Investigação da atividade toxicológica de análogos de estatinas em modelos experimentais in vitro

As estatinas são fármacos inibidores competitivos da enzima hidroxi-3-metil-glutaril Coenzima A (HMGCoA) redutase, amplamente utilizados para o controle da hipercolesterolemia total e, em especial, para a redução dos níveis séricos de LDLc (Low Density Lipoprotein cholesterol). Além do efeito primário, esses fármacos apresentam vários efeitos secundários, chamados de efeitos pleiotrópicos, envolvendo atividade anti-inflamatória, antitumoral e antiparasitária. Para o desenvolvimento de inovações na área de química medicinal é imprescindível avaliar o risco de efeitos adversos para saúde ou, em outras palavras, a segurança terapêutica do novo produto nas condições propostas de uso. Nesse sentido, o objetivo desse trabalho foi investigar a genotoxicidade de quatro análogos inibidores da biossíntese de lipídios, da classe das estatinas, em modelos experimentais in vitro, testados previamente contra o clone W2 de Plasmodium falciparum a fim de se obter o IC50 dessas moléculas frente ao patógeno. Foram desenvolvidas quatro novas moléculas (PCSR02.001, PCSR09.001, PCSR08.002 e PCSR10.002). Para a avaliação da toxicidade, foram realizados o teste de mutagenicidade bacteriana (teste de Ames), o ensaio de viabilidade celular utilizando o reagente WST-1 e o ensaio de indução de micronúcleos, ambos utilizando uma linhagem ovariana (CHO-K1) e uma linhagem hepática (HepG2). Levando em conta o fato de nenhuma das amostras ter induzido efeitos mutagênicos nas linhagens de S. enterica sorovar Typhimurium, e PCSR10.002 ter apresentado citotoxicidade sugere-se então que este composto seja o mais tóxico. Comparativamente, PCSR10.002 foi mais genotóxico e citotóxico para a linhagem CHO-K1 do que para a linhagem HepG2. PCSR02.001 apresentou elevado potencial genotóxico para células ovarianas, mas não foi capaz de induzir a formação de micronúcleos em células hepáticas, apresentando, portanto um perfil similar ao observado em PCSR10.002. Assim como a atorvastatina, PCSR09.001 apresentou elevado potencial pró-apoptótico para a linhagem de hepatócitos. Já PCSR08.002, apresentou aumento na apoptose de CHO-K1. A indução de apoptose não é necessariamente um evento negativo, já que é pouco lesiva e responsável pela eliminação de células danificadas. Porém, as respostas de apoptose induzidas por esse composto foram muito inferiores àquelas induzidas pela atorvastatina (cerca de 4 vezes menor que a atorvastatina). PCSR08.002 foi aquele se mostrou menos tóxico e essa amostra foi a que teve menor risco relativo, em uma análise global das respostas de citotoxicidade e não demonstrou ter potencial genotóxico para as linhagens utilizadas nesse estudo. Conclui-se, portanto, que a análise da atividade toxicológica utilizando modelos experimentais in vitro dessas estatinas constitui um importante passo para o estabelecimento de novos candidatos à fármacos com maior segurança.

Benefícios do treinamento intervalado de alta intensidade (natação) na obesidade (estudo experimental)

É um desafio na sociedade moderna controlar a obesidade e comorbidades associadas na população. O objetivo do estudo foi avaliar o impacto do treinamento intervalado de alta intensidade no contexto da obesidade induzida por dieta em modelo animal. Camundongos C57BL/6 foram alimentados com ração padrão (grupo magro - LE) ou dieta rica em gordura (grupo obeso - OB). Após 12 semanas, os animais foram divididos em grupos não treinados (LE-NT e OB-NT) e grupos treinados (LE-T e OB-T) e teve início um protocolo de exercício. Nos grupos treinados em comparação aos grupos não treinados observou-se que o treinamento intervalado de alta intensidade levou a reduções significativas na massa corporal, glicemia e tolerância oral à glicose, colesterol total, triglicérides, lipoproteína de baixa densidade-colesterol, aspartato transaminase e alanina aminotransferase no fígado. Além disso, nos grupos treinados, o protocolo de exercício melhorou a imunodensidade de insulina nas ilhotas, reduziu os níveis de citocinas inflamatórias, adiposidade e esteatose hepática. O treinamento de alta intensidade melhorou a beta-oxidação e os níveis de receptores ativados por proliferador de peroxissomo (PPAR)-alfa e reduziu os níveis de lipogênese e de PPAR-gama no fígado. No músculo esquelético, o treinamento de alta intensidade também melhorou o PPAR-alfa e transportador de glicose (GLUT) -4 e reduziu os níveis de PPAR-gama. Esses achados reforçam a noção de que o treinamento de alta intensidade é relevante como uma abordagem não farmacológica para controlar a resistência à insulina, glicemia, e esteatose hepática. Em conclusão, treinamento de alta intensidade leva à perda de massa corporal e pode atenuar os efeitos adversos causados pela ingestão crônica de uma dieta rica em gordura. Apesar de uma ingestão contínua dessa dieta, o treinamento de alta intensidade melhora as enzimas hepáticas e o perfil inflamatório.

Compact three-dimensional silicon termination solutions for high voltage SOI SuperJunction

This paper demonstrates and discusses novel "three dimensional" silicon based junction isolation/termination solutions suitable for high density ultra-low-resistance Lateral Super-Junction structures. The proposed designs are both compact and effective in safely distributing the electrostatic potential away from the active device area. The designs are based on the utilization of existing layers in the device fabrication line, hence resulting in no extra complexity or cost increase. The study/demonstration is done through extensive experimental measurements and numerical simulations. © 2012 IEEE.

Application of gel-casting to the fabrication of 1-3 piezoelectric ceramic-polymer composites for high-frequency ultrasound devices

A modified gel-casting technique was used to fabricate a 1-3 piezoelectric ceramic/polymer composite substrate formed by irregular-shaped pillar arrays of small dimensions and kerfs. This technique involves the polymerization of aqueous piezoelectric (PZT) suspensions with added water-soluble epoxy resin and polyamine-based hardener that lead to high strength, high density and resilient ceramic bodies. Soft micromoulding was used to shape the ceramic segments, and micropillars with lateral features down to 4 m and height-to-width aspect ratios of ∼10 were achieved. The composite exhibited a clear thickness resonance mode at approximately 70 MHz and a k eff ∼ 0.51, demonstrating that the ceramic micropillars possess good electrical properties. Furthermore, gel-casting allows the fabrication of ceramic structures with non-conventional shapes; hence, device design is not limited by the standard fabrication methods. This is of particular benefit for high-frequency transducers where the critical design dimensions are reduced. © 2012 IOP Publishing Ltd.

High-power quantum-dot superluminescent LED with broadband drive current insensitive emission spectra using a tapered active region

High-power and broadband quantum-dot (QD) superluminescent light-emitting diodes are realized by using a combination of self-assembled QDs with a high density, large inhomogeneous broadening, a tapered angled pump region, and etched V groove structure. This broad-area device exhibits greater than 70-nm 3-dB bandwidth and drive current insensitive emission spectra with 100-mW output power under continuous-wave operation. For pulsed operation, greater than 200-mW output power is obtained.

Silicon doping induced increment of quantum dot density

Low-indium-content self-assembled InGaAs/GaAs quantum dots (SAQD) were grown using solid-source molecular beam epitaxy (MBE) and investigated by atomic force microscopy and photoluminescence (PL) spectroscopy. Silicon, which was doped at different quantum dot (QD) growth stages, markedly increased the density of QD. We obtained high density In0.35Ga0.65As/GaAs(001) quantum dots of 10(11)/cm(2) at a growth temperature of 520degreesC. PL spectra and distribution statistics show the high quality and uniformity of our silicon-doped samples. The density increment can be explained using the lattice-hardening mechanism due to silicon doping.

Structural and optical characterization of InAs nanostructures grown on (001) and high index InP substrates

The effects of InP substrate orientations on self-assembled InAs quantum dots (QDs) have been investigated by molecular beam epitaxy (MBE). A comparison between atomic force microscopy (AFM) and photoluminescence (PL) spectra shows that a high density of smaller InAs islands can be obtained by using such high index substrates. On the other hand, by introducing a lattice-matched underlying In0.52Al0.24Ga0.24As layer, the InAs QDs can be much more uniform in size and have a great improvement in PL properties. More importantly, 1.55-mu m luminescence at room temperature (RT) can be realized in InAs QDs deposited on (001) InP substrate with underlying In0.52Al0.24Ga0.24As layer. (C) 2000 Elsevier Science B.V. All rights reserved.

Temperature dependent photoluminescence of an In(Ga)As/GaAs quantum dot system with different areal density

We have systematically studied the temperature dependent photoluminescence of a self-assembled In(Ga)As/GaAs quantum dot (QD) system with different areal densities from similar to 10(9) to similar to 10(11) cm(-2). Different carrier channels are revealed experimentally and confirmed theoretically via a modified carrier equation model considering a new carrier transfer channel, i.e. continuum states ( CS). The wetting layer is demonstrated to be the carrier quenching channel for the low-density QDs but the carrier transfer channel for the high-density QDs. In particular, for the InGaAs/GaAs QDs with a medium density of similar to 10(10) cm(-2), the CS is verified to be an additional carrier transfer channel in the low temperature regime of 10-60 K, which is studied in detail via our models. The possible carrier channels that act on different temperature regimes are further discussed, and it is demonstrated that density is not a crucial factor in determining the carrier lateral coupling strength.

NEW TYPE OF SILICON MATERIAL WITH VERY HIGH-QUALITY SURFACE-LAYER ON INSULATING DEFECT LAYER

A new-type silicon material, silicon on defect layer (SODL) was proved to have a very high quality surface microstructure which is necessary for commercially feasible high-density very large scale integrated circuits (VLSI). The structure of the SODL material was viewed by transmission electron microscopy. The SODL material was also proved to have a buried defect layer with an insulating resistivity of 5.7 x 10(10) OMEGA-cm.

Aggregation and precipitation in high dose as ion implanted Ge0.5Si0.5 alloy

Thermally stimulated redistribution and precipitation of excess arsenic in Ge0.5Si0.5 alloy has been studied by X-ray photoelectron spectroscopy (XPS), cross sectional transmission electron microscopy (XTEM) and X-ray energy disperse spectrometry (EDS). Samples were prepared by the implantation of 6 X 10(6) As+ cm(-2) and 100 keV with subsequent thermal processing at 800 degrees C and 1000 degrees C for 1 h. The XPS depth profiles from the implanted samples before and after the thermal annealing indicate that there is marked redistribution of the elements in heavily arsenic-implanted Ge0.5Si0.5 alloys during the annealing, including: (1) diffusion of As from the implanted region to the surface; (2) aggregation of Ge in the vicinity of the surface. A high density of precipitates was observed near the surface which were by XTEM and EDS identified as an arsenide. It is suggested that most of the implanted As in Ge0.5Si0.5 alloy exists in the form of GeAs.

Surface Initiated Polymerization from Substrates of Low Initiator Density and Its Applications in Biosensors

Surface initiated polymerization (SIP) has become an attractive method for tailoring physical and chemical properties of surfaces for a broad range of applications. Most of those application relied on the merit of a high density coating. In this study we explored a long overlooked field of SIP. SIP from substrates of low initiator density. We combined ellipsometry with AFM to investigate the effect of initiatior density and polymerization time on the morphology of polymer coatings. In addition, we carefully adjusted the nanoscale separation of polymer chains to achieve a balance between nonfouling and immobilization capacities. We further tested the performance of those coating on various biosensors, such as quartz crystal microbalance, surface plasmon resonance, and protein microarrays. The optimized matrices enhanced the performance of those biosensors. This report shall encourage researches to explore new frontiers in SIP that go beyond polymer brushes.

DETERMINING THE DENSITY DEPENDENCE OF THE NUCLEAR SYMMETRY ENERGY USING HEAVY-ION REACTIONS

We review recent progress in the determination of the subsaturation density behavior of the nuclear symmetry energy from heavy-ion collisions as well as the theoretical progress in probing the high density behavior of the symmetry energy in heavy-ion reactions induced by high energy radioactive beams. We further discuss the implications of these results for the nuclear effective interactions and the neutron skin thickness of heavy nuclei.

Biomolecule-nanoparticle hybrids for electrochemical biosensors

Inorganic nanoparticles (NPs) with attractive electronic, optical, magnetic, thermal and catalytic properties have attracted great interest due to their important applications in physics, chemistry, biology, medicine, materials science and interdisciplinary fields. Biomolecule-NP hybrid systems, which combine recognition and catalytic properties of biomolecules with electronic, optical, magnetic and catalytic properties of NPs, are particularly new materials with synergistic properties originating from the components of the hybrid composites. The biomolecule-NP hybrid system has excellent prospects for interfacing biological recognition events with electronic signal transduction so as to design a new generation of bioelectronic devices with high sensitivity.