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51.
Elene C. Pereira-Maia Ivina P. Souza Kelen J. R. C. Nunes Alexandre A. Castro Teodorico C. Ramalho Fernando Steffler Helio A. Duarte Ana Pacheli Poliana Chagas Luiz C. A. Oliveira 《RSC advances》2018,8(19):10310
A new class of polyoxoniobate complex has been synthesized and characterized as a novel anticancer agent for photodynamic therapy. The complex inhibits the growth of chronic myelogenous leukemia cells with an IC50 value of 30 μM, in the dark. However, upon exposure to light (365 nm) there is a fivefold increase in the cytotoxic activity. Light radiation activate the complex with the formation of radical species capable of interacting with DNA according to our experimental and theoretical data.A new class of polyoxoniobate complex has been synthesized and characterized as a novel anticancer agent for photodynamic therapy.In this work, we prepared a photosensitive peroxoniobium complex presenting a balance with an active radical phase when illuminated with radiation of 365 nm. A versatile niobium species of amorphous structure was obtained by the reaction of niobium ammonium oxalate with ammonium hydroxide up to pH 7. The material obtained, a niobium oxyhydroxide (NbO2(OH)) (white solid),1,2 can be modified with the generation of NbO2(OH)O2˙− peroxo groups (yellow solid).3 The yellow compound is formed by treatment with H2O2. The absorption radiation in the visible region due to the charge transfer transition between the peroxo group and the niobium is shown in Fig. 1.Open in a separate windowFig. 1UV-Vis profile of the catalysts.This complex with the radical as an intermediate is favored in the presence of visible and UV radiation. This property is of interest for photodynamic therapy of cancer (PDT), which involves the exposure of malignant cells containing a photosensitizer molecule to light irradiation, in the presence of oxygen species. The photoactivated drug produces reactive oxygen species that initiate a series of events, resulting in cell death. Selective light activation allows a preferential tumor destruction in comparison to healthy tissues.4 Several metal complexes exhibit photocytotoxicity under UV or visible light,5,6 but data about niobium compounds are very scarce in the literature.7The polyoxoniobate, generated from niobium oxyhydroxide described here can be very active in the treatment of diseased cells when illuminated with visible or UV radiation due to its light absorption capacity because of the peroxo groups formed. The peroxoniobium complex has some advantages, such as ease synthesis and in mild conditions, high solubility, low activity under light off, and resistance to inactivation by thiol reagents. Moreover, it is nontoxic8 and does not employ noble metals like most of the compounds proposed in the literature. Actually, niobium oxide was tested as a bone implant component and showed absence of inflammatory cells or degeneration of the osteoblasts without any sign of damage to the preexisting bone tissue, showing compatibility with the bone tissue.9–11The innovative part in the process of obtaining the polyoxoniobate complex presented in this work consists in the leaching of the complex when treating the niobium oxyhydroxide with H2O2. With the treatment, a yellow solid and a leached yellow liquid is obtained, which is the complex containing peroxoniobium in its structure, sensitive to the UV-Vis radiation generating radical species. This species generated with the leaching at neutral pH presents high negative charge and a kinetic volume of 223 nm. The XRD of the lyophilized polyoxoniobate indicated strong amorphous character. However, the polyoxoniobate is known to form well defined polyoxometalates such as Lindqvist ([Nb6O19]8−) and decaniobate ([Nb10O28]6−). Fig. 2 shows a comparison between the experimental and PBE/LANL2DZ/aug-cc-pVDZ DFT IR spectra. It is clear that the pattern of the decaniobate structure is closer to the experimental spectrum. One should keep in mind that DFT frequencies are normally 10% underestimated with respect to the experimental values. The broader absorption below 600 cm−1 can be attributed to the interaction between different decaniobate structures forming the amorphous solid. The calculated peaks at 710, 760 and 860 cm−1 are related to the experimental peaks of 800, 870 and 910 cm−1 indicating that decaniobate is the local arrangement of the polyoxoniobate complex.Open in a separate windowFig. 2Infrared spectra for experimental procedures, Lindqvist and decaniobate structures (simulated). The line shape chosen was Lorentzian and the half-width is about 20.The generation of reactive oxygen under radiation was confirmed by the reaction of the complex with an organic dye, which was monitored by UV-Vis spectroscopy (Fig. 3). The spectrum of the dye solution shows the characteristic peak of the methylene blue (MB) at 663 nm (black trace). It can be clearly seen that in the presence of the peroxoniobium complex and radiation (365 nm) the signal decreased indicating the reaction of the peroxoniobium complex with the dye (blue trace). In the absence of light, there is no decrease in the signal related to the dye, indicating the need of the radiation to activate the oxidation action of the peroxoniobium complex. The equilibrium in which the radical species forms it is not necessary to use a photosensitizer agent, such as porphyrins.4 A further investigation was carried out by 31P NMR (Fig. S1†) using guanosine as model molecule able to react with the peroxoniobium complex. The 31P NMR spectrum shown in Fig. S1-a† corresponds to 5-GMP and revealed that the phosphorus atom in the structure exhibits a chemical shift at δ 5.93. When 5-GMP and the polyoxoniobate are in contact, no significant changes are observed in the 31P spectrum, only a small displacement of the phosphorus signal to δ 5.90 (Fig. S1-b†). However, when the 5-GMP and polyoxoniobate mixture is submitted to radiation (Fig. S1-c†), an interaction between the compounds occurs, giving rise to a new species that presents a different chemical shift in the P spectrum (δ 5.27).Open in a separate windowFig. 3UV-Vis profile of the reaction of the Nb complex with the organic dye (10 mg L−1).The effect of the peroxoniobium on the growth of K562 cells was evaluated after 4 h of incubation. The compound inhibits K562 cell growth in a concentration-dependent manner, with an IC50 of 30.0 ± 1.5 μmol L−1. Ammonium niobate(v) oxalate was also tested and it has no effect on K562 cells up to 100 μM. The cytotoxic activity of polyoxoniobate increases by 5 times upon 5 min of UV-A light irradiation, with an IC50 value of 6.2 ± 0.4 μmol L−1 (Fig. 4). The higher activity, when exposed to light, associated to the low toxicity of niobium compounds place the peroxoniobium complex as a candidate for photodynamic therapy.Open in a separate windowFig. 4Photocytotoxic effect of the peroxoniobium complex. K562 cells were incubated for 4 h in the presence of different complex concentrations, in the dark (black bars) and after 5 min of UV-A light exposure (red bars). The values are the average of three independent experiments.There are few reports in the literature about the cytotoxic activity of niobium compounds. A peroxo niobium complex with ascorbic acid (K3[Nb(Asc)(O2)3]) is moderately active in HL60 human leukemia cells but not in K562 human myelogenous leukemia cells.12 A tetrameric Nb28-containing cluster inhibits the growth of the human breast cancer MCF-7 cells line with an IC50 value of 5.21, after 48 h of incubation.13Methylene blue (MB) is one of the main photosensitizing agents used in PDT due to its good tissue penetration and low cytotoxicity.14 It is active in several types of tumors upon irradiation with red laser light.15 This fact allied to the ability of the peroxoniobium compound to interact with MB (Fig. 3) prompted us to investigate its effect in the MB photocytotoxicity. We have first checked that exposure to UV-A light did not affect the cytotoxicity of MB in K562 cells (Table 1). Afterwards, the photocytotoxicity of MB in K562 cells was assessed in the presence of the peroxoniobium complex at its IC50 value. Cells were incubated with increasing concentrations of MB and irradiated for 5 min with UV-A light, in the absence and the presence of 6.5 μM of the peroxoniobium complex. Upon light irradiation, 6.5 μM of peroxoniobium complex doubles the effect of MB. Therefore, the peroxoniobium compound prepared is a promising candidate for PDT therapy, alone or in combination with other sensitizing agents, such as methylene blue dye (Table 1).Effect of the peroxoniobum complex on the photocytotoxicity of methylene blue (MB) in K562 cells
Open in a separate windowaIC50 Methylene blue concentration required to inhibit 50% of cell growth under dark conditions.bIC50 Methylene blue concentration required to inhibit 50% of cell growth after 5 min of UV-A irradiation.cAssays were performed in the presence of 6.5 μM of the peroxoniobium complex.The peroxoniobium complex (Fig. S2†) and the DNA/complex systems were thus fully optimized at DFT level,16 with conjugate gradient and quasi-Newton–Raphson algorithms. The final geometries were obtained with the density functional Becke''s three-parameter exchange functional and the gradient-corrected functional of Lee, Yang and Paar (B3LYP),17 using LanL2DZ basis set.The DICKERSON-DREW B-DNA DODECAMER was obtained from the Protein Data Bank (PDB), with code 4C64 and resolution: 1.32 Å (ref. 18 and 19) and it was chosen as model according to previous works, and has shown suitable for our calculations.20 As previously discussed, the Nb complexes (Fig. S2†) were entirely optimized at the DFT level, to obtain the most stable initial geometries to perform the calculations with the DNA structure. It is important to mention that the more stable complex/DNA system is related to a higher cytotoxicity potential. The following species were considered for this theoretical investigation: Complex a (no radical groups), Complex b (protonated structure) and Complex c (radicals formation). The natural charges of all atoms were elucidated, and according to these data, it is possible to realize more pronounced negative charges referred to the radical species. The protonated substituent (OOH) presented a charge value equals to −0.534 a.u., while the corresponding radical (deprotonated) has shown a charge value significantly lower (−1.170 a.u.). The same is observed for the substituent (OH), with a charge value of −0.379 a.u., and the corresponding radical (−0.739 a.u.). The formation of more negative charges suggests to the highest reactivity of Complex c, in relation to the other complexes. Complex a was put together with DNA in three distinct regions (Fig. S3†), and after performing the optimization, the Nb complex reactivity was analyzed in these zones.PM6 calculations were performed in order to evaluate the Nb complex (Complex a) affinity in different DNA regions. These results are presented in Table S1.† as relative interaction energy values. The Complex a, when put into different regions of DNA, presented quite relevant changes in relation to the intermolecular interaction energy. Thus, Complex a, when docked into the central region of DNA, showed a more favorable energy (Fig. 5). After the optimization structure, the region with the highest interaction between DNA and Nb complexes was considered for other calculations.Open in a separate windowFig. 5Representation of the DNA-complex system.According to our theoretical methodology, we have the energy minimizations for the systems: free DNA (EDNA), free complex (Ecomplex) and DNA-complex system (Esystem). In line with those systems, the affinity energy was calculated using the following equation:E = EDNA/complex − Ecomplex − EDNA1The results from this methodology are described in Table S2,† also as relative interaction energy values. By using the strategy described at the ESI,† it was possible to analyze the efficiency of Nb complexes towards DNA, evaluating which factors contribute most to this reactivity. Our first results indicate that the Nb complex, in general, presents a significant affinity with DNA, with a pronounced increase in the affinity/reactivity in the presence of radical groups (–OO˙. radical for example). According to our calculations, Complex a showed an intermediate reactivity towards DNA, presenting a significantly higher energy value than that obtained for Complex c. The energy difference between Complex a and c was 2.88 kcal mol−1. On the other hand, the energy difference between Complex b and c was remarkable, about 5.01 kcal mol−1. Complex c presented good interaction potential with DNA, undoubtedly due to the radical groups added to the complex structure, coherent with the experimental observations. According to the computational investigation, we can conclude that all Nb complex species (without and with radical groups) presented reactivity and stability when docked into the DNA crystallographic structure. These results corroborate with the experimental data observed in the reaction of guanosine with the niobium complex shown in the 31P NMR of Fig. S1.† Furthermore, the addition of radical groups substantially increases the affinity of the complex towards DNA, supported by the obtaining of more stable structures for the complex/DNA system (lowest energy values), suggesting higher levels of cytotoxicity. 相似文献
| Compound | IC50a | IC50 irradiatedb |
|---|---|---|
| MB | 7.3 ± 0.4 | 7.0 ± 0.5 |
| MB + NbO2(OH)–O2−c | 6.3 ± 0.3 | 3.0 ± 0.1 |
52.
da Luz PL Favarato D Faria-Neto JR Lemos P Chagas AC 《Clinics (S?o Paulo, Brazil)》2008,63(4):427-432
An abnormal ratio of triglycerides to HDL-cholesterol (TG/HDL-c) indicates an atherogenic lipid profile and a risk for the development of coronary disease. OBJECTIVE: To investigate the association between lipid levels, specifically TG/HDL-c, and the extent of coronary disease. METHODS: High-risk patients (n=374) submitted for coronary angiography had their lipid variables measured and coronary disease extent scored by the Friesinger index. RESULTS: The subjects consisted of 220 males and 154 females, age 57.2+/-11.1 years, with total cholesterol of 210+/-50.3 mg/dL, triglycerides of 173.8+/-169.8 mg/dL, HDL-cholesterol (HDL-c) of 40.1+/-12.8 mg/dL, LDL-cholesterol (LDL-c) of 137.3+/-46.2 mg/dL, TG/HDL-c of 5.1+/-5.3, and a Friesinger index of 6.6+/-4.7. The relationship between the extent of coronary disease (dichotomized by a Friesenger index of 5 and lipid levels (normal vs. abnormal) was statistically significant for the following: triglycerides, odds ratio of 2.02 (1.31-3.1; p=0.0018); HDL-c, odds ratio of 2.21 (1.42-3.43; p=0.0005); and TG/HDL-c, odds ratio of 2.01(1.30-3.09; p=0.0018). However, the relationship was not significant between extent of coronary disease and total cholesterol [1.25 (0.82-1.91; p=0.33)] or LDL-c [1.47 (0.96-2.25; p=0.0842)]. The chi-square for linear trends for Friesinger >4 and lipid quartiles was statistically significant for triglycerides (p=0.0017), HDL-c (p=0.0001), and TG/HDL-c (p=0.0018), but not for total cholesterol (p=0.393) or LDL-c (p=0.0568). The multivariate analysis by logistic regression OR gave 1.3+/-0.79 (p= .0001) for TG/HDL-c, 0.779+/-0.074 (p= .0001) for HDL-c, and 1.234+/-0.097 (p=0.03) for LDL. Analysis of receiver operating characteristic curves showed that only TG/HDL-c and HDL-c were useful for detecting extensive coronary disease, with the former more strongly associated with disease. CONCLUSIONS: Although some lipid variables were associated with the extent of coronary disease, the ratio of triglycerides to HDL-cholesterol showed the strongest association with extent. 相似文献
53.
Electron microscopic findings on the nerve of the biventer cervicis muscle of the chick, which was completely transected and immediately after submitted to an adequate microsurgical nerve suture, confirmed our previous statement that proper microsurgical nerve suture may impede the Wallerian degeneration that normally occurs in the distal segment of a completely transected nerve. 相似文献
54.
55.
Larissa Acioli Pereira Paula Fontes Gontijo Jorge Alcântara Farran Antonio Carlos Palandri Chagas Edson Renato Romano Luis Carlos Bento de Souza 《Revista portuguesa de cardiologia》2013,32(6):541-544
Pseudoaneurysm of the left ventricular outflow tract (LVOT) is a rare disease with high morbidity and mortality, resulting from left ventricular damage due to myocardial infarction, infective endocarditis or surgical trauma. A case of giant pseudoaneurysm of the LVOT, even more rarely reported in the literature, is described. The lesion was detected 12 years after aortic valve replacement for infective endocarditis in a young patient, a former intravenous drug user. As it is an uncommon disease, little is known about its clinical presentation and treatment. 相似文献
56.
Francisco das Chagas Monteiro Júnior Cacionor Pereira da Cunha Júnior Pedro Antônio Muniz Ferreira José Aldemir Teixeira Nunes Ronald Lopes Brito José Bonifácio Barbosa Natália Ribeiro Mandarino Joyce Santos Lages Natalino Salgado Filho Valter Correia de Lima 《Revista portuguesa de cardiologia》2013,32(12):975-980
Introduction and ObjectivesAlthough carotid intima-media thickness (CIMT) is considered a surrogate marker of subclinical atherosclerosis, with known value in risk stratification, its routine use in hypertensive patients is not recommended. The aim of this study was to determine the prevalence of subclinical atherosclerosis through measurement of CIMT and its impact on reclassification of risk in hypertensive patients.MethodsThis was a cross-sectional study of 94 middle-aged (56.99±11.89 years) hypertensive outpatients without overt cardiovascular disease, 68.1% female. All participants underwent clinical examination, biochemical tests, echocardiogram and measurement of CIMT by high-resolution ultrasound.ResultsAlthough the majority of patients were stratified as low (63.5%) or intermediate risk (23%) according to their Framingham score, a high prevalence (75.3%) of increased CIMT was observed in the overall sample, including in the low (61%) and intermediate risk groups (93.8%). CIMT measurement resulted in risk reclassification of 70.31% of the patients, 61% of those at low risk being reclassified as intermediate risk and 93.8% of those at intermediate risk being reclassified as high risk.ConclusionIn these hypertensive outpatients, predominantly middle-aged and female, CIMT measurement revealed a high prevalence of subclinical atherosclerosis and resulted in risk reclassification in the majority of cases. 相似文献
57.
Almeida Mda C Aquino EM 《Cadernos de saúde pública / Ministério da Saúde, Funda??o Oswaldo Cruz, Escola Nacional de Saúde Pública》2011,27(12):2386-2400
This study evaluated the association between adolescent pregnancy and the completion of basic education, mediated by macrosocial indicators. A cross-sectional household survey was conducted with individuals between the ages of 18 and 24 in three Brazilian cities. For the purposes of this study, individuals between the ages of 20 and 24 were selected from this sample survey that included 4,634 people. A total of 29.6% of the girls declared that they had become pregnant prior to reaching the age of 20, while 21.4% of the boys stated that they had made a girl pregnant in adolescence. Girls from households with a per capita family income of US$70 or less and who became pregnant at least once during adolescence were more likely to have not completed basic education; whereas from households with a per capita family income of US$70 or less, with parents who separated before the adolescent reached the age of 20 and that had made a partner pregnant prior reaching the age of 20 were more likely to have not completed basic education. It is vital that the school system provides girls and boys with guidance on sexuality and contraception and encourages them to remain in education. 相似文献
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