Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Más filtros

Bases de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Chemistry ; 30(7): e202303194, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37967312

RESUMEN

Developing peptide-based materials with controlled morphology is a critical theme of soft matter research. Herein, we report the formation of a novel, patterned cross-ß structure formed by self-assembled C3 -symmetric peptide amphiphiles based on diphenylalanine and benzene-1,3,5-tricarboxamide (BTA). The cross-ß motif is an abundant structural element in amyloid fibrils and aggregates of fibril-forming peptides, including diphenylalanine. The incorporation of topological constraints on one edge of the diphenylalanine fragment limits the number of ß-strands in ß-sheets and leads to the creation of an unconventional offset-patterned cross-ß structure consisting of short 3×2 parallel ß-sheets stabilized by phenylalanine zippers. In the reported assembly, two patterned cross-ß structures bind parallel arrays of BTA stacks in a superstructure within a single-molecule-thick nanoribbon. In addition to a threefold network of hydrogen bonds in the BTA stack, each molecule becomes simultaneously bound by hydrogen bonds from three ß-sheets and four phenylalanine zippers. The diffuse layer of alkyl chains with terminal polar groups prevents the nanoribbons from merging and stabilizes cross-ß-structure in water. Our results provide a simple approach to the incorporation of novel patterned cross-ß motifs into supramolecular superstructures and shed light on the general mechanism of ß-sheet formation in C3 -symmetric peptide amphiphiles.


Asunto(s)
Amiloide , Péptidos , Estructura Secundaria de Proteína , Péptidos/química , Amiloide/química , Conformación Proteica en Lámina beta , Fenilalanina
2.
Int J Mol Sci ; 22(11)2021 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-34073117

RESUMEN

We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal-curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of ß-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.


Asunto(s)
Curcumina/farmacología , Trasplante de Células Madre Mesenquimatosas , Nanoconjugados/uso terapéutico , Fármacos Neuroprotectores/farmacología , Recuperación de la Función , Traumatismos de la Médula Espinal/terapia , Acetales/uso terapéutico , Animales , Células Cultivadas , Femenino , Humanos , Células Madre Pluripotentes Inducidas , Células Madre Mesenquimatosas , Células-Madre Neurales , Polímeros/uso terapéutico , Ratas , Ratas Sprague-Dawley
3.
Drug Discov Today ; 26(6): 1369-1381, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33677144

RESUMEN

The success of preclinical drug discovery strongly relies on the ability of experimental models to resemble human pathophysiology. The number of compounds receiving approval for clinical use is limited, and this has led to the development of more physiologically relevant cellular models aimed at making preclinical results more prone to be successfully translated into clinical use. In this review, we summarize the technologies available in the field of high-throughput screening (HTS) using complex cellular models, and describe collaborative initiatives, such as EU-OPENSCREEN, which can efficiently support researchers to easily access state-of-the-art chemical biology platforms for improving the drug discovery process.


Asunto(s)
Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Investigación/organización & administración , Animales , Conducta Cooperativa , Evaluación Preclínica de Medicamentos/métodos , Humanos , Técnicas In Vitro , Modelos Biológicos , Proyectos de Investigación
4.
Sci Rep ; 10(1): 2056, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32029842

RESUMEN

The lack of effective pharmacological treatments for acute kidney injury (AKI) remains a significant public health problem. Given the involvement of apoptosis and regulated necrosis in the initiation and progression of AKI, the inhibition of cell death may contribute to AKI prevention/recovery. Curcuminoids are a family of plant polyphenols that exhibit attractive biological properties that make them potentially suitable for AKI treatment. Now, in cultured tubular cells, we demonstrated that a crosslinked self-assembled star-shaped polyglutamate (PGA) conjugate of bisdemethoxycurcumin (St-PGA-CL-BDMC) inhibits apoptosis and necroptosis induced by Tweak/TNFα/IFNγ alone or concomitant to caspase inhibition. St-PGA-CL-BDMC also reduced NF-κB activation and subsequent gene transcription. In vivo, St-PGA-CL-BDMC prevented renal cell loss and preserved renal function in mice with folic acid-induced AKI. Mechanistically, St-PGA-CL-BDMC inhibited AKI-induced apoptosis and expression of ferroptosis markers and also decreased the kidney expression of genes involved in tubular damage and inflammation, while preserving the kidney expression of the protective factor, Klotho. Thus, due to renal accumulation and attractive pharmacological properties, the application of PGA-based therapeutics may improve nephroprotective properties of current AKI treatments.


Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Diarilheptanoides/farmacología , Túbulos Renales/efectos de los fármacos , Ácido Poliglutámico/farmacología , Sustancias Protectoras/farmacología , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/inmunología , Lesión Renal Aguda/patología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Línea Celular , Diarilheptanoides/química , Diarilheptanoides/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Ácido Fólico/toxicidad , Glucuronidasa/metabolismo , Humanos , Túbulos Renales/patología , Proteínas Klotho , Ratones , Conformación Molecular , FN-kappa B/metabolismo , Necrosis/tratamiento farmacológico , Necrosis/inmunología , Necrosis/patología , Ácido Poliglutámico/química , Ácido Poliglutámico/uso terapéutico , Sustancias Protectoras/química , Sustancias Protectoras/uso terapéutico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacos
5.
SLAS Discov ; 24(3): 398-413, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30616481

RESUMEN

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3 H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.


Asunto(s)
Conducta Cooperativa , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos , Europa (Continente) , Ensayos Analíticos de Alto Rendimiento , Humanos , Relación Estructura-Actividad
6.
Macromol Rapid Commun ; 39(19): e1800265, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30062740

RESUMEN

The high incidence of prostate carcinogenesis has prompted the search for novel effective treatment approaches. We have employed curcumin (Curc) and diethylstilbestrol (DES) to synthesize a series of polyacetal (PA)-based combination conjugates for prostate cancer (PCa) treatment. Given their bihydroxyl functionalities, Curc and DES molecules were incorporated into a PA mainchain using a one-pot reaction between diols and divinyl ethers. The PA-conjugates released both drugs under acidic conditions, such as those found in the tumor microenvironment, endosomes, or lysosomes, while remaining stable at neutral pH 7.4. The drug ratio was optimized to achieve anticancer drug synergism with elevated cytotoxicity against LNCaP-hormone-dependent human PCa cells conferred via the induction of S phase cell cycle arrest by the upregulation of p53 and CDK inhibitors p21Waf/CIP1 and downregulation of cyclin D1. The application of rationally designed PA-Curc-DES combination conjugates represents a potentially exciting new treatment for prostate cancer.


Asunto(s)
Acetales/química , Antineoplásicos , Curcumina/química , Dietilestilbestrol/química , Polímeros/química , Neoplasias de la Próstata/tratamiento farmacológico , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Humanos , Masculino , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología
7.
Biomaterials ; 113: 18-30, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27810639

RESUMEN

Spinal cord injury (SCI) suffers from a lack of effective therapeutic strategies. Animal models of acute SCI have provided evidence that transplantation of ependymal stem/progenitor cells of the spinal cord (epSPCs) induces functional recovery, while systemic administration of the anti-inflammatory curcumin provides neuroprotection. However, functional recovery from chronic stage SCI requires additional enhancements in available therapeutic strategies. Herein, we report on a combination treatment for SCI using epSPCs and a pH-responsive polymer-curcumin conjugate. The incorporation of curcumin in a pH-responsive polymeric carrier mainchain, a polyacetal (PA), enhances blood bioavailability, stability, and provides a means for highly localized delivery. We find that PA-curcumin enhances neuroprotection, increases axonal growth, and can improve functional recovery in acute SCI. However, when combined with epSPCs, PA-curcumin also enhances functional recovery in a rodent model of chronic SCI. This suggests that combination therapy may be an exciting new therapeutic option for the treatment of chronic SCI in humans.


Asunto(s)
Acetales/química , Antiinflamatorios no Esteroideos/uso terapéutico , Curcumina/uso terapéutico , Preparaciones de Acción Retardada/química , Polímeros/química , Traumatismos de la Médula Espinal/terapia , Médula Espinal/efectos de los fármacos , Trasplante de Células Madre , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Células Cultivadas , Curcumina/administración & dosificación , Curcumina/química , Femenino , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/uso terapéutico , Ratas Sprague-Dawley , Recuperación de la Función , Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/fisiopatología , Trasplante de Células Madre/métodos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA