RESUMEN
Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD+) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Glioma/tratamiento farmacológico , Ensayos Analíticos de Alto Rendimiento/métodos , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Muerte Celular , Línea Celular Tumoral , Sinergismo Farmacológico , Femenino , Glioma/genética , Glioma/metabolismo , Humanos , Lactonas/farmacología , Lactonas/uso terapéutico , Masculino , Metabolómica , Ratones , Panobinostat/farmacología , Panobinostat/uso terapéutico , Pirroles/farmacología , Pirroles/uso terapéutico , Reproducibilidad de los Resultados , Análisis de Secuencia de ARN , Transcripción Genética/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/patología , Inmunosupresores/uso terapéutico , Metotrexato/uso terapéutico , Vaina de Mielina/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Trastornos del Conocimiento/genética , Modelos Animales de Enfermedad , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Vaina de Mielina/patología , Vaina de Mielina/ultraestructura , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Compuestos Orgánicos/uso terapéutico , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Urea/análogos & derivados , Urea/metabolismoRESUMEN
Skin protection and control of its microbial pathogens are highly important demands; natural biological agents are the ideals for that. Collagen (Cg) was extracted and characterized from skin and scales of Nile tilapia fish (Oreochromis niloticus), chitosan (Cts) was extracted from shrimp shells and extract of oak (Quercus infectoria) galls (OGE) was prepared. The antimicrobial potentialities of extracted agents, Cts and OGE, were qualitatively proved against skin pathogens, Staphylococcus aureus and Candida albicans, including both antibiotic sensitive and resistant strains, neither Cg nor negative control exhibited antimicrobial actions toward examined strain. The entire agents were loaded onto cotton fabrics and evaluated for antimicrobial actions and durability. Loaded textiles with the combined extracts' composite were the most effectual followed by individual treatments with OGE and Cts, respectively. Treated textiles upheld most of their antimicrobial activity after 2 laundering cycles toward all microbial pathogens. This invention could be consequently applied for production of skin protectant and hygienic fabrics.