenvolvimento Ósseo/fisiologia , Humanos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Transdução de Sinais , Compostos de Vanádio/metabolismoRESUMO
The synthesis and spectral and magnetic characterization of VO(2+) complexes with Ibuprofen (2-(4-isobutylphenyl)propionic acid), Naproxen (6-methoxy-alpha-methyl-2-naphthalene acetic acid) and Tolmetin (1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid) were studied. The complexes [VO(Ibu)(2)] x 5CH(3)OH, [VO(Nap)(2)] x 5CH(3)OH and [VO(Tol)(2)] were obtained from methanolic solutions under nitrogen atmosphere. The biological activities of these complexes on the proliferation of two osteoblast-like cells in culture (MC3T3E1 and UMR106) were compared with that of the vanadyl(IV) cation. The complexes exhibited different effects depending on the concentration and the cellular type, while no effect was observed for their parent drugs.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Osteoblastos/efeitos dos fármacos , Vanadatos/síntese química , Vanadatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ibuprofeno/química , Ibuprofeno/farmacologia , Camundongos , Naproxeno/química , Naproxeno/farmacologia , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Ratos , Análise Espectral , Tolmetino/química , Tolmetino/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Vanadatos/químicaRESUMO
BACKGROUND: The tissue accumulation of protein-bound advanced glycation endproducts (AGE) may be involved in the etiology of diabetic chronic complications, including osteopenia. The aim of this study was to investigate the effect of an AGE-modified type I collagen substratum on the adhesion, spreading, proliferation and differentiation of rat osteosarcoma UMR106 and mouse non-transformed MC3T3E1 osteoblastic cells. We also studied the role of reactive oxygen species (ROS) and nitric oxide synthase (NOS) expression on these AGE-collagen mediated effects. RESULTS: AGE-collagen decreased the adhesion of UMR106 cells, but had no effect on the attachment of MC3T3E1 cells. In the UMR106 cell line, AGE-collagen also inhibited cellular proliferation, spreading and alkaline phosphatase (ALP) activity. In preosteoblastic MC3T3E1 cells (24-hour culture), proliferation and spreading were significantly increased by AGE-collagen. After one week of culture (differentiated MC3T3E1 osteoblasts) AGE-collagen inhibited ALP activity, but had no effect on cell number. In mineralizing MC3T3E1 cells (3-week culture) AGE-collagen induced a decrease in the number of surviving cells and of extracellular nodules of mineralization, without modifying their ALP activity. Intracellular ROS production, measured after a 48-hour culture, was decreased by AGE-collagen in MC3T3E1 cells, but was increased by AGE-collagen in UMR106 cells. After a 24-hour culture, AGE-collagen increased the expression of endothelial and inducible NOS, in both osteoblastic cell lines. CONCLUSIONS: These results suggest that the accumulation of AGE on bone extracellular matrix could regulate the proliferation and differentiation of osteoblastic cells. These effects appear to depend on the stage of osteoblastic development, and possibly involve the modulation of NOS expression and intracellular ROS pathways.
Assuntos
Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Produtos Finais de Glicação Avançada/farmacologia , Osteoblastos/citologia , Estresse Oxidativo , Animais , Calcificação Fisiológica , Adesão Celular/efeitos dos fármacos , Diferenciação Celular , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Glicosilação , Camundongos , Óxido Nítrico Sintase/metabolismo , Osteoblastos/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais CultivadasRESUMO
In chronically uncompensated diabetes mellitus, an increase has been observed in the content of advanced glycation endproduct (AGE)-modified proteins in various tissues, including bone. This increase can lead to a local imbalance in the secretion of cytokines and growth factors, and has been implicated in the pathophysiology of the longterm complications of diabetes. We have previously shown that the proliferation and differentiation of UMR106 rat osteosarcoma and MC3T3E1 mouse calvaria-derived cell lines are regulated by AGE-modified proteins, possibly through the recognition of these AGEs by specific membrane-associated receptors. In the present study, we investigated the effects of AGE-proteins on the secretion of insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBPs) by both osteoblast-like cell lines. In the case of MC3T3E1 cells, this was studied throughout their successive stages of development: proliferation, differentiation and mineralisation. For every condition, cells were incubated 24 hours with increasing concentrations of either bovine serum albumin (BSA) or AGE-BSA. IGF-I in conditioned media was separated from IGFBPs by acid gel filtration-centrifugation, and measured by radioimmunoassay. IGFBPs in conditioned media were analysed by a semi-quantitative western ligand blot. In UMR106 cells, low doses of AGE-BSA significantly decreased the secretion of both IGF-I (56% of control) and a 24 kDa IGFBP (80% of control). Results for MC3T3E1 cells, which predominantly secrete 29 kDa IGFBPs, were dependent on the stage of development. In proliferating preosteoblastic cells, AGE-BSA decreased the secretion of IGF-I (34%-37% of control) while increasing the secretion of IGFBP (124%-127% of control). On the other hand, secretion of these components of the IGF system by mature (differentiated) cells was unaffected by the presence of AGE-BSA. When these cells finally attained mineralisation, incubation with AGE-modified BSA provoked an increase both in IGFBP (131%-169% of control) and in IGF-I secretion (119%-123% of control). The presented evidence suggests that the modulation of growth and development by AGE-modified proteins, previously described for both cell lines, could be the result of an autocrine-paracrine mechanism involving the IGF-IGFBP system.
Assuntos
Produtos Finais de Glicação Avançada/farmacologia , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Osteoblastos/fisiologia , Animais , Bovinos , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Senescência Celular/fisiologia , Camundongos , Minerais/metabolismo , Osteoblastos/citologia , Ratos , Soroalbumina Bovina/farmacologiaRESUMO
A new vanadyl(IV) complex of the disaccharide lactose was obtained in aqueous solution at pH = 13. The sodium salt of the complex, of composition Na4[VO(lactose)2].3H2O, has been characterized by elemental analysis and by ultraviolet-visible, diffuse reflectance, and infrared spectroscopies. Its magnetic susceptibility and thermal behavior were also investigated. The inhibitory effect on alkaline phosphatase activity was tested for this compound as well as for the vanadyl(IV) complexes with maltose, sucrose, glucose, fructose, and galactose. For comparative purposes, the free ligands and the vanadyl(IV) cation were also studied. The free sugars and the sucrose/VO complex exhibited the lowest inhibitory effect. Lactose-VO, maltose-VO, and the free VO2+ cation showed an intermediate inhibition potential, whereas the monosaccharide/VO complexes appeared as the most potent inhibitory agents.