RESUMEN
Alzheimer's disease (AD) heavily impacts human lives and is becoming serious as societies age. Inhibiting and disaggregating ß-amyloid aggregates is a possible solution for AD therapy. In this study, a novel type of nanozyme based on Ru3+-chelated nanoscale metal organic frameworks (Ru3+-NMOFs), displaying strong peroxidase-like activity, was proposed as an inhibitor and disaggregator of ß-amyloid aggregates. As a high concentration of hydrogen peroxide is present at the sites of ß-amyloid aggregates, Ru3+-NMOFs could catalyze the conversion of hydrogen peroxide to hydroxyl radicals. Thus, these hydroxyl radicals would attack the ß-amyloid chain, oxidizing it to enhance its hydrophilicity, which results in a decreased hydrophobic interaction and reduced degree of aggregation. Ru3+-NMOFs could effectively inhibit as well as disaggregate ß-amyloid fibrils both in vitro and in vivo. Additionally, the reduction of the ß-amyloid aggregates and the attenuation of reactive oxygen species transfer led to lower levels of inflammatory factors, which could be beneficial in alleviating AD symptoms. In a typical treatment, Ru3+-NMOFs could mitigate the paralysis of C. elegans CL2120 and elevate survival rates. This study opens a new avenue for MOF-based nanozymes as potential treatment agents for AD therapy.
RESUMEN
The misfolding and aggregation of α-synuclein monomers usually cause the occurrence and development of Parkinson's disease (PD). It is important to develop effective methods for detection of α-synuclein aggregates. Carbon dots (CDs) could be the potential fluorescence probe for this purpose owing to their appreciated optical properties. However, undefined structure of CDs and complicated three-dimensional structure of protein severely hindered the design of fluorescence probe towards protein aggregates. Herein, a red emissive fluorescent amphiphilic CD, named as CL-9, was designed with a high sensitivity to α-synuclein fibrils by a one-step heating process, using the ternary carbon source, including Congo red, l-tryptophan and urea. The CL-9 exhibited turn-on red emissive fluorescence towards α-synuclein fibril, but remained no change towards its monomer. Compared with the original Congo red dye, CL-9 exhibited stronger turn-on red fluorescence towards α-synuclein fibrils with better anti-photobleaching resistance, biocompatibility and signal-to-noise ratio. The CL-9 was successful as a fluorescent probe to image α-synuclein fibrils in NL-5901 C. elegans. The present study provided a feasible approach using the multiple carbon sources to construct the CDs based fluorescence probe targeting amyloid proteins.
Asunto(s)
Carbono , Colorantes Fluorescentes , alfa-Sinucleína , alfa-Sinucleína/química , alfa-Sinucleína/análisis , Carbono/química , Colorantes Fluorescentes/química , Animales , Puntos Cuánticos/química , Humanos , Caenorhabditis elegans/metabolismo , Rojo Congo/química , Amiloide/química , Tamaño de la Partícula , Imagen ÓpticaRESUMEN
The aggregation of amyloid proteins is highly related to the occurrence and development of neurodegenerative and metabolic diseases. The detection of amyloid fibrils or monitoring fibrillation process would be necessary to understand the fundamental knowledge about the diseases and further facilitate the research for the drug discovery and disease treatment. In this study, three proto-berberine alkaloids, i.e. berberine, palmatine and coptisine, were examined as three distinctive fluorescent probes to detect amyloid fibrils. These three alkaloids were found to be sensitive to the microenvironment, i.e. viscosity and polarity, with varied fluorescence intensity. They could sensitively probe insulin and lysozyme fibrils with turn-on fluorescence, but did not respond to protein monomers, merited with advantages of larger Stokes shift, greenish-yellow fluorescence and no interference with the fibrillation process. Hydrophobic, electrostatic and hydrogen bond interactions were explored to exist between alkaloids and the fibrils. Moreover, these alkaloids succeeded in monitoring the aggregation process of amyloid proteins in vitro and imaging the fibrils in living cells. The present study demonstrates that the three alkaloids could be the potential candidate fluorescent probes for amyloid fibrils.
Asunto(s)
Alcaloides , Alcaloides de Berberina , Amiloide , Colorantes Fluorescentes/química , Fluorescencia , Proteínas AmiloidogénicasRESUMEN
The microvascular profile has been included in the WHO glioma grading criteria. Nevertheless, microvessels in gliomas of the same WHO grade, e.g., WHO IV glioblastoma (GBM), exhibit heterogeneous and polymorphic morphology, whose possible clinical significance remains to be determined. In this study, we employed a fractal geometry-derived parameter, microvascular fractal dimension (mvFD), to quantify microvessel complexity and developed a home-made macro in Image J software to automatically determine mvFD from the microvessel-stained immunohistochemical images of GBM. We found that mvFD effectively quantified the morphological complexity of GBM microvasculature. Furthermore, high mvFD favored the survival of GBM patients as an independent prognostic indicator and predicted a better response to chemotherapy of GBM patients. When investigating the underlying relations between mvFD and tumor growth by deploying Ki67/mvFD as an index for microvasculature-normalized tumor proliferation, we discovered an inverse correlation between mvFD and Ki67/mvFD. Furthermore, mvFD inversely correlated with the expressions of a glycolytic marker, LDHA, which indicated poor prognosis of GBM patients. Conclusively, we developed an automatic approach for mvFD measurement, and demonstrated that mvFD could predict the prognosis and response to chemotherapy of GBM patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas , Glioma , Interpretación de Imagen Asistida por Computador/métodos , Microvasos/patología , Neovascularización Patológica/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Fractales , Glioma/diagnóstico por imagen , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Inmunohistoquímica , Microvasos/diagnóstico por imagen , Clasificación del Tumor/métodos , Neovascularización Patológica/diagnóstico por imagen , PronósticoRESUMEN
Here, we report our results from quantitative structure-activity relationship studies on tyrosinase inhibitors. Interactions between benzoic acid derivatives and tyrosinase active sites were also studied using a molecular docking method. These studies indicated that one possible mechanism for the interaction between benzoic acid derivatives and the tyrosinase active site is the formation of a hydrogen-bond between the hydroxyl (aOH) and carbonyl oxygen atoms of Tyr98, which stabilized the position of Tyr98 and prevented Tyr98 from participating in the interaction between tyrosinase and ORF378. Tyrosinase, also known as phenoloxidase, is a key enzyme in animals, plants and insects that is responsible for catalyzing the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones. In the present study, the bioactivities of 48 derivatives of benzaldehyde, benzoic acid, and cinnamic acid compounds were used to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field (CoMFA) and comparative molecular similarity indices (CoMSIA) analyses. After superimposition using common substructure-based alignments, robust and predictive 3D-QSAR models were obtained from CoMFA (q2 = 0.855, r2 = 0.978) and CoMSIA (q2 = 0.841, r2 = 0.946), with 6 optimum components. Chemical descriptors, including electronic (Hammett sigma), hydrophobic (pi), and steric (MR) parameters, hydrogen bond acceptor (H-acc), and indicator variable (I), were used to construct a 2D-QSAR model. The results of this QSAR indicated that pi, MR, and H-acc account for 34.9, 31.6, and 26.7% of the calculated biological variance, respectively. The molecular interactions between ligand and target were studied using a flexible docking method (FlexX). The best scored candidates were docked flexibly, and the interaction between the benzoic acid derivatives and the tyrosinase active site was elucidated in detail. We believe that the QSAR models built here provide important information necessary for the design of novel tyrosinase inhibitors.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Monofenol Monooxigenasa/antagonistas & inhibidores , Agaricales/química , Benzoatos/química , Benzoatos/farmacología , Dominio Catalítico , Fenómenos Químicos , Química Física , Diseño Asistido por Computadora , Diseño de Fármacos , Enlace de Hidrógeno , Ligandos , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Electricidad EstáticaRESUMEN
Phenoloxidase (PO) is a key enzyme in insect development, responsible for catalyzing the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones. In the present study, the kinetic assay in air-saturated solutions and the kinetic behavior of PO from Pieris rapae (Lepidoptera) larvae in the oxidation of L-tyrosine (a monophenol) and L-DOPA (l-3, 4-dihydroxyphenylalanine) (a diphenol) was studied. The inhibitory effects of 3-hydroxy-4-methoxybenzaldehyde thiosemicarbazone (3-H-4-MBT) on the monophenolase and diphenolase activities of PO were also studied. The results show that 3-H-4-MBT can inhibit both the monophenolase and diphenolase activities of PO. The lag period of L-tyrosine oxidation catalyzed by the enzyme was obviously lengthened and the steady-state activities of the enzyme sharply decreased. The inhibitor was found to be noncompetitively reversible with a K I (K I = K IS) of 0.30 micromol/L and an estimated IC50 of 0.14 +/- 0.02 micromol/L for monophenolase and 0.26 +/- 0.04 micromol/L for diphenolase. In the time course of the oxidation of L-DOPA catalyzed by the enzyme in the presence of different concentrations of 3-H-4-MBT, the rate decreased with increasing time until a straight line was approached. The microscopic rate constants for the reaction of 3-H-4-MBT with the enzyme were determined.
Asunto(s)
Mariposas Diurnas/enzimología , Guayacol/análogos & derivados , Tiosemicarbazonas/farmacología , Animales , Guayacol/química , Guayacol/farmacología , Cinética , Larva/enzimología , Levodopa/metabolismo , Modelos Moleculares , Estructura Molecular , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/química , Monofenol Monooxigenasa/metabolismo , Oxidación-Reducción/efectos de los fármacos , Oxidorreductasas/antagonistas & inhibidores , Oxidorreductasas/química , Oxidorreductasas/metabolismo , Unión Proteica , Tiosemicarbazonas/química , Tirosina/metabolismoRESUMEN
Phenoloxidase (PO), also known as tyrosinase, is a key enzyme in insect development, responsible for catalyzing the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones. Inhibition of PO may provide a basis for novel environmentally friendly insecticides. In the present study, we determined the inhibitory activities and IC50 values of 57 compounds belonging to the benzaldehyde thiosemicarbazone, benzaldehyde, and benzoic acid families against phenoloxidase from Pieris rapae (Lepidoptera) larvae. In addition, the inhibitory kinetics of 4-butylbenzaldehyde thiosemicarbazone against PO was measured in air-saturated solutions for the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA). The results indicated that the compound is a reversible noncompetitive inhibitor. The bioactivity results were used to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models using two molecular field analysis techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). After carrying out superimposition using common substructure-based alignment, robust and predictive 3D-QSAR models were obtained from CoMFA (q2=0.926, r2=0.986) and CoMSIA (q2=0.933, r2=0.984) with six optimum components. The 3D-QSAR model built here will provide hints for the design of novel PO inhibitors. The molecular interactions between the ligands and the target were studied using a flexible docking method (FlexX). The best scored candidates were docked flexibly, and the interaction between the representative compound 4-butylbenzaldehyde thiosemicarbazone and the active site was elucidated in detail.
Asunto(s)
Benzaldehídos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Monofenol Monooxigenasa/antagonistas & inhibidores , Tiosemicarbazonas/farmacología , Benzaldehídos/química , Ácido Benzoico/química , Ácido Benzoico/farmacología , Enlace de Hidrógeno , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Tiosemicarbazonas/químicaRESUMEN
In this paper, the methanol- and water extracts of Sophora alopecuroids were applied respectively with emamectin, to study their effects on the growth, development, and fecundity of diamondback moth Plutella xylostella. The results showed that the oral toxicity of the mixtures to the 3rd larvae of P. xylostella was much higher than that of emamectin, with the medium lethal concentration (LC50) of methanol extract plus emamectin, water extract plus emamectin, and emamectin being 0.19, 0.32 and 0.51 mg L(-1), respectively. The pupated percentage, emergence percentage, and fecundity of P. xylotella were obviously negatively affected after treated the 3rd larvae with sub-lethal dosage of the mixtures and emamectin.