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1.
J Mater Chem B ; 9(37): 7835-7847, 2021 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-34586144

RESUMEN

Alzheimer's disease (AD) is an incurable neurodegenerative disease. Repairing damaged nerves and promoting nerve regeneration are key ways to relieve AD symptoms. However, due to the lack of effective strategies to deliver nerve growth factor (NGF) to the brain, achieving neuron regeneration is a major challenge for curing AD. Herein, a ROS-responsive ruthenium nanoplatform (R@NGF-Se-Se-Ru) drug delivery system for AD management by promoting neuron regeneration and Aß clearance was investigated. Under near-infrared (NIR) irradiation, nanoclusters have good photothermal properties, which can effectively inhibit the aggregation of Aß and disaggregate Aß fibrils. Interestingly, the diselenide bond in the nanoclusters is broken, and the nanoclusters are degraded into small ruthenium nanoparticles in the high reactive oxygen species (ROS) environment of the diseased area. Besides, NGF can promote neuronal regeneration and repair damaged nerves. Furthermore, R@NGF-Se-Se-Ru efficiently crosses the blood-brain barrier (BBB) owing to the covalently grafted target peptides of RVG (R). In vivo studies demonstrate that R@NGF-Se-Se-Ru nanoclusters decrease Aß deposits, inhibit Aß-induced cytotoxicity, and promote neurite outgrowth. The study confirms that promoting both Aß clearance and neuron regeneration is an important therapeutic target for anti-AD drugs and provides a novel insight for AD therapy.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Portadores de Fármacos/química , Nanoestructuras/química , Factor de Crecimiento Nervioso/uso terapéutico , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Materiales Biocompatibles/química , Materiales Biocompatibles/metabolismo , Materiales Biocompatibles/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular Tumoral , Hemólisis/efectos de los fármacos , Humanos , Rayos Infrarrojos , Factor de Crecimiento Nervioso/química , Factor de Crecimiento Nervioso/farmacología , Regeneración Nerviosa/efectos de los fármacos , Proyección Neuronal/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Rutenio/química , Selenio/química
2.
Food Funct ; 12(17): 7676-7687, 2021 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-34259275

RESUMEN

The aim of the study was to evaluate the neuroprotective function of sea cucumber ovum peptide-derived NDEELNK and explore the underlying molecular mechanisms. NDEELNK exerted the neuroprotective effect by improving the acetylcholine (ACh) level and reducing the acetylcholinesterase (AChE) activity in PC12 cells. By molecular docking, we confirmed that the NDEELNK backbone and AChE interacted through hydrophobic and hydrogen bonds in contact with the amino acid residues of the cavity wall. NDEELNK increased superoxide dismutase (SOD) activity and decreased reactive oxygen species (ROS) production, thereby reducing mitochondrial dysfunction and enhancing energy metabolism. Our results demonstrated that NDEELNK supplementation alleviated scopolamine-induced PC12 cell damage by improving the cholinergic system, increasing energy metabolism and upregulating the expression of phosphorylated protein kinase A (p-PKA), brain-derived neurotrophic factor (BNDF) and nerve growth factor (NGF) signaling proteins in in vitro experiments. These results demonstrated that the sea cucumber ovum peptide-derived NDEELNK might play a protective role in PC12 cells.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Trastornos de la Memoria/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Fármacos Neuroprotectores/farmacología , Péptidos/farmacología , Escopolamina/efectos adversos , Pepinos de Mar/química , Acetilcolinesterasa/genética , Acetilcolinesterasa/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/química , Factor Neurotrófico Derivado del Encéfalo/genética , Proteínas Quinasas Dependientes de AMP Cíclico/química , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Metabolismo Energético/efectos de los fármacos , Humanos , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/genética , Simulación del Acoplamiento Molecular , Factor de Crecimiento Nervioso/química , Factor de Crecimiento Nervioso/genética , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Ratas , Regulación hacia Arriba/efectos de los fármacos
3.
Phytomedicine ; 36: 128-136, 2017 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-29157806

RESUMEN

BACKGROUND: Protection of cochlear function and reconstruction of neuronal networks in damaged auditory sensory structures is crucial for therapeutic treatment of diabetic hearing loss. Nerve growth factor (NGF) has been used as a novel therapeutic target to protect against the neurodegenerative effects of Diabetes Mellitus (DM). PURPOSE: We aimed to evaluate the potential effect of trigonelline (TRG) on reducing auditory damage produced by DM using NGF as a potential marker. METHOD: Docking simulations were carried out using Autodock Vina software and visualized using Discovery Studio. Morphological analysis of hair cells and neuromasts was performed on alloxan-induced diabetic zebrafish by fluorescence and scanning electron microscopy. Blockage of NGF receptor phosphorylation with K-252a was used to evaluate TRG and NGF action. Further assessment of NGF by ELISA on a primary culture of spiral ganglion cells was performed as a marker of neuronal function on the hearing system. Finally, auditory function was assessed in LepR(db/db) mice using auditory brainstem response (ABR) and transient evoked otoacoustic emission (TEOAE) during 8 weeks. RESULTS: Docking simulations showed that TRG binds to the active site of NGF through molecular interactions with Lysine88 (Lys88) and Tyrosine52 (Tyr52). TRG treatment significantly reduced hair cell loss and neuromast damage in diabetic zebrafish (P < .05). Further evaluation revealed a significant increase in the number of neuromasts after NGF administration (P < .001). TRG and NGF action was suppressed during blockage of NGF receptor phosphorylation. Moreover, spiral ganglion cells revealed significant elevation on NGF values after TRG treatment (P < .05). In vivo evaluation of LepR(db/db) mice revealed a significant reduction in the auditory damage produced under diabetic progression, characterized by reduced ABR hearing threshold shifts and increased signal-to-noise ratio in TEOAE (P < .05). CONCLUSIONS: This study suggests that the enhanced hearing function produced by TRG may be mediated by NGF, providing a potential therapeutic strategy for diabetic hearing loss.


Asunto(s)
Alcaloides/farmacología , Umbral Auditivo/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Células Ciliadas Auditivas/efectos de los fármacos , Factor de Crecimiento Nervioso/metabolismo , Alcaloides/química , Animales , Carbazoles/farmacología , Dominio Catalítico , Simulación por Computador , Diabetes Mellitus Experimental/fisiopatología , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Femenino , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Alcaloides Indólicos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Factor de Crecimiento Nervioso/química , Emisiones Otoacústicas Espontáneas/efectos de los fármacos , Ratas Sprague-Dawley , Pez Cebra
4.
Mater Sci Eng C Mater Biol Appl ; 67: 590-598, 2016 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-27287158

RESUMEN

Nanoporous anodized alumina membranes (AAMs) have numerous biomedical applications spanning from biosensors to controlled drug delivery and implant coatings. Although the use of AAM as an alternative bone implant surface has been successful, its potential as a neural implant coating remains unclear. Here, we introduce conductive and nerve growth factor-releasing AAM substrates that not only provide the native nanoporous morphology for cell adhesion, but also induce neural differentiation. We recently reported the fabrication of such conductive membranes by coating AAMs with a thin C layer. In this study, we investigated the influence of electrical stimulus, surface topography, and chemistry on cell adhesion, neurite extension, and density by using PC 12 pheochromocytoma cells in a custom-made glass microwell setup. The conductive AAMs showed enhanced neurite extension and generation with the electrical stimulus, but cell adhesion on these substrates was poorer compared to the naked AAMs. The latter nanoporous material presents chemical and topographical features for superior neuronal cell adhesion, but, more importantly, when loaded with nerve growth factor, it can provide neurite extension similar to an electrically stimulated CAAM counterpart.


Asunto(s)
Óxido de Aluminio/química , Conductividad Eléctrica , Membranas Artificiales , Factor de Crecimiento Nervioso , Animales , Adhesión Celular/efectos de los fármacos , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Factor de Crecimiento Nervioso/química , Factor de Crecimiento Nervioso/farmacocinética , Factor de Crecimiento Nervioso/farmacología , Células PC12 , Ratas
5.
J Tissue Eng Regen Med ; 10(8): 656-68, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-23950083

RESUMEN

Spinal cord injury results in tissue necrosis in and around the lesion site, commonly leading to the formation of a fluid-filled cyst. This pathological end point represents a physical gap that impedes axonal regeneration. To overcome the obstacle of the cavity, we have explored the extent to which axonal substrates can be bioengineered through electrospinning, a process that uses an electrical field to produce fine fibres of synthetic or biological molecules. Recently, we demonstrated the potential of electrospinning to generate an aligned matrix that can influence the directionality and growth of axons. Here, we show that this matrix can be supplemented with nerve growth factor and chondroitinase ABC to provide trophic support and neutralize glial-derived inhibitory proteins. Moreover, we show how air-gap electrospinning can be used to generate a cylindrical matrix that matches the shape of the cord. Upon implantation in a completely transected rat spinal cord, matrices supplemented with NGF and chondroitinase ABC promote significant functional recovery. An examination of these matrices post-implantation shows that electrospun aligned monofilaments induce a more robust cellular infiltration than unaligned monofilaments. Further, a vascular network is generated in these matrices, with some endothelial cells using the electrospun fibres as a growth substrate. The presence of axons within these implanted matrices demonstrates that they facilitate axon regeneration following spinal cord injury. Collectively, these results demonstrate the potential of electrospinning to generate an aligned substrate that can provide trophic support, directional guidance cues and regeneration-inhibitory neutralizing compounds to regenerating axons following spinal cord injury. Copyright © 2016 John Wiley & Sons, Ltd.


Asunto(s)
Axones/metabolismo , Condroitina ABC Liasa , Factor de Crecimiento Nervioso , Traumatismos de la Médula Espinal/terapia , Regeneración de la Medula Espinal/efectos de los fármacos , Andamios del Tejido/química , Animales , Axones/patología , Condroitina ABC Liasa/química , Condroitina ABC Liasa/farmacología , Factor de Crecimiento Nervioso/química , Factor de Crecimiento Nervioso/farmacología , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología
6.
ACS Chem Neurosci ; 6(8): 1379-92, 2015 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-25939060

RESUMEN

Ever since the discovery of its neurite growth promoting activity in sympathetic and sensory ganglia, nerve growth factor (NGF) became the prototype of the large family of neurotrophins. The use of primary cultures and clonal cell lines has revealed several distinct actions of NGF and other neurotrophins. Among several models of NGF activity, the clonal cell line PC12 is the most widely employed. Thus, in the presence of NGF, through the activation of the transmembrane protein TrkA, these cells undergo a progressive mitotic arrest and start to grow electrically excitable neuritis. A vast number of studies opened intriguing aspects of NGF mechanisms of action, its biological properties, and potential use as therapeutic agents. In this context, identifying and utilizing small portions of NGF is of great interest and involves several human diseases including Alzheimer's disease. Here we report the specific action of the peptide encompassing the 1-14 sequence of the human NGF (NGF(1-14)), identified on the basis of scattered indications present in literature. The biological activity of NGF(1-14) was tested on PC12 cells, and its binding with TrkA was predicted by means of a computational approach. NGF(1-14) does not elicit the neurite outgrowth promoting activity, typical of the whole protein, and it only has a moderate action on PC12 proliferation. However, this peptide exerts, in a dose and time dependent fashion, an effective and specific NGF-like action on some highly conserved and biologically crucial intermediates of its intracellular targets such as Akt and CREB. These findings indicate that not all TrkA pathways must be at all times operative, and open the possibility of testing each of them in relation with specific NGF needs, biological actions, and potential therapeutic use.


Asunto(s)
Factor de Crecimiento Nervioso/química , Factor de Crecimiento Nervioso/farmacología , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Animales , Aumento de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Simulación del Acoplamiento Molecular , Factor de Crecimiento Nervioso/genética , Neuritas/efectos de los fármacos , Neuritas/fisiología , Neurogénesis/efectos de los fármacos , Fármacos Neuroprotectores/química , Células PC12 , Fosforilación/efectos de los fármacos , Ratas , Receptor trkA/metabolismo , Factores de Tiempo
7.
Colloids Surf B Biointerfaces ; 110: 450-7, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-23759386

RESUMEN

In order to fabricate a tissue scaffold with the neurotrophic and electrical activities, conductive nerve growth factor (NGF)-conjugated polypyrrole-poly(l-lactic acid) (PPy-PLLA) composite fibers were prepared by oxidation polymerization and EDC chemistry with poly-l-lysine. PPy nanoparticles (∼70nm diameter) accumulated on PLLA fiber surface to form a rough thick shell (∼200nm thickness). These NGF-conjugated PPy-PLLA fibers could support PC12 neurite outgrowth and extension. Especially, 40% and 74% increase in PC12 neurite outgrowth and extension, respectively, could be obtained under electrical stimulation of 100mV/cm voltages through the composite fibers. A mechanism for the interaction between neurite extension and the NGF-conjugated PPy-PLLA fibers under electro-stimulation was proposed, to explain the synergistic effect of the rough PPy shell, conjugated NGF and electricity on neurite outgrowth and elongation.


Asunto(s)
Ácido Láctico/farmacología , Factor de Crecimiento Nervioso/química , Neuritas/efectos de los fármacos , Polímeros/farmacología , Pirroles/farmacología , Animales , Conductividad Eléctrica , Ácido Láctico/química , Neuritas/metabolismo , Oxidación-Reducción , Células PC12 , Tamaño de la Partícula , Poliésteres , Polimerizacion , Polímeros/química , Pirroles/química , Ratas , Propiedades de Superficie
8.
Zhongguo Zhong Yao Za Zhi ; 36(17): 2358-60, 2011 Sep.
Artículo en Chino | MEDLINE | ID: mdl-22121803

RESUMEN

OBJECTIVE: To search for low-molecular-weight neuritogenic compounds from the traditional Chinese medicine (TCM). METHOD: An extract library of TCM was prepared. Targeted isolation guided by biological screening led to the discovery of compound 1, and its structure was elucidated by analysis of spectroscopic methods and comparison of spectroscopic data with these reported from the literature. RESULT: A neuritogenic compound 1, 3-O-beta-D-glucopyranosyl-22E, 24R-5alpha, 8alpha-epidioxyergosta-6, 22-diene, was isolated and identified from the methanol extract of T. fuciformis. This compound showed a significant neuritogenic activity against PC12 cells at 3 micromol x L(-1)). CONCLUSION: Methonal extract of T. fuciformis and targeted compound 1 both showed significant neuritogenic activity against PC12 cells. These results suggested that the extract and compound 1 might be used to prevent and treat neurodegenerative disease such as Alzheimer's disease.


Asunto(s)
Basidiomycota/química , Medicamentos Herbarios Chinos/química , Factor de Crecimiento Nervioso/química , Animales , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Estructura Molecular , Factor de Crecimiento Nervioso/aislamiento & purificación , Factor de Crecimiento Nervioso/farmacología , Neuritas/efectos de los fármacos , Células PC12 , Ratas
9.
Chem Pharm Bull (Tokyo) ; 56(1): 60-3, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18175976

RESUMEN

In the screening of biologically active constituents from woody plants, the methanol extract of leaves of Chamaecyparis obtusa showed potent neurite outgrowth-promoting activity in neuronal PC12 cells. The ethyl acetate-soluble fraction of the methanol extract showed potent activity and was separated by means of various chromatographic methods to give the two new compounds 1 and 2, as well as 11 known lignan and sesquiterpene derivatives. The structures of the new compounds were determined to be 9-O-acetyldihydrosesamin (1) and 9-O-(11-hydroxyeudesman-4-yl)dihydrosesamin (2), respectively, in NMR studies including 2D-NMR experiments. Of the 13 compounds, the known compound hinokinin (5) and the new compound 2 showed potent neurite outgrowth-promoting activity in PC 12 cells.


Asunto(s)
4-Butirolactona/análogos & derivados , Chamaecyparis/química , Dioxoles/aislamiento & purificación , Dioxoles/farmacología , Lignanos/aislamiento & purificación , Lignanos/farmacología , Factor de Crecimiento Nervioso/aislamiento & purificación , Factor de Crecimiento Nervioso/farmacología , Neuritas/efectos de los fármacos , Plantas Medicinales/química , 4-Butirolactona/química , 4-Butirolactona/aislamiento & purificación , 4-Butirolactona/farmacología , Animales , Benzodioxoles , Dioxoles/química , Lignanos/química , Estructura Molecular , Factor de Crecimiento Nervioso/química , Células PC12 , Hojas de la Planta/química , Ratas
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