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2.
J Phys Chem B ; 123(41): 8704-8716, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31532675

RESUMO

In this study, 2 groups of 10 modified ligand systems with modified P3 and P2 side chains are used to study the binding mechanism with thrombin. Experimental results show that the binding affinity is enhanced by complex ligand side chains. The binding free energy obtained from the polarized protein-specific charge (PPC) force field combined with the newly developed interaction entropy (IE) method is consistent with the experimental values with a high correlation coefficient. On the contrary, poor correlation is obtained using the traditional normal mode (Nmode) method for calculating the entropy change. Furthermore, the binding free energy and hot-spot residue energy are decomposed, and the common hot-spot residues in the two groups of systems are Trp50, Leu96, Ile179, Asp199, Cyx201, Ser226, Trp227, Gly228, and Gly230. The electrostatic and van der Waals interaction energies were found to be the main contributors in the binding energy difference. CH-π and CH-CH interactions of Leu96 ligands are significantly related to the energy change due to the modified side chain, and the hydrogen bond between Asp199 and the ligand provides a strong electrostatic interaction, contributing to the binding free energy. Investigating the B-factor, principal component, and binding pocket also explains the change in the binding affinity caused by the modified side chains in ligands from the viewpoint of conformational change. This study demonstrates that the new IE method is superior to the Nmode method in the predicting binding free energy and emphasizes the importance of electronic polarization in molecular dynamics simulation. Moreover, from the viewpoint of energy and structure analysis, this study reveals the origin of the change in binding free energy in modified ligands with different binding sites.

3.
Phys Chem Chem Phys ; 20(24): 16641-16649, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29873368

RESUMO

Fluorescent base analogues are of great importance as sensitive probes to detect the dynamic structures of DNA. In this research, the structural and photophysical properties of 13-mer oligonucleotides containing 4-aminophthalimide:2,4-diaminopyrimidine (4AP:DAP) (4AP0, 4AP') were characterized using both molecular dynamics simulations and quantum mechanics methods. The results indicate that the 4AP:DAP pair is well adapted to the overall B-DNA structure with higher stability and π-stacking abilities. The structural overlap of 4AP' and 4AP0 with the neighboring adenines only lies in the 5'-direction which results in the structure distortion from native B-DNA. Furthermore, the photophysical properties of the fluorescent base monomers and the B-DNA duplex were explored in detail. A very important result is that the hydrogen bond interaction does not have more effect on the fluorescence band apart from the slight red-shifts. In particular, the identity of the neighboring bases stacked with 4AP has an important effect on the fluorescence band. How the local environment can alter the photophysical features of the nucleobases when they are incorporated into the DNA duplex is elucidated.


Assuntos
DNA/química , Corantes Fluorescentes/química , Sondas Moleculares/química , Ftalimidas/química , Pirimidinas/química , Pareamento de Bases , DNA/genética , Fluorescência , Ligações de Hidrogênio , Simulação de Dinâmica Molecular , Sondas Moleculares/genética , Teoria Quântica
4.
Org Biomol Chem ; 16(21): 3952-3960, 2018 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-29749412

RESUMO

Ferroptosis is a non-apoptotic, iron dependent form of regulated cell death that is characterized by the accumulation of lipid hydroperoxides. It has drawn considerable attention owing to its putative involvement in diverse neurodegenerative diseases. Ferrostatins are the first identified inhibitors of ferroptosis and they inhibit ferroptosis by efficiently scavenging free radicals in lipid bilayers. However, their further medicinal application has been limited due to the deficient knowledge of the lipid peroxyl radical-trapping mechanism. In this study, experimental and theoretical methods were performed to illustrate the possible lipid hydroperoxide inhibition mechanism of ferrostatins. The results show that an ortho-amine (-NH) moiety from ferrostatins can simultaneously interact with lipid radicals, and then form a planar seven-membered ring in the transition state, and finally present greater reactivity. NBO analysis shows that the formed planar seven-membered ring forces ortho-amines into better alignment with the aromatic π-system. It significantly increases the magnitudes of amine conjugation and improves spin delocalization in the transition state. Additionally, a classical H-bond type interaction was discovered between a radical and an o-NH group as another transition state stabilizing effect. This type of radical-trapping mechanism is novel and has not been found in diphenylamine or traditional polyphenol antioxidants. It can be said that o-phenylenediamine is a privileged pharmacophore for the design and development of ferroptosis inhibitors.


Assuntos
Morte Celular/efeitos dos fármacos , Cicloexilaminas/farmacologia , Desenho de Drogas , Fenilenodiaminas/farmacologia , Antioxidantes/farmacologia , Depuradores de Radicais Livres , Humanos , Peróxidos Lipídicos/metabolismo , Peróxidos Lipídicos/farmacologia , Relação Estrutura-Atividade
5.
Phys Chem Chem Phys ; 19(20): 13153-13159, 2017 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-28489094

RESUMO

Ferroptosis is a recently discovered iron-dependent form of non-apoptotic cell death caused by the accumulation of membrane lipid peroxidation products, which is involved in various pathological conditions of the brain, kidney, liver and heart. A potent spiroquinoxalinamine derivative named liproxstatin-1 is discovered by high-throughput screening, which is able to suppress ferroptosis via lipid peroxide scavenging in vivo. Thus, molecular simulations, density functional theory (DFT) and variational transition-state theory with a small-curvature tunneling (SCT) coefficient are utilized to elucidate the detailed mechanisms of inactivation of a lipid peroxide radical by liproxstatin-1. H-atom abstracted from liproxstatin-1 by a CH3OO˙ radical occurs preferentially at the aromatic amine site (1'-NH) under thermodynamic and frontier molecular orbital analysis. The value of a calculated rate constant at 300 K is up to 6.38 × 103 M-1 S-1, indicating that the quantum tunneling effect is responsible for making a free radical trapping reaction more efficient by liproxstatin-1. The production of a liproxstatin-1 radical is easily regenerated to the active reduced form by ubiquinol in the body to avoid secondary damage by free radicals. A benzene ring and the higher HOMO energy are beneficial to enhance the lipid radical scavenging activity based on the structure-activity relationship study. Overall, the present results provide theoretical insights into the exploration of novel ferroptosis inhibitors.


Assuntos
Radicais Livres/química , Peróxidos Lipídicos/química , Quinoxalinas/química , Compostos de Espiro/química , Ferro/química , Ferro/metabolismo , Cinética , Simulação de Dinâmica Molecular , Fosfatidilcolinas/química , Teoria Quântica , Relação Estrutura-Atividade , Termodinâmica , Ubiquinona/análogos & derivados , Ubiquinona/química
6.
Inorg Chem ; 56(9): 5392-5401, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28414433

RESUMO

Recently, a new synthetic methodology of rhodium-catalyzed carboamination/cyclopropanation from the same starting materials at different reaction conditions has been reported. It provides an efficient strategy for the stereospecific formation of both carbon- and nitrogen-based functionalities across an alkene. Herein we carried out a detailed theoretical mechanistic exploration for the reactions to elucidate the switch between carboamination and cyclopropanation as well as the origin of the chemoselectivity. Instead of the experimentally proposed RhIII-RhI-RhIII catalytic mechanism, our results reveal that the RhIII-RhV-RhIII mechanism is much more favorable in the two reactions. The chemoselectivity is attributed to a combination of electronic and steric effects in the reductive elimination step. The interactions between alkene and the rhodacycle during the alkene migration insertion control the stereoselectivity in the carboamination reactions. The present results disclose a dual role of the methanol solvent in controlling the chemoselectivity.

7.
Dalton Trans ; 46(16): 5288-5296, 2017 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-28379232

RESUMO

Computational studies have been applied to gain insight into the mechanism of Pd(ii) catalyzed α-C-H functionalization of N-methoxy cinnamamide. The results show that the whole catalytic cycle proceeds via sequential six steps, including (i) catalyst Pd(t-BuNC)2 oxidation with O2, (ii) O-H deprotonation, (iii) t-BuNC migratory insertion to the Pd-C bond, (iv) acyl migration, (v) C-H activation and (vi) reductive elimination. The regioselectivity for different C-H activation sites depends on the coordination structures of α-C or ß-C to the palladium(ii) center. The coordination of α-C to the palladium(ii) center shows a regular planar quadrilateral structure, which is stable. However, the ß-C coordinating to the palladium(ii) center mainly exhibits a distorted quadrilateral structure, which is relatively unstable. Thus, the barrier of α-C-H activation is much lower than that of ß-C-H activation. The present results provide a deep understanding of the site-selectivity of C-H activation.

8.
Phys Chem Chem Phys ; 19(16): 10413-10426, 2017 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-28379245

RESUMO

The detailed formation mechanisms of C-ribonucleoside and N-ribonucleoside via the reaction of 2,4,6-triaminopyrimidine (TAP) with (d)-ribose in aqueous solution were explored using density functional theory (DFT). The calculations indicate that five isomers (α,ß-furanose, α,ß-pyranose and open-chain aldehyde) of (d)-ribose can exist in equilibrium in aqueous solution. In contrast to cyclic isomers, an open-chain aldehyde is most feasible to react with TAP. In general, the formation pathways of C-nucleoside and N-nucleoside proceed in three steps including nucleophilic addition, dehydration and cyclization. The calculated apparent activation energies are 28.8 kcal mol-1 and 29.2 kcal mol-1, respectively. It suggests that both C- and N-nucleoside can be formed in aqueous solution, which is in good agreement with the experimental results. The water molecule plays an important "H-bridge" role by the hydrogen atom relay. Finally, a model structure of nucleobase, which will be beneficial for the C-C glycosidic bond formation, is proposed.


Assuntos
Modelos Moleculares , Pirimidinas/química , Ribonucleosídeos/química , Ribose/química , Carbono/química , Conformação Molecular , Nitrogênio/química , Pirimidinas/metabolismo , Ribonucleosídeos/metabolismo , Ribose/metabolismo , Termodinâmica , Água/química
9.
Phys Chem Chem Phys ; 18(41): 28492-28501, 2016 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-27711557

RESUMO

The addition of the unnatural P:Z base pair to the four naturally occurring DNA bases expands the genetic alphabet and yields an artificially expanded genetic information system (AEGIS). Herein, the structural feature of oligonucleotides containing a novel unnatural P:Z base pair is characterized using both molecular dynamics and quantum chemistry. The results show that the incorporation of the novel artificial base pair (P:Z) preserves the global conformational feature of duplex DNA except for some local structures. The Z-nitro group imparts new properties to the groove width, which widens the major groove. The unnatural oligonucleotides containing mismatched base pairs exhibit low stability. This ensures efficient and high-fidelity replication. In general, the incorporation of the P:Z pair strengthens the stability of the corresponding DNA duplex. The calculated results also show that the thermostability originates from both hydrogen interaction and stacking interaction. The Z-nitro group plays an important role in enhancing the stability of the H-bonds and stacking strength of the P:Z pair. Overall, the present results provide theoretical insights in the exploration of artificially expanded genetic information systems.


Assuntos
Conformação de Ácido Nucleico , Nucleotídeos/química , Oligonucleotídeos/química , Pareamento de Bases , Modelos Moleculares
10.
J Mol Graph Model ; 70: 153-162, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27723563

RESUMO

Recent experiments show that small molecules can bind onto the allosteric sites of HIV-1 protease (PR), which provides a starting point for developing allosteric inhibitors. However, the knowledge of the effect of such binding on the structural dynamics and binding free energy of the active site inhibitor and PR is still lacking. Here, we report 200ns long molecular dynamics simulation results to gain insight into the influences of two allosteric molecules (1H-indole-6-carboxylic acid, 1F1 and 2-methylcyclohexano, 4D9). The simulations demonstrate that both allosteric molecules change the PR conformation and stabilize the structures of PR and the inhibitor; the residues of the flaps are sensitive to the allosteric molecules and the flexibility of the residues is pronouncedly suppressed; the additions of the small molecules to the allosteric sites strengthen the binding affinities of 3TL-PR by about 12-15kal/mol in the binding free energy, which mainly arises from electrostatic term. Interestingly, it is found that the action mechanisms of 1F1 and 4D9 are different, the former behaviors like a doorman that keeps the inhibitor from escape and makes the flaps (door) partially open; the latter is like a wedge that expands the allosteric space and meanwhile closes the flaps. Our data provide a theoretical support for designing the allosteric inhibitor.


Assuntos
Sítio Alostérico , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Simulação de Dinâmica Molecular , Sítios de Ligação , Conformação Proteica , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Termodinâmica , Fatores de Tempo
11.
Biomed Pharmacother ; 69: 82-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25661342

RESUMO

Deacetyl-mycoepoxydiene (DM), a novel secondary metabolite produced by the plant endophytic fungi Phomosis sp., induced the reorganization of cytoskeleton in actively growing MCF-7 cells by promoting polymerization of tubulin. DM could induce cell cycle arrest at G2/M in MCF-7 cells. Additionally, DM-induced apoptosis was characterized with up-regulating caspase-3, Bax, caspase-9, parp, and p21 while down-regulating Bcl-2 activation. DM conferred dose- and time-dependent inhibitory effects upon cell proliferation of MCF-7 cells both in cultured cells and nude mice with human breast carcinoma xenografts. The results obtained from these in vitro and in vivo models provide new data revealing the potential for DM as a novel microtubule inhibitor.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/isolamento & purificação , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/isolamento & purificação , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Endófitos/química , Fungos/química , Microtúbulos/efeitos dos fármacos , Pironas/isolamento & purificação , Pironas/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Fase G2/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Microtúbulos/metabolismo , Polimerização , Pironas/química , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cell Mol Neurobiol ; 32(3): 435-42, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22109513

RESUMO

In this report, the sulfated polysaccharide (SJP) from the body wall of the sea cucumber Stichopus japonicas was extracted and tested for its capacity to affect migration and differentiation of neural stem/progenitor cells. SJP is an intensely sulfated polysaccharide with a molecular weight of 1.79 × 10(5) Da that is capable of promoting neurosphere attachment and migration in a dose-dependent manner. Moreover, SJP effectively maintains cell viability even after being deprived of mitogens. Our current results demonstrate that neurosphere are differentiated into neuronal and glial cells when exposed to SJP. These effects were accompanied by an up-regulation of the adhesion molecule, N-cadherin. In addition, we observed that blocking of PI3K activity inhibited N-cadherin-mediated activity. This SJP-induced up-regulation of N-cadherin mediates neurosphere adhesion migration and differentiation via the PI3K/Akt signaling pathway. These results suggest that SJP could be used as a therapeutic agent to mobilize neuroblast migration under conditions of brain injury and disease.


Assuntos
Caderinas/biossíntese , Movimento Celular/fisiologia , Proteínas do Tecido Nervoso/biossíntese , Polissacarídeos/fisiologia , Stichopus , Regulação para Cima/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Movimento Celular/efeitos dos fármacos , Feminino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Polissacarídeos/isolamento & purificação , Gravidez , Ratos , Ratos Wistar , Pepinos-do-Mar , Sulfatos/isolamento & purificação , Sulfatos/farmacologia , Regulação para Cima/efeitos dos fármacos
13.
Neurosci Lett ; 503(1): 37-42, 2011 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-21855606

RESUMO

In this report, we demonstrate that the sulfated polysaccharide, Haishen (HS), which was isolated from the body wall of the sea cucumber Stichopus japonicus can induce morphological transformation and proliferation of astrocytes in vitro when combined with basic fibroblast growth factor 2 (FGF-2). Cell morphology showed no change when induced by HS or FGF-2 alone. However, combinational treatment of HS and FGF-2 promoted transformation of normal astrocyte into a stella morphology (stellation), along with an increase in the expression and rearrangement of glial fibrillary acidic protein (GFAP). Further analysis of HS- and FGF-2-treated cells indicated a reduced percentage of cells in the G0/G1 phase, whereas the cell proliferation index (S phase) was increased. The proportion of 5-bromo-2-deoxyuridine (BrdU)-positive cells increased in response to the combination of HS and FGF-2. With respect to cell cycle signaling, immunoblotting assay demonstrated an accumulation of Cyclin D1. These observations suggest that HS may play a role in astrocyte morphological transformation and proliferation, and this activation requires a synergism with FGF-2.


Assuntos
Astrócitos/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Polissacarídeos/farmacologia , Pepinos-do-Mar/química , Animais , Animais Recém-Nascidos , Contagem de Células , Células Cultivadas , Córtex Cerebral/citologia , Ciclina D1/metabolismo , Relação Dose-Resposta a Droga , Fator 2 de Crescimento de Fibroblastos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Ratos , Ratos Wistar , Fatores de Tempo
14.
Tumour Biol ; 32(1): 53-61, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20711700

RESUMO

Gastric carcinoma is a common type of malignant tumors and is associated with high death rates. The pathogenesis of gastric carcinoma is still unclear, and increasing evidence shows that many factors contribute to this process. Chromokinesin KIF4 is involved in multiple critical cellular processes. Recently, it has become apparent that KIF4 plays a crucial suppressive role in tumorigenesis. However, the role of KIF4 in human gastric cancer is still unclear. In this study, we examined expression profiles of KIF4 in gastric carcinoma specimens and generated gastric cancer cells that stably express GFP-KIF4 fusion protein (designated as BGC-GFP-KIF4 cells) followed by cell proliferation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and soft agar colony-formation assays. Simultaneously, we further examined the capability of tumor formation of BGC-GFP-KIF4 cells in nude mice. The results showed that among 23 gastric carcinoma specimens, 13 cases (56.6%) had lower expression of KIF4 compared with corresponding adjacent tissues. In addition, there was a significant correlation between low expression of KIF4 and poor differentiation of tumor (P = 0.024). Overexpression of KIF4 in BGC cells inhibited cell proliferation in vitro, as well as their ability to form tumors in vivo. Our findings suggest that human chromokinesin KIF4 functions as an inhibitor of gastric cancer cell proliferation and might serve as a novel biological target to cure human gastric carcinoma.


Assuntos
Adenocarcinoma/patologia , Proliferação de Células , Mucosa Gástrica/metabolismo , Cinesina/metabolismo , Neoplasias Gástricas/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/prevenção & controle , Animais , Apoptose , Western Blotting , Adesão Celular , Diferenciação Celular , Feminino , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Estômago/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/prevenção & controle , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Biochem Biophys Res Commun ; 403(3-4): 398-404, 2010 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-21093411

RESUMO

Baicalin is a flavonoid compound purified from plant Scutellaria baicalensis Georgi. We aimed to evaluate the neuroprotective effects of baicalin against cerebral ischemic reperfusion injury. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 24 h. Baicalin at doses of 50, 100 and 200 mg/kg was intravenously injected after ischemia onset. Twenty-four hours after reperfusion, the neurological deficit was scored and infarct volume was measured. Hematoxylin and eosin (HE) staining was performed to analyze the histopathological changes of cortex and hippocampus neurons. We examined the levels of NF-κB p65 in ischemic cortexes by Western blot analysis and RT-PCR assay. The results showed that the neurological deficit scores were significantly decreased from 2.0 ± 0.7 to 1.2 ± 0.4 and the volume of infarction was reduced by 25% after baicalin injection. Histopathological examination showed that the increase of neurons with pycnotic shape and condensed nuclear in cortex and hippocampus were not observed in baicalin treated animals. Further examination showed that NF-κB p65 in cortex was increased after ischemia reperfusion injury, indicating the molecular mechanism of ischemia reperfusion injury. The level of NF-κB p65 was decreased by 73% after baicalin treatment. These results suggest that baicalin might be useful as a potential neuroprotective agent in stroke therapy. The neuroprotective effects of baicalin may relate to inhibition of NF-κB p65.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Flavonoides/uso terapêutico , Infarto da Artéria Cerebral Média/complicações , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Fator de Transcrição RelA/antagonistas & inibidores , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Fator de Transcrição RelA/biossíntese
16.
J Bacteriol ; 192(13): 3540-4, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20418393

RESUMO

Besides inhibiting RecA activity at the protein level, Deinococcus radiodurans RecX can suppress RecA induction at the transcriptional level. The regulation of RecX on recA induction is independent of RecA activity, and its N terminus is involved in this process.


Assuntos
Proteínas de Bactérias/metabolismo , Deinococcus/metabolismo , Recombinases Rec A/metabolismo , Proteínas de Bactérias/genética , Deinococcus/genética , Regulação Bacteriana da Expressão Gênica/genética , Regulação Bacteriana da Expressão Gênica/fisiologia , Recombinases Rec A/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Appl Microbiol Biotechnol ; 76(1): 193-201, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17387468

RESUMO

The coding sequence for an iron superoxide dismutase (fe-sod) was amplified from the Nostoc commune genome. Recombinant Fe-SOD was overexpressed in Escherichia coli, accounting for approximately 76% of total bacterial protein. Fe-SOD was purified from bacterial lysate by Ni-NTA column chromatography and used to generate an anti-SOD antibody. The purified Fe-SOD was encapsulated in liposomes and delivered to HepG2 liver tumor cells to eliminate cellular superoxide anions. The SOD-loaded cells exhibited lower reactive oxygen species (ROS) levels and higher reduced glutathione (GSH) levels. In Fe-SOD-treated cells, the cell cycle was delayed in the G(1) phase, and HepG2 cell growth slowed in association with dephosphorylation of the serine-threonine kinase Akt. Low-dose H(2)O(2) stimulated Akt phosphorylation, implying that Akt activation in HepG2 cells is redox-sensitive. Akt phosphorylation was abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitors, suggesting that PI3K is an upstream mediator of Akt activation in HepG2 cells. This study provides insight into recombinant Fe-SOD-induced signaling mechanisms in liver tumor cells and suggests the feasibility of using Fe-SOD as an antitumor agent.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes/farmacologia , Superóxido Dismutase/farmacologia , Linhagem Celular Tumoral/citologia , Humanos , Nostoc commune/metabolismo , Oxirredução , Estresse Oxidativo/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/biossíntese , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
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