RESUMO
The production of reactive oxygen species (ROS), such as hydroxyl radicals, by ultrasonic activation of semiconductor nanoparticles (NPs), including TiO2, has excellent potential for use in sonodynamic therapy and for the sonocatalytic degradation of pollutants. However, TiO2 NPs have limitations including low yields of generated ROS that result from fast electron-hole recombination. In this study, we first investigated the sonocatalytic activity of TiO2-supported Au nanoclusters (NCs) (Au NCs/TiO2) by monitoring the production of hydroxyl radicals (â¢OH) under ultrasonication conditions. The deposition of Au144 NCs on TiO2 NPs was found to enhance sonocatalytic activity for â¢OH production by approximately a factor of 2. Electron-hole recombination in ultrasonically excited TiO2 NPs is suppressed by Au144 NCs acting as an electron trap; this charge separation resulted in enhanced â¢OH production. In contrast, the deposition of Au25 NCs on TiO2 NPs resulted in lower sonocatalytic activity due to less charge separation, which highlights the effectiveness of combining Au144 NCs with TiO2 NPs for enhancing sonocatalytic activity. The sonocatalytic action that forms electron-hole pairs on the Au144/TiO2 catalyst is due to both heat and sonoluminescence from the implosive collapse of cavitation bubbles. Consequently, the ultrasonically excited Au144 (3 wt. %)/TiO2 catalyst exhibited higher catalytic activity for the production of â¢OH because of less light shadowing effect, in contrast to the lower catalytic activity when irradiated with only external light.
Assuntos
Nanopartículas/química , Titânio/química , Catálise , Elétrons , Espécies Reativas de Oxigênio/síntese química , Espécies Reativas de Oxigênio/químicaRESUMO
Developing multifunctional nanomaterials with chemodynamic therapy (CDT)-based combination therapy has increasingly become a promising strategy for cancer treatment. Herein, a metal-phenolic network-based multifunctional nanocomposite (PID@Fe-TA) via the noncovalent interaction of multiple nontoxic raw materials has been designed to integrate the synergistic effect of CDT, photothermal therapy (PTT) and chemotherapy into one nanoplatform for breast cancer treatment. Benefiting from the pH-responsive properties and the assistance of near infrared (NIR) laser irradiation, the outer shell Fe3+-tannic acid (TA) complexes of PID@Fe-TA can be easily degraded into Fe3+ and TA as well as to release chemotherapeutic drugs (doxorubicin, DOX) and photothermal transforming agents (indocyanine green, ICG) in a tumor microenvironment (TME) or cancer cells. The released TA can accelerate the reduction of Fe3+ to Fe2+ for ensuring effective conversion of hydrogen peroxide (H2O2) into a highly toxic hydroxyl radical (ËOH) via the Fenton reaction. The exposed DOX can enter the cell nucleus to induce chemotherapy. The released ICG can locate the distribution of nanocomposites in the body. Besides, the heat generated from PID@Fe-TA after NIR laser irradiation can further promote the therapeutic effect of PPT-enhanced CDT. Importantly, an excellent therapeutic efficacy is achieved both in in vitro and in vivo via the CDT/PTT/chemotherapy combination based on this "all-in-one" nanoplatform, providing a good paradigm for effective cancer eradication.
Assuntos
Neoplasias da Mama/terapia , Terapia Combinada/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Nanocompostos/química , Espécies Reativas de Oxigênio/síntese química , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Tratamento Farmacológico/métodos , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Metais/química , Fenóis/química , Fototerapia/métodosRESUMO
Currently, due to the HIV latency mechanism, the search continues for effective drugs to combat this issue and provide a cure for AIDS. Gnidimacrin activates latent HIV-1 replication and inhibits HIV-1 infection at picomolar concentrations. This natural diterpene was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells. Therefore, gnidimacrin is an excellent lead compound, and its anti-HIV potential merits further investigation. Twenty-nine modified gnidimacrin derivatives were synthesized and evaluated in assays for HIV replication and latency activation to establish which molecular structures must be maintained and which can tolerate changes that may be needed for better pharmacological properties. The results indicated that hydroxyl substituents at C-5 and C-20 are essential, while derivatives modified at 3-OH with aromatic esters retain anti-HIV replication and latent activation activities. The half-lives of the potent GM derivatives are over 20 h, which implies that they are stable in the plasm even though they contain ester linkages. The established structure-activity relationship should be useful in the development of gnidimacrin or structurally related compounds as clinical trial candidates.
Assuntos
Fármacos Anti-HIV/síntese química , Diterpenos/síntese química , HIV-1/efeitos dos fármacos , Extratos Vegetais/síntese química , Latência Viral/efeitos dos fármacos , Animais , Fármacos Anti-HIV/farmacologia , Diterpenos/farmacologia , HIV-1/fisiologia , Humanos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Raízes de Plantas , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/síntese química , Espécies Reativas de Oxigênio/farmacologia , Relação Estrutura-Atividade , Latência Viral/fisiologiaRESUMO
Developing anti-melanoma agents with increased activity and specificity is highly desirable due to the increasing incidence, highly metastatic malignancy, and high mortality rate of melanoma. Abnormal redox characteristics such as higher levels of tyrosinase, NAD(P)H: quinone oxidoreductase-1 (NQO1) and reactive oxygen species (ROS) observed in melanoma cells than in other cancer cells and normal cells illustrate their redox vulnerability and have opened a window for developing prooxidative anti-melanoma agents (PAAs) to target the vulnerability. However, how to design PAAs which promote selectively the ROS accumulation in melanoma cells remains a challenge. This work describes a promising redox cycle-based strategy for designing a catechol-type diphenylbutadiene as such type of PAA. This molecule is capable of constructing an efficient catalytic redox cycle with tyrosinase and NQO1 in melanoma B16F1 cells to induce selectively the ROS (mainly including hydrogen peroxide, H2O2) accumulation in the cells, resulting in highly selective suppression of melanoma B16F1 cells over tyrosinase-deficient HeLa and normal L-02 cells.
Assuntos
Butadienos/farmacologia , Catecóis/química , Melanoma Experimental/tratamento farmacológico , Espécies Reativas de Oxigênio/farmacologia , Animais , Butadienos/síntese química , Butadienos/química , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanoma Experimental/patologia , Camundongos , Monofenol Mono-Oxigenase/genética , NAD(P)H Desidrogenase (Quinona)/genética , Metástase Neoplásica , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/síntese química , Espécies Reativas de Oxigênio/químicaRESUMO
INTRODUCTION: Lung ischemia-reperfusion injury after thoracoabdominal aortic occlusion represents a major complication, which increases morbidity and mortality. In the present study we hypothesized that lazaroid U-74389G intravenous administration protects from lung ischemia-reperfusion injury through lipid peroxidation inhibition. MATERIALS AND METHODS: A total of 24 pigs were randomized in three groups. Group I (nâ¯=â¯8) underwent sham operation, group II (nâ¯=â¯8) underwent thoracoabdominal aortic occlusion for 45min and received placebo and group III (nâ¯=â¯8) received 3 doses of lazaroid (3â¯mg/kg) 60 and 30min before thoracoabdominal aortic occlusion and at 30min during thoracoabdominal aortic occlusion (duration 45min). Aortic occlusion was performed with aortic balloon-catheters under fluoroscopic guidance. All animals were sacrificed at the 7â¯tâ¯h postoperative day and lung specimens were harvested for molecular analysis. RESULTS: mRNA levels of leukotrienes LB4 (LTB4R2), LC4 (LTC4S) and nitric oxide synthase (NOS) isoforms including iNOS, nNOS and eNOS were determined with real-time RT-qPCR. Nitric oxide can either induce (iNOS) or inhibit (nNOS and eNOS) lipid peroxidation based on its specific isoform origin. Group III showed significantly reduced mRNA levels of LTB4R2 (-63.7%), LTC4S (-35.9%) and iNOS (-60.2%) when compared with group II (P < 0.05, for all). The mRNA levels of nNOS was significantly increased (+37.4%), while eNOS was slightly increased (+2.1%) in group III when compared with group II (P < 0.05 and P = 0.467 respectively). CONCLUSION: Lazaroid U-74389G may represent an effective pharmacologic intervention in reducing lung ischemia-reperfusion injury following thoracoabdominal aortic occlusion.
Assuntos
Antioxidantes/farmacologia , Arteriopatias Oclusivas/complicações , Lesão Pulmonar/tratamento farmacológico , Pregnatrienos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Aorta Torácica , Arteriopatias Oclusivas/metabolismo , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Masculino , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/síntese química , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , SuínosRESUMO
Interfacing photosynthetic proteins specifically photosystem 1 (PS1) with electrodes enables light-induced charge separation processes for powering semiartificial photobiodevices with, however, limited long-term stability. Here, we present the in-depth evaluation of a PS1/Os-complex-modified redox polymer-based biocathode by means of scanning photoelectrochemical microscopy. Focalized local illumination of the bioelectrode and concomitant collection of H2O2 at the closely positioned microelectrode provide evidence for the formation of partially reduced oxygen species under light conditions. Long-term evaluation of the photocathode at different O2 concentrations as well as after incorporating catalase and superoxide dismutase reveals the particularly challenging issue of avoiding the generation of reactive species. Moreover, the evaluation of films prepared with inactivated PS1 and free chlorophyll points out additional possible pathways for the generation of oxygen radicals. To avoid degradation of PS1 during illumination and hence to enhance the long-term stability, the operation of biophotocathodes under anaerobic conditions is indispensable.
Assuntos
Clorofila/química , Oxigênio/química , Complexo de Proteína do Fotossistema I/química , Espécies Reativas de Oxigênio/síntese química , Proteínas de Bactérias/química , Técnicas Eletroquímicas/métodos , Espectroscopia de Ressonância de Spin Eletrônica , Luz/efeitos adversos , Microeletrodos , Oxirredução , Polímeros/química , Proteólise/efeitos da radiaçãoRESUMO
The phototransformation and environmental implications of graphene oxide (GO) have been widely studied in order to understand its implications upon release into the environment. However, very little is known about the formation of reactive oxygen species (ROS) by GO under solar irradiation. Currently there are no studies on the mechanism of ROS formation by GO or the amount of ROS catalyzed by the nanomaterials in the environment. In this study, we carefully investigated the different types and formation mechanisms of ROS generated by GO in the presence of simulated solar irradiation. The effect of GO's photoactivity on bisphenol A (BPA), a representative organic co-pollutant, was also studied. The conduction band electron (eaq-) of GO led to the formation of different ROS including OH, O2-, and 1O2. Among the three types of ROS investigated, O2- was the most abundant species generated during simulated solar irradiation of GO. BPA was degraded, mainly due to the oxidative potential of the valence band holes produced during solar irradiation of GO. This study advances understanding of the photoactivity of GO and its potential impact on other possible environmental co-pollutants.
Assuntos
Compostos Benzidrílicos/química , Grafite/química , Óxidos/química , Fenóis/química , Espécies Reativas de Oxigênio/síntese química , Água/química , Catálise , Poluentes Ambientais/efeitos da radiação , Grafite/efeitos da radiação , Nanoestruturas/química , Oxirredução , Óxidos/efeitos da radiaçãoRESUMO
Ruthenium polypyridine complexes have shown promise as agents for photodynamic therapy (PDT) and tools for molecular biology (chromophore-assisted light inactivation). To accomplish these tasks, it is important to have at least target selectivity and great reactive oxygen species (ROS) photogeneration: two properties that are not easily found in the same molecule. To prepare such new agents, we synthesized two new ruthenium complexes that combine an efficient DNA binding moiety (dppz ligand) together with naphthyl-modified (1) and anthracenyl-modified (2) bipyridine as a strong ROS generator bound to a ruthenium complex. The compounds were fully characterized and their photophysical and photochemical properties investigated. Compound 2 showed one of the highest quantum yields for singlet oxygen production ever reported (ΦΔ= 0.96), along with very high DNA binding (log Kb = 6.78). Such photochemical behavior could be ascribed to the lower triplet state involving the anthracenyl-modified bipyridine, which is associated with easier oxygen quenching. In addition, the compounds exhibited moderate selectivity toward G-quadruplex DNA and binding to the minor groove of DNA, most likely driven by the pendant ligands. Interestingly, they also showed DNA photocleavage activity even upon exposure to a yellow light-emitting diode (LED). Regarding their biological activity, the compounds exhibited an exciting antibacterial action, particularly against Gram-positive bacteria, which was enhanced upon blue LED irradiation. Altogether, these results showed that our strategy succeeded in producing light-triggered DNA binding agents with pharmacological and biotechnological potential.
Assuntos
Complexos de Coordenação/farmacologia , DNA/química , Substâncias Intercalantes/farmacologia , Rutênio/química , 2,2'-Dipiridil/síntese química , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacologia , 2,2'-Dipiridil/efeitos da radiação , Antracenos/síntese química , Antracenos/química , Antracenos/farmacologia , Antracenos/efeitos da radiação , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/efeitos da radiação , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Dano ao DNA , Etídio/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/efeitos da radiação , Ligantes , Luz , Oxigênio/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/efeitos da radiação , Espécies Reativas de Oxigênio/síntese químicaRESUMO
It is demonstrated that carboxylic acid-functionalized titanium dioxide (TiO2) NPs produce significantly higher levels of reactive oxygen species (ROS) after visible light irradiation (400-800nm, 1600mW/cm2) in comparison to nonfunctionalized TiO2 NPs. The level of ROS produced under these irradiation conditions was not capable of generating oxidatively induced DNA damage in a cell-free system for TiO2 concentrations of 0.5mg/L or 5mg/L. In addition, specific incorporation of the acrylic acid-functionalized TiO2 NPs into dental composites allowed us to utilize the generated ROS to enhance photopolymerization (curing and degree of vinyl conversion (DC)) of resin adhesives and create mechanically superior and biocompatible materials for dental applications. Incorporation of the TiO2 NPs into selected dental composites increased the mean DC values by ≈7%. The modified TiO2 materials and dental composite materials were extensively characterized using thermogravimetric analysis, electron microscopy, Fourier transform infrared spectroscopy, and electron paramagnetic resonance. Notably, dental adhesives incorporated with acrylic acid-functionalized TiO2 NPs produced stronger bonds to human teeth following visible light curing in comparison to traditional dental adhesives not containing NPs with an increase in the shear bond strength of ≈29%. In addition, no leaching of the incorporated NPs was detectable from the dental adhesives after 2500 thermal cycles using inductively coupled plasma-optical emission spectroscopy, indicating that biocompatibility of the adhesives was not compromised after extensive aging. These findings suggest that NP-induced ROS may be useful to produce enhanced nanocomposite materials for selected applications in the medical device field. STATEMENT OF SIGNIFICANCE: Titanium dioxide nanoparticles (TiO2 NPs) have unique photocatalytic, antibacterial and UV-absorbing properties that make them beneficial additives in adhesives and composites. However, there is concern that the reactive oxygen species (ROS) produced by photoactivated TiO2 NPs might pose toxicological risks. We demonstrate that it is possible to incorporate acid-functionalized TiO2 NPs into dental resins which can be applied as dental adhesives to human teeth. The ROS generated by these NPs through visible-light irradiation may be utilized to increase the degree of vinyl conversion of resins, leading to adhesives that have an enhanced shear-bond strength to human teeth. Investigation into the potential genotoxicity of the NPs and their potential for release from dental composites indicated a low risk of genotoxic effects.
Assuntos
Cimentos Dentários/química , Cura Luminosa de Adesivos Dentários/métodos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Espécies Reativas de Oxigênio/síntese química , Titânio/química , Dente/química , Adesividade , Cimentos Dentários/efeitos da radiação , Dureza , Luz , Teste de Materiais , Tamanho da PartículaRESUMO
The synthesis of a small library of CR-6 (a potent ROS and RNS scavenger agent) derivatives bearing covalent linkage with different endogen nutrients that have specific transport through the blood-brain barrier (BBB) is reported. The synthetic sequence involved the preparation of a common precursor ester 6 derived from CR-6, which was easily converted into the carboxylic acid 7a or the amino derivative 11, for its further coupling with the required substrates through amide bonds. Antioxidant in vitro (DPPH) and cellular assays (CAA) with the SH-S5SY cell line performed on these library members revealed that the couplings did not affect the antioxidant activity elicited by CR-6 itself. More interestingly, results from the intraperitoneal administration of selected library components in rats showed that compounds 2b, 2c and 2d were able to pass across the BBB. In particular, the amino acid compound 2d was the most penetrating derivative (15.8 ± 1.7 nmol/g brain with respect to the 4.0 ± 1.2 nmol/g brain found for the parent CR-6).
Assuntos
Barreira Hematoencefálica/metabolismo , Espécies Reativas de Nitrogênio/química , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo , Animais , Transporte Biológico , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Masculino , Permeabilidade , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Nitrogênio/síntese química , Espécies Reativas de Oxigênio/síntese químicaRESUMO
Proton-pumping NADH:ubiquinone oxidoreductase (complex I) is the largest and most complicated enzyme of the respiratory chain. Fourteen central subunits represent the minimal form of complex I and can be assigned to functional modules for NADH oxidation, ubiquinone reduction, and proton pumping. In addition, the mitochondrial enzyme comprises some 30 accessory subunits surrounding the central subunits that are not directly associated with energy conservation. Complex I is known to release deleterious oxygen radicals (ROS) and its dysfunction has been linked to a number of hereditary and degenerative diseases. We here review recent progress in structure determination, and in understanding the role of accessory subunits and functional analysis of mitochondrial complex I. For the central subunits, structures provide insight into the arrangement of functional modules including the substrate binding sites, redox-centers and putative proton channels and pump sites. Only for two of the accessory subunits, detailed structures are available. Nevertheless, many of them could be localized in the overall structure of complex I, but most of these assignments have to be considered tentative. Strikingly, redox reactions and proton pumping machinery are spatially completely separated and the site of reduction for the hydrophobic substrate ubiquinone is found deeply buried in the hydrophilic domain of the complex. The X-ray structure of complex I from Yarrowia lipolytica provides clues supporting the previously proposed two-state stabilization change mechanism, in which ubiquinone redox chemistry induces conformational states and thereby drives proton pumping. The same structural rearrangements may explain the active/deactive transition of complex I implying an integrated mechanistic model for energy conversion and regulation. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.
Assuntos
Complexo I de Transporte de Elétrons/química , Complexo I de Transporte de Elétrons/ultraestrutura , Proteínas Mitocondriais/química , Proteínas Mitocondriais/ultraestrutura , Bombas de Próton/química , Espécies Reativas de Oxigênio/síntese química , Sequência de Aminoácidos , Transporte de Elétrons , Ativação Enzimática , Modelos Químicos , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Oxirredução , Conformação Proteica , Estrutura Terciária de Proteína , Bombas de Próton/ultraestrutura , Relação Estrutura-AtividadeRESUMO
Alcoholic liver disease (ALD) develops in approximately 20% of alcoholic patients, with a higher prevalence in females. ALD progression is marked by fatty liver and hepatocyte necrosis, as well as apoptosis, inflammation, regenerating nodules, fibrosis, and cirrhosis.(1) ALD develops via a complex process involving parenchymal and nonparenchymal cells, as well as recruitment of other cell types to the liver in response to damage and inflammation. Hepatocytes are damaged by ethanol, via generation of reactive oxygen species and induction of endoplasmic reticulum stress and mitochondrial dysfunction. Hepatocyte cell death via apoptosis and necrosis are markers of ethanol-induced liver injury. We review the mechanisms by which alcohol injures hepatocytes and the response of hepatic sinusoidal cells to alcohol-induced injury. We also discuss how recent insights into the pathogenesis of ALD will affect the treatment and management of patients.
Assuntos
Etanol/efeitos adversos , Hepatócitos/efeitos dos fármacos , Hepatopatias Alcoólicas/etiologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Fígado/citologia , Fígado/fisiopatologia , Hepatopatias Alcoólicas/fisiopatologia , Masculino , Fenótipo , Espécies Reativas de Oxigênio/síntese químicaRESUMO
This review discusses the functional properties of mitochondrial Complex I originating from its presence in an assembled form as a supercomplex comprising Complex III and Complex IV in stoichiometric ratios. In particular several lines of evidence are presented favouring the concept that electron transfer from Complex I to Complex III is operated by channelling of electrons through Coenzyme Q molecules bound to the supercomplex, in contrast with the hypothesis that the transfer of reducing equivalents from Complex I to Complex III occurs via random diffusion of the Coenzyme Q molecules in the lipid bilayer. Furthermore, another property provided by the supercomplex assembly is the control of generation of reactive oxygen species by Complex I. This article is part of a Special Issue entitled Respiratory Complex I, edited by Volker Zickermann and Ulrich Brandt.
Assuntos
Complexo I de Transporte de Elétrons/química , Complexo I de Transporte de Elétrons/metabolismo , Mitocôndrias/enzimologia , Espécies Reativas de Oxigênio/síntese química , Ubiquinona/química , Ubiquinona/metabolismo , Animais , Transporte de Elétrons , Complexo I de Transporte de Elétrons/ultraestrutura , Ativação Enzimática , Humanos , Modelos Químicos , Simulação de Dinâmica Molecular , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/ultraestrutura , Oxirredução , Conformação Proteica , Bombas de Próton/química , Bombas de Próton/ultraestrutura , Relação Estrutura-Atividade , Ubiquinona/ultraestruturaRESUMO
Complex I (NADH:ubiquinone oxidoreductase) is critical for respiration in mammalian mitochondria. It oxidizes NADH produced by the Krebs' tricarboxylic acid cycle and ß-oxidation of fatty acids, reduces ubiquinone, and transports protons to contribute to the proton-motive force across the inner membrane. Complex I is also a significant contributor to cellular oxidative stress. In complex I, NADH oxidation by a flavin mononucleotide, followed by intramolecular electron transfer along a chain of iron-sulfur clusters, delivers electrons and energy to bound ubiquinone. Either at cluster N2 (the terminal cluster in the chain) or upon the binding/reduction/dissociation of ubiquinone/ubiquinol, energy from the redox process is captured to initiate long-range energy transfer through the complex and drive proton translocation. This review focuses on current knowledge of how the redox reaction and proton transfer are coupled, with particular emphasis on the formation and role of semiquinone intermediates in both energy transduction and reactive oxygen species production. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.
Assuntos
Complexo I de Transporte de Elétrons/química , Complexo I de Transporte de Elétrons/ultraestrutura , Transferência de Energia , NAD/química , Espécies Reativas de Oxigênio/síntese química , Ubiquinona/química , Sítios de Ligação , Catálise , Transporte de Elétrons , Ativação Enzimática , Modelos Químicos , Simulação de Dinâmica Molecular , NAD/ultraestrutura , Oxirredução , Ligação Proteica , Conformação Proteica , Ubiquinona/ultraestruturaRESUMO
Parkinson's disease (PD) is a common neurodegenerative disease characterized by a substantial decrease of dopaminergic neurons in the substantia nigra pars compacta. The neurological deterioration during PD can be, in part, attributed to elevated levels of reactive oxygen species (ROS). Radical scavengers have previously been shown to protect dopaminergic cells from toxic effects in vitro. Hence, new approaches need to be investigated to improve the administration of antioxidants in order to provide neuroprotection. Polymers exhibiting catechol structures offer one such approach due to their interesting physicochemical properties. In the present study a photocrosslinkable dopamine-containing poly(ß-amino ester) (DPAE) was synthesized from poly(ethylene glycol) diacrylate (PEGDA) and dopamine hydrochloride using Michael type addition. A water-in-oil emulsion technique was used to photo-crosslink the polymer into spherical microparticles. DPAE microspheres featured excellent scavenging properties towards 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) radicals in a dose dependent manner and could even reduce the dissolved oxygen content of physiological solution. Furthermore, the concentrations required for radical scavenging were shown to be non-toxic towards dopaminergic SH-SY5Y cells as well as primary astrocytes and primary embryonic rat ventral midbrain cultures.
Assuntos
Sequestradores de Radicais Livres/química , Doenças Neurodegenerativas/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/síntese química , Animais , Compostos de Bifenilo/química , Dopamina , Humanos , Doença de Parkinson/patologia , Picratos/química , Polietilenoglicóis/farmacologia , Polímeros , Ratos , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/farmacologiaRESUMO
Molecular modeling and molecular dynamics simulations play an important role in the functional characterization of complex I. With its large size and complicated function, linking quinone reduction to proton pumping across a membrane, complex I poses unique modeling challenges. Nonetheless, simulations have already helped in the identification of possible proton transfer pathways. Simulations have also shed light on the coupling between electron and proton transfer, thus pointing the way in the search for the mechanistic principles underlying the proton pump. In addition to reviewing what has already been achieved in complex I modeling, we aim here to identify pressing issues and to provide guidance for future research to harness the power of modeling in the functional characterization of complex I. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.
Assuntos
Complexo I de Transporte de Elétrons/química , Complexo I de Transporte de Elétrons/ultraestrutura , Modelos Químicos , Simulação de Dinâmica Molecular , Bombas de Próton/química , Bombas de Próton/ultraestrutura , Transporte de Elétrons , Ativação Enzimática , Oxirredução , Conformação Proteica , Espécies Reativas de Oxigênio/síntese químicaRESUMO
Photodynamic therapy (PDT) is based on the dye-sensitized photooxidation of biological matter in the target tissue, and utilizes light activated drugs for the treatment of a wide variety of malignancies. Quinones and porphyrins moiety are available naturally and involved in the biological process. Quinone metabolites perform a variety of key functions in plants which includes pathogen protection, oxidative phosphorylation, and redox signaling. Quinones and porphyrin are biologically accessible and will not create any allergic effects. In the field of photodynamic therapy, porphyrin derivatives are widely used, because it absorb in the photodynamic therapy window region (600-900 nm). Hence, researchers synthesize drugs based on porphyrin structure. Benzoquinone and its simple polycyclic derivatives such as naphthaquinone and anthraquinones absorb at lower wavelength region (300-400 nm), which is lower than porphyrin. Hence they are not involved in PDT studies. However, higher polycyclic quinones absorb in the photodynamic therapy window region (600-900 nm), because of its conjugation and can be used as PDT agents. Redox cycling has been proposed as a possible mechanism of action for many quinone species. Quinones are involved in the photodynamic as well as enzymatic generation of reactive oxygen species (ROS). Generations of ROS may be measured by optical, phosphorescence and EPR methods. The photodynamically generated ROS are also involved in many biological events. The photo-induced DNA cleavage by quinones correlates with the ROS generating efficiencies of the quinones. In this review basic reactions involving photodynamic generation of ROS by quinones and their biological applications were discussed.
Assuntos
Espectroscopia de Ressonância de Spin Eletrônica/métodos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Quinonas/química , Espécies Reativas de Oxigênio/síntese química , Espectrometria de Fluorescência/métodos , Hidróxidos/síntese química , Hidróxidos/efeitos da radiação , Luz , Fármacos Fotossensibilizantes/efeitos da radiação , Quinonas/administração & dosagem , Quinonas/efeitos da radiação , Espécies Reativas de Oxigênio/efeitos da radiação , Oxigênio Singlete/química , Oxigênio Singlete/efeitos da radiação , Superóxidos/síntese química , Superóxidos/efeitos da radiaçãoRESUMO
Respiratory complex I couples NADH:quinone oxidoreduction to ion translocation across the membrane, contributing to the buildup of the transmembrane difference of electrochemical potential. H(+) is well recognized to be the coupling ion of this system but some studies suggested that this role could be also performed by Na(+). We have previously observed NADH-driven Na(+) transport opposite to H(+) translocation by menaquinone-reducing complexes I, which indicated a Na(+)/H(+) antiporter activity in these systems. Such activity was also observed for the ubiquinone-reducing mitochondrial complex I in its deactive form. The relation of Na(+) with complex I may not be surprising since the enzyme has three subunits structurally homologous to bona fide Na(+)/H(+) antiporters and translocation of H(+) and Na(+) ions has been described for members of most types of ion pumps and transporters. Moreover, no clearly distinguishable motifs for the binding of H(+) or Na(+) have been recognized yet. We noticed that in menaquinone-reducing complexes I, less energy is available for ion translocation, compared to ubiquinone-reducing complexes I. Therefore, we hypothesized that menaquinone-reducing complexes I perform Na(+)/H(+) antiporter activity in order to achieve the stoichiometry of 4H(+)/2e(-). In agreement, the organisms that use ubiquinone, a high potential quinone, would have kept such Na(+)/H(+) antiporter activity, only operative under determined conditions. This would imply a physiological role(s) of complex I besides a simple "coupling" of a redox reaction and ion transport, which could account for the sophistication of this enzyme. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.
Assuntos
Complexo I de Transporte de Elétrons/química , Complexo I de Transporte de Elétrons/ultraestrutura , Bombas de Próton/química , Bombas de Próton/ultraestrutura , Sódio/química , Transporte de Elétrons , Ativação Enzimática , Modelos Químicos , Simulação de Dinâmica Molecular , Oxirredução , Conformação Proteica , Prótons , Espécies Reativas de Oxigênio/síntese químicaRESUMO
Kinetic characteristics of the proton-pumping NADH:quinone reductases (respiratory complexes I) are reviewed. Unsolved problems of the redox-linked proton translocation activities are outlined. The parameters of complex I-mediated superoxide/hydrogen peroxide generation are summarized, and the physiological significance of mitochondrial ROS production is discussed. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.
Assuntos
Complexo I de Transporte de Elétrons/química , Complexo I de Transporte de Elétrons/ultraestrutura , NAD/química , Bombas de Próton/química , Bombas de Próton/ultraestrutura , Espécies Reativas de Oxigênio/síntese química , Transporte de Elétrons , Ativação Enzimática , Modelos Químicos , Simulação de Dinâmica Molecular , NAD/ultraestrutura , Oxirredução , Conformação ProteicaRESUMO
Redox-dependent conformational changes are currently discussed to be a crucial part of the reaction mechanism of the respiratory complex I. Specialized difference Fourier transform infrared techniques allow the detection of side-chain movements and minute secondary structure changes. For complex I, (1)H/(2)H exchange kinetics of the amide modes revealed a better accessibility of the backbone in the presence of NADH and quinone. Interestingly, the presence of phospholipids, that is crucial for the catalytic activity of the isolated enzyme complex, changes the overall conformation. When comparing complex I samples from different species, very similar electrochemically induced FTIR difference spectra and very similar rearrangements are reported. Finally, the information obtained with variants and from Zn(2+) inhibited samples for the conformational reorganization of complex I upon electron transfer are discussed in this review. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.