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1.
J Chem Phys ; 151(14): 144307, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615216

RESUMO

Historically, structure determination of nanocrystals, proteins, and macromolecules required the growth of high-quality crystals sufficiently large to diffract X-rays efficiently while withstanding radiation damage. The development of the X-ray free-electron laser has opened the path toward high resolution single particle imaging, and the extreme intensity of the X-rays ensures that enough diffraction statistics are collected before the sample is destroyed by radiation damage. Still, recovery of the structure is a challenge, in part due to the partial fragmentation of the sample during the diffraction event. In this study, we use first-principles based methods to study the impact of radiation induced ionization of six amino acids on the reconstruction process. In particular, we study the fragmentation and charge rearrangement to elucidate the time scales involved and the characteristic fragments occurring.


Assuntos
Aminoácidos/química , Aminoácidos/efeitos da radiação , Teoria da Densidade Funcional , Modelos Químicos , Simulação de Dinâmica Molecular , Eletricidade Estática , Fatores de Tempo , Raios X
2.
J Phys Chem Lett ; 10(20): 6355-6359, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31568720

RESUMO

The structure of water molecules in contact with zwitterionic lipid molecules is of great biological relevance, because biological membranes are largely composed of such lipids. The interaction of the interfacial water molecules with the amphiphilic lipid molecules drives the formation of membranes and greatly influences various processes at the membrane surface, as the field that arises from the aligned interfacial water molecules masks the charges of the lipid headgroups from the approaching metabolites. To increase our understanding of the influence of water molecules on biological processes we study their structure at the interface using sum-frequency generation spectroscopy and molecular dynamics simulations. Interestingly, we find that water molecules at zwitterionic lipid molecules are mainly oriented by the field arising between the two oppositely charged molecular moieties within the lipid headgroups.


Assuntos
Bicamadas Lipídicas/química , Água/química , Ligações de Hidrogênio , Simulação de Dinâmica Molecular , Estrutura Molecular , Fosfatidilcolinas/química , Eletricidade Estática
3.
Phys Chem Chem Phys ; 21(41): 22782-22793, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31595896

RESUMO

The theoretical assignment of electronic spectra of polyatomic molecules is a challenging problem that requires the specification of the character of a large number of electronic states. We propose a procedure for automatically determining the character of electronic transitions and apply it to the study of UV spectra of DNA bases in the gas phase and in the aqueous environment. The procedure is based on the computation of electronic wave function overlaps and accounts for an extensive sampling of nuclear geometries. Novelties of this work are the theoretical assignment of the electronic spectra of DNA bases up to 190 nm and a state specific analysis of solvation effects. By accounting for different effects contributing to the total solvent shift we obtained a good agreement between the computed and experimental spectra. Effects of vibrational averaging, temperature and solvent-induced structural changes shift excitation energies to lower values. Solvent-solute electrostatic interactions are state specific and strongly destabilize nRyd states, and to lesser extent nπ* and πRyd states. Altogether, this results in the stabilization of ππ* states and destabilization of nπ*, πRyd and nRyd states in solution.


Assuntos
Técnicas de Química Analítica/métodos , DNA/química , Solventes/química , Análise Espectral , Gases/química , Eletricidade Estática , Raios Ultravioleta
4.
Se Pu ; 37(11): 1173-1178, 2019 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-31642269

RESUMO

A rapid screening method was developed to determine sibutramine and five derivatives in health food by high performance liquid chromatography-quadrupole/electrostatic orbitrap high-resolution mass spectrometry (HPLC-Q/Orbitrap HRMS). The sample was extracted with methanol via ultrasonic-assisted extraction coupled with high-speed centrifugation. Separation was performed on a Hypersil Gold column (100 mm×2.1 mm, 3 µm) by gradient elution with methanol/water (containing 0.15%(v/v) formic acid) as the mobile phase. The positive full mass scan/date-dependent MS2 (Full MS/dd-MS2) mode was used during MS detection, and quantification was achieved by resolution of the precursor mass. The analytes in the sample were separated, and accurate mass and MS2 fragment ions were simultaneously attained within 8 min. The results indicated that the obtained mass accuracy errors of the six analytes were less than 1×10-6. Good linearities were obtained in the range of 0.5-20.0 µg/L, and all correlation coefficients were higher than 0.999. The limits of quantification were 25 µg/kg and the recoveries were in the range of 93.5%-103.5% with relative standard deviations of 1.5%-7.7%. This simple-pretreatment, rapid, accurate, high-sensitivity, and high-selectivity method can be used in the rapid screening and quantitative analysis of sibutramine and its derivatives in health food.


Assuntos
Ciclobutanos/análise , Análise de Alimentos/métodos , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Eletricidade Estática
5.
J Chem Phys ; 151(11): 114903, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31542006

RESUMO

DNA confinement in a nanochannel typically is understood via mapping to the confinement of an equivalent neutral polymer by hard walls. This model has proven to be effective for confinement in relatively large channels where hairpin formation is frequent. An analysis of existing experimental data for Escherichia coli DNA extension in channels smaller than the persistence length, combined with an additional dataset for λ-DNA confined in a 34 nm wide channel, reveals a breakdown in this approach as the channel size approaches the Odijk regime of strong confinement. In particular, the predicted extension distribution obtained from the asymptotic solution to the weakly correlated telegraph model for a confined wormlike chain deviates significantly from the experimental distribution obtained for DNA confinement in the 34 nm channel, and the discrepancy cannot be resolved by treating the alignment fluctuations or the effective channel size as fitting parameters. We posit that the DNA-wall electrostatic interactions, which are sensible throughout a significant fraction of the channel cross section in the Odijk regime, are the source of the disagreement between theory and experiment. Dimensional analysis of the wormlike chain propagator in channel confinement reveals the importance of a dimensionless parameter, reflecting the magnitude of the DNA-wall electrostatic interactions relative to thermal energy, which has not been considered explicitly in the prevailing theories for DNA confinement in a nanochannel.


Assuntos
DNA Bacteriano/química , DNA Viral/química , Modelos Químicos , Nanoestruturas/química , Bacteriófago lambda/genética , DNA Bacteriano/genética , DNA Viral/genética , Escherichia coli/genética , Polímeros/química , Eletricidade Estática
6.
Phys Chem Chem Phys ; 21(38): 21485-21496, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31535114

RESUMO

As a non-catalytic domain, carbohydrate binding modules (CBMs) are often considered to play some key roles in the degradation and recognition of polysaccharides catalyzed by cellulases. In this work, we investigated the recognition dynamics of cello- or xylo-saccharides by two typical CBMs (CBM16-1 and CBM22-2), which are grouped into Type B CBMs. By combining extensive molecular dynamics, principle component analysis, and binding free energy calculations, we constructed several complex models of the two CBMs in both complex cello- and xylo-oligosaccharides. The corresponding substrate recognition affinity and critical residues having significant contributions were systematically investigated. The residues containing aromatic side chain groups were shown to contribute significantly to substrate binding. The calculated binding free energies were in fairly good agreement with the experimental measurements with the absolute mean error of 0.69 kcal mol-1. The overall electrostatic interactions were shown to have negative effects on substrate recognition. Further metadynamics simulations revealed the substrate dissociation process.


Assuntos
Celulases/química , Simulação de Dinâmica Molecular , Oligossacarídeos/química , Sítios de Ligação , Análise de Componente Principal , Ligação Proteica , Conformação Proteica , Eletricidade Estática , Termodinâmica
7.
J Phys Chem Lett ; 10(20): 5997-6002, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31545052

RESUMO

The classical method for evaluating the waveguide ability only focuses on the optical loss coefficient. However, for the micro- or submicroscale, an organic waveguide is demonstrated by the present study whose scale effect should not be neglected. We found that the optical loss coefficient increased remarkably when decreasing the sectional size of the microfibers. Furthermore, simulations based on Finite-Difference Time-Domain also demonstrated the size-dependent effect of the waveguide. Both the experimental and simulating results showed that the optical loss coefficient converges to a certain value, which means that the scale effect can be neglected as the sectional size is large enough. On the basis of the present study, we suggest that the scale-dependent effect on the sectional size of the waveguide should be investigated by evaluating the waveguide ability by the optical loss coefficient.


Assuntos
Cumarínicos/efeitos da radiação , ortoaminobenzoatos/efeitos da radiação , Cumarínicos/química , Cristalização , Fluorescência , Luz , Manufaturas/efeitos da radiação , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Difração de Raios X , ortoaminobenzoatos/química
8.
Chem Pharm Bull (Tokyo) ; 67(9): 906-914, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474728

RESUMO

An aminoalkyl methacrylate copolymer, Eudragit® E (EUD-E), has gained tremendous attention as a solid dispersion carrier because it efficiently stabilizes drugs in the amorphous state. Furthermore, EUD-E remarkably enhances drug dissolution in water. This review focuses on the interaction between drugs and EUD-E in solution, which contributes to the enhancement of drug concentration. Studies examining interactions between acidic drugs and EUD-E in organic solvents have revealed that the interaction occurs predominantly by electrostatic interaction, including hydrogen bonding and dipolar interactions. Other studies on interactions in aqueous solution found evidence for strong electrostatic interactions between acidic drugs and EUD-E in ion exchange experiments. 1H-NMR studies using high-resolution magic-angle spinning, nuclear Overhauser effect spectroscopy, diffusion, and relaxation time measurements successfully identified the interaction site and strength in aqueous solution. Hydrophobic and ionic interactions occurred between drugs and EUD-E. The conformation of EUD-E, which was affected by the ionic strength and pH of the aqueous media, also influenced the interaction. The knowledge discussed in this review will be helpful in designing solid dispersion formulations with EUD-E, which will efficiently enhance drug concentration and subsequent absorption into the body.


Assuntos
Preparações Farmacêuticas/química , Ácidos Polimetacrílicos/química , Água/química , Ligações de Hidrogênio , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Solubilidade , Solventes/química , Eletricidade Estática
9.
Phys Chem Chem Phys ; 21(37): 20951-20964, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31524891

RESUMO

As a promising drug target in the treatment of lung cancer, anaplastic lymphoma kinase (ALK) and its mutations have been studied widely through the development of multiple generations of inhibitors. Experiments have found that compared with the wild-type, the L1198F and C1156Y/L1198F mutations resulted in resistance to 5P8 inhibitors, and the C1156Y mutation resulted in resistance to VGH inhibitors. In this study, the newly developed interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field was utilized to explore the origin of the resistance mechanism of the ALK mutant system. The calculated binding free energy was consistent with the experimental results. Per-residue binding free energy decomposition showed that the predicted hot-spot residues (LEU1122, LEU/PHE1198, MET1199, GLY1202 and LEU1256) were almost identical across systems. Especially, the GLU1197 residue played an important role in inducing drug-resistance for both inhibitors. The electrostatic interaction of GLU1197, PHE1198 and MET1199 mainly resulted in the resistances of the L1198F and C1156Y/L1198F mutations to 5P8. And the van der Waals interaction energy of LEU1256 residue, and electrostatic energy and entropy change of GLU1197 resulted in the resistances of the C1156Y mutations to VGH. The indicated origins of the drug-resistance in the ALK systems provide a theoretical foundation for the design of potent inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/genética , Resistencia a Medicamentos Antineoplásicos/genética , Entropia , Mutação/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/genética , Eletricidade Estática
10.
Chem Commun (Camb) ; 55(77): 11619-11622, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31501844

RESUMO

Mesoporous organosilica nanoparticles (PHT-PMO) have been prepared from an octa-triethoxysilylated Zn phthalocyanine precursor. These PHT-PMO nanoparticles had no dark toxicity but high phototoxicity when irradiated at 650 nm, and remarkable near-infrared phototoxicity when excited at 760 and 810 nm. The PHT-PMO were then aminated to promote electrostatic complexation with siRNA. Transfection experiments were performed upon NIR irradiation and photochemical internalization was very efficient, leading to 65% luciferase extinction in MCF-7 cancer cells expressing stable luciferase.


Assuntos
Indóis/química , Nanopartículas/química , Compostos Organometálicos/química , Fotoquimioterapia/métodos , RNA Interferente Pequeno/química , Silanos/química , Sobrevivência Celular , Cetrimônio/química , Humanos , Raios Infravermelhos , Luciferases/genética , Células MCF-7 , Processos Fotoquímicos , Porosidade , RNA Interferente Pequeno/metabolismo , Eletricidade Estática , Propriedades de Superfície
11.
Int J Nanomedicine ; 14: 4911-4929, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456637

RESUMO

Background: Apocynin (APO) is a bioactive phytochemical with prominent anti-inflammatory and anti-oxidant activities. Designing a nano-delivery system targeted to potentiate the gastric antiulcerogenic activity of APO has not been investigated yet. Chitosan oligosaccharide (COS) is a low molecular weight chitosan and its oral nanoparticulate system for potentiating the antiulcerogenic activity of the loaded APO has been described here. Methods: COS-nanoparticles (NPs) loaded with APO (using tripolyphosphate [TPP] as a cross-linker) were prepared by ionic gelation method and fully characterized. The chosen formula was extensively evaluated regarding in vitro release profile, kinetic analysis, and stability at refrigerated and room temperatures. Ultimately, the in vivo antiulcerogenic activity against ketoprofen (KP)-induced gastric ulceration in rats was assessed by macroscopic parameters including Paul's index and antiulcerogenic activity, histopathological examination, immunohistochemical (IHC) evaluation of cyclooxygenase-2 (COX-2) expression level in ulcerated gastric tissue, and biochemical measurement of oxidative stress markers and nitric oxide (NO) levels. Results: The selected NPs formula with COS (0.5 % w/v) and TPP (0.1% w/v) was the most appropriate one with drug entrapment efficiency percentage of 35.06%, particle size of 436.20 nm, zeta potential of +38.20 mV, and mucoadhesive strength of 51.22%. It exhibited a biphasic in vitro release pattern as well as high stability at refrigerated temperature for a 6-month storage period. APO-loaded COS-NPs provoked marvelous antiulcerogenic activity against KP-induced gastric ulceration in rats compared with free APO treated group, which was emphasized by histopathological, IHC, and biochemical studies. Conclusion: In conclusion, APO-loaded COS-NPs could be considered as a promising oral phytopharmaceutical nanoparticulate system for management of gastric ulceration.


Assuntos
Acetofenonas/administração & dosagem , Acetofenonas/farmacologia , Quitosana/química , Mucosa Gástrica/efeitos dos fármacos , Nanopartículas/química , Oligossacarídeos/química , Compostos Fitoquímicos/administração & dosagem , Compostos Fitoquímicos/farmacologia , Acetofenonas/uso terapêutico , Administração através da Mucosa , Animais , Biomarcadores/metabolismo , Varredura Diferencial de Calorimetria , Ciclo-Oxigenase 2/metabolismo , Liberação Controlada de Fármacos , Cinética , Masculino , Nanopartículas/ultraestrutura , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Estômago/efeitos dos fármacos , Estômago/patologia , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Suínos , Difração de Raios X
12.
13.
Int J Nanomedicine ; 14: 4991-5015, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371943

RESUMO

Purpose: This study evaluates the cytotoxicity of AuNPs coated with polyallylamine (AuNPs-PAA) and conjugated or not to the epidermal growth factor receptor (EGFR)-targeting antibody Cetuximab (AuNPs-PAA-Ctxb) in normal human kidney (HK-2), liver (THLE-2) and microvascular endothelial (TIME) cells, and compares it with two cancer cell lines that are EGFR-overexpressing (A431) or EGFR-negative (MDA-MB-453). Results: Conjugation of Cetuximab to AuNPs-PAA increased the AuNPs-PAA-Ctxb interactions with cells, but reduced their cytotoxicity. TIME cells exhibited the strongest reduction in viability after exposure to AuNPs-PAA(±Ctxb), followed by THLE-2, MDA-MB-453, HK-2 and A431 cells. This cell type-dependent sensitivity was strongly correlated to the inhibition of thioredoxin reductase (TrxR) and glutathione reductase (GR), and to the depolarization of the mitochondrial membrane potential. Both are suggested to initiate apoptosis, which was indeed detected in a concentration- and time-dependent manner. The role of oxidative stress in AuNPs-PAA(±Ctxb)-induced cytotoxicity was demonstrated by co-incubation of the cells with N-acetyl L-cysteine (NAC), which significantly decreased apoptosis and mitochondrial membrane depolarization. Conclusion: This study helps to identify the cells and tissues that could be sensitive to AuNPs and deepens the understanding of the risks associated with the use of AuNPs in vivo.


Assuntos
Antioxidantes/metabolismo , Ouro/química , Nanopartículas Metálicas/química , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cetuximab/farmacologia , Endocitose/efeitos dos fármacos , Glutationa Redutase/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanopartículas Metálicas/ultraestrutura , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Tamanho da Partícula , Poliaminas/química , Substâncias Protetoras/farmacologia , Eletricidade Estática , Tiorredoxina Dissulfeto Redutase/metabolismo
14.
Int J Nanomedicine ; 14: 5073-5085, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371948

RESUMO

Purpose: To potentiate the anticancer activity of curcumin (CUR) by improving its cell penetration potentials through formulating it into nanostructured lipid carriers (NLCs) and using the prepared NLCs in photodynamic therapy. Methods: A 3×4 factorial design was used to obtain 12 CUR-NLCs using two factors on different levels: (1) the solid lipid type at four levels and (2) the solid to liquid lipid ratio at three levels. Olive oil, Tween 80 and lecithin were chosen as liquid lipid, surfactant and co-surfactant, respectively. CUR-NLCs prepared by high shear hot homogenization method were evaluated by determination of particle size (PS), polydispersity index, zeta potential (ZP), entrapment efficiency percent, drug loading percent and in vitro drug release. Optimization was based on the evaluation results using response surface modeling (RSM). Optimized formulae were tested for their in vitro release pattern and for dark and photo-cytotoxic anticancer activity on breast cancer cell line in comparison to free CUR. Results: Evaluation tests showed the appropriateness of NLCs prepared from glyceryl monooleate and Geleol™ helped choosing two optimized formulae, PE3 and GE3. PE3 (prepared using glyceryl monooleate) showed enhanced release rates compared to GE3 (prepared from Geleol) and superior cytotoxic anticancer activity compared to both GE3 and free CUR under both light and dark conditions. The small mean PS, spherical shape as well as the negative ZP enhanced the internalization of the NLCs within cells. Modulation and inhibition of P-glycoprotein expression by glyceryl monooleate synergized the cytotoxic activity of CUR. Conclusion: CUR loading in NLCs enhanced its cell penetration and cytotoxic anticancer properties both in dark and in light conditions.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Curcumina/uso terapêutico , Portadores de Fármacos/química , Lipídeos/química , Nanoestruturas/química , Ácidos Oleicos/química , Azeite de Oliva/química , Fotoquimioterapia , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Liberação Controlada de Fármacos , Feminino , Humanos , Células MCF-7 , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Eletricidade Estática
15.
Int J Nanomedicine ; 14: 5435-5448, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409997

RESUMO

Background: Ramipril (RMP) suffers from poor aqueous solubility along with sensitivity to mechanical stress, heat, and moisture. The aim of the current study is to improve RMP solubility and stability by designing solid self-nanoemulsifying drug delivery system (S-SNEDDS) as tablet. Methods: The drug was initially incorporated in different liquid formulations (L-SNEDDS) which were evaluated by equilibrium solubility, droplet size, and zeta potential studies. The optimized formulation was solidified into S-SNEDDS powder by the adsorbent Syloid® and compressed into a self-nanoemulsifying tablet (T-SNEDDS). The optimized tablet was evaluated by drug content uniformity, hardness, friability, disintegration, and dissolution tests. Furthermore, pure RMP, optimized L-SNEDDS, and T-SNEDDS were enrolled in accelerated and long-term stability studies. Results: Among various liquid formulations, F5 L-SNEDDS [capmul MCM/transcutol/HCO-30 (25/25/50%w/w)] showed relatively high drug solubility, nano-scaled droplet size, and high negative zeta potential value. The optimized SNEDDS solidification with Syloid® at ratio (1:1) resulted in a compressible powder with an excellent flowability. The optimized tablet (T-SNEDDS) showed accepted content uniformity, hardness, friability, and disintegration time (<15 minutes). The optimized L-SNEDDS, S-SNEDDS, and T-SNEDDS showed superior enhancement of RMP dissolution compared to the pure drug. Most importantly, T-SNEDDS showed significant (P<0.05) improvement of RMP stability compared to the pure drug and L-SNEDDS in both accelerated and long-term stability studies. Conclusion: RMP-loaded T-SNEDDS offers a potential oral dosage form that provides combined improvement of RMP dissolution and chemical stability.


Assuntos
Sistemas de Liberação de Medicamentos , Emulsões/química , Nanopartículas/química , Ramipril/farmacologia , Administração Oral , Adsorção , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Dureza , Nanopartículas/ultraestrutura , Tamanho da Partícula , Controle de Qualidade , Solubilidade , Eletricidade Estática , Comprimidos/química , Fatores de Tempo , Difração de Raios X
16.
Int J Nanomedicine ; 14: 5061-5071, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371947

RESUMO

Background: Photodynamic therapy (PDT) is widely recognized as a promising way to cure cancer. However, the limited tumor homing property of currently available drug delivery systems (DDSs) is the bottleneck for the delivery of photodynamic agents. Purpose: In our study, we decorated silica nanoparticles (SLN) with cell membrane (CM) derived from SGC7901 cells to construct carrier (CM/SLN) which was able to to specifically target the homogenous SGC7901 cells. Materials and methods: Furthermore, the decent drug loading capability of CM/SLN was adopted to load photodynamic agent chlorins e6 (Ce6) to finally construct aDDS suitable for tumor-targeted PDT of gastric cancer. Results: The experimental results suggested that CM/SLN/Ce6 was nano-sized particles with good dispersion and stability in physiological conditions. Moreover, due to the modification of CM,CM/SLN/Ce6 could specifically target the homogenous SGC7901 cells both in vitro and in vivo. Most importantly, further in vivo results demonstrated that the CM/SLN/Ce6 showed a better anticancer outcome compared to SLN/Ce6. Conclusion: CM/SLN/Ce6 might be a promising platform for effective tumor targeted PDT of gastric cancer.


Assuntos
Membrana Celular/patologia , Nanopartículas/química , Fotoquimioterapia , Porfirinas/uso terapêutico , Dióxido de Silício/química , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Coloides , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Camundongos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Porfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Eletricidade Estática , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos
17.
Inorg Chem ; 58(17): 11351-11363, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31433627

RESUMO

Iron storage in biology is carried out by cage-shaped proteins of the ferritin superfamily, one of which is the dodecameric protein Dps. In Dps, four distinct steps lead to the formation of metal nanoparticles: attraction of ion-aquo complexes to the protein matrix, passage of these complexes through translocation pores, oxidation of these complexes at ferroxidase centers, and, ultimately, nanoparticle formation. In this study, we investigated Dps from Listeria innocua to structurally characterize these steps for Co2+, Zn2+, and La3+ ions. The structures reveal that differences in their ion coordination chemistry determine alternative metal ion-binding sites on the areas of the surface surrounding the translocation pore that captures nine La3+, three Co2+, or three Zn2+ ions as aquo clusters and passes them on for translocation. Inside these pores, ion-selective conformational changes at key residues occur before a gating residue to actively move ions through the constriction zone. Ions upstream of the Asp130 gate residue are typically hydrated, while ions downstream directly interact with the protein matrix. Inside the cavity, ions move along negatively charged residues to the ferroxidase center, where seven main residues adapt to the three different ions by dynamically changing their conformations. In total, we observed more than 20 metal-binding sites per Dps monomer, which clearly highlights the metal-binding capacity of this protein family. Collectively, our results provide a detailed structural description of the preparative steps for amino acid-assisted biomineralization in Dps proteins, demonstrating unexpected protein matrix plasticity.


Assuntos
Proteínas de Bactérias/química , Proteínas de Ligação a DNA/química , Listeria/química , Metais Pesados/química , Proteínas de Bactérias/biossíntese , Proteínas de Ligação a DNA/biossíntese , Modelos Moleculares , Eletricidade Estática
18.
J Chem Theory Comput ; 15(9): 5135-5143, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31390206

RESUMO

Predicting the assembly of multiple proteins into specific complexes is critical to understanding their biological function in an organism and thus the design of drugs to address their malfunction. Proteins are flexible molecules, which inherently pose a problem to any protein docking computational method, where even a simple rearrangement of the side chain and backbone atoms at the interface of binding partners complicates the successful determination of the correct docked pose. Herein, we present a means of representing protein surface, electrostatics, and local dynamics within a single volumetric descriptor. We show that our representations can be physically related to the surface-accessible solvent area and mass of the protein. We then demonstrate that the application of this representation into a protein-protein docking scenario bypasses the need to compensate for, and predict, specific side chain packing at the interface of binding partners. This representation is leveraged in our de novo protein docking software, JabberDock, which can accurately and robustly predict difficult target complexes with an average success rate of >54%, which is comparable to or greater than the currently available methods.


Assuntos
Simulação de Acoplamento Molecular , Proteínas/química , Eletricidade Estática , Termodinâmica , Ligação Proteica , Propriedades de Superfície
19.
J Chem Theory Comput ; 15(9): 4982-5000, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31411469

RESUMO

In this work, we report the development of Drude polarizable force field parameters for the carboxylate and N-acetyl amine derivatives, extending the functionality of the existing Drude polarizable carbohydrate force field. The force field parameters have been developed in a hierarchical manner, reproducing the quantum mechanical gas-phase properties of small model compounds representing the key functional group in the carbohydrate derivatives, including optimization of the electrostatic and bonded parameters. The optimized parameters were then used to generate the models for carboxylate and N-acetyl amine carbohydrate derivatives. The transferred parameters were further tested and optimized to reproduce crystal geometries and J-coupling data from nuclear magnetic resonance experiments. The parameter development resulted in the incorporation of d-glucuronate, l-iduronate, N-acetyl-d-glucosamine (GlcNAc), and N-acetyl-d-galactosamine (GalNAc) sugars into the Drude polarizable force field. The parameters developed in this study were then applied to study the conformational properties of glycosaminoglycan polymer hyaluronan, composed of d-glucuronate and N-acetyl-d-glucosamine, in aqueous solution. Upon comparing the results from the additive and polarizable simulations, it was found that the inclusion of polarization improved the description of the electrostatic interactions observed in hyaluronan, resulting in enhanced conformational flexibility. The developed Drude polarizable force field parameters in conjunction with the remainder of the Drude polarizable force field parameters can be used for future studies involving carbohydrates and their conjugates in complex, heterogeneous systems.


Assuntos
Aminas/química , Carboidratos/química , Simulação de Dinâmica Molecular , Teoria Quântica , Eletricidade Estática
20.
Int J Nanomedicine ; 14: 4397-4412, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417251

RESUMO

Background: Graphene magnetite nanocomposites (G/Fe3O4) exhibit light photothermal conversion upon enhancement by 808 nm IR laser excitation. We evaluated the cytotoxic and photothermal effects of G/Fe3O4 on a HepG2 human liver cancer cell model. Methods: Graphene nanosheets (rGO), magnetite nanoparticles (Fe3O4), and G/Fe3O4 were prepared by chemical methods and characterized using transmission electron microscopy, Raman spectroscopy, zeta analysis, and vibrating sample magnemeter. Dark and light cytotoxicity were screened with colorimetric Sulforhodamine B cell viability assay after 24 and 48 hours. DNA fragmentation and some apoptotic genes on a transcriptional RNA level expression were performed. All prepared nanomaterials were evaluated for their photothermal effect at concentrations of 10 and 50 µg/mL. The power density incident on the cells by 300 mW 808 IR diode laser was 0.597 W/cm2. Results: Treatment of HepG2 with 400 µg/mL of rGO, Fe3O4, and G/Fe3O4 showed alteration in cell morphology after 24 hours of cell treatment and revealed toxic effects on cellular DNA. Evaluation of the cytotoxic effects showed messenger RNA (mRNA) in ß-actin and Bax apoptotic genes, but no expression of mRNA of caspase-3 after 24 hours of cell exposure, suggesting the involvement of an intrinsic apoptotic caspase-independent pathway. A photothermal effect was observed for G/Fe3O4 after irradiation of the HepG2 cells. A marked decrease was found in cell viability when treated with 10 and 50 µg/mL G/Fe3O4 from 40% to 5% after 48 hours of cell treatment. Conclusion: Results indicate that G/Fe3O4 nanocomposite was effective at transformation of light into heat and is a promising candidate for cancer therapy.


Assuntos
Grafite/química , Hipertermia Induzida , Raios Infravermelhos , Neoplasias Hepáticas/terapia , Nanopartículas de Magnetita/química , Modelos Biológicos , Nanocompostos/química , Fototerapia , Apoptose/genética , Sobrevivência Celular/genética , Fragmentação do DNA , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Nanopartículas de Magnetita/ultraestrutura , Nanocompostos/ultraestrutura , Oxirredução , Análise Espectral Raman , Eletricidade Estática , Difração de Raios X
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