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Glioblastoma (GBM) is the most aggressive and lethal malignant brain tumor, and it is challenging to cure with surgery and treatment. The prevention of permanent brain damage and tumor invasion, which is the ultimate cause of recurrence, are major obstacles in GBM treatment. Besides, emerging treatment modalities and newer genetic findings are helping to understand and manage GBM in patients. Accordingly, researchers are focusing on advanced nanomaterials-based strategies for tackling the various problems associated with GBM. In this context, researchers explored novel strategies with various alternative treatment approaches such as early detection techniques and theranostics approaches. In this review, we have emphasized the recent advancement of GBM cellular models and their roles in designing GBM therapeutics. We have added a special emphasis on the novel genetic and drug target findings as well as strategies for early detection. Besides, we have discussed various theranostic approaches such as hyperthermia therapy, phototherapy and image-guided therapy. Approaches utilized for targeted drug delivery to the GBM were also discussed. This article also describes the recentin vivo, in vitroandex vivoadvances using innovative theranostic approaches.
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Glioblastoma , Hipertermia Inducida , Humanos , Medicina de Precisión , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Hipertermia Inducida/métodos , Fototerapia , Sistemas de Liberación de MedicamentosRESUMEN
INTRODUCTION: Prion diseases are a group of rare and lethal, rapidly progressive neurodegenerative diseases arising due to conversion of the physiological cellular prion protein into its pathological counterparts, denoted as 'prions.' These agents are resistant to inactivation by standard decontamination procedures and can be transmitted between individuals, consequently driving the irreversible brain damage typical of the diseases. AREAS COVERED: Since its infancy, prion research has mainly depended on animal models for untangling the pathogenesis of the disease as well as for the drug development studies. With the advent of prion-infected cell lines, relevant animal models have been complemented by a variety of cell-based models presenting a much faster, ethically acceptable alternative. EXPERT OPINION: To date, there are still either no effective prophylactic regimens or therapies for human prion diseases. Therefore, there is an urgent need for more relevant cellular models that best approximate in vivo models. Each cellular model presented and discussed in detail in this review has its own benefits and limitations. Once embarking in a drug screening campaign for the identification of molecules that could interfere with prion conversion and replication, one should carefully consider the ideal cellular model.
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Enfermedades por Prión , Priones , Animales , Desarrollo de Medicamentos , Evaluación Preclínica de Medicamentos , Humanos , Enfermedades por Prión/tratamiento farmacológico , Proteínas Priónicas , Priones/metabolismoRESUMEN
Advances in the research of nanoparticles (NPs) with controlled charge and size are driven by their potential application in the development of novel technologies and innovative therapeutics. This work reports the synthesis, characterization, and comprehensive biological evaluation of AgNPs functionalized by N,N,N-trimethyl-(11-mercaptoundecyl) ammonium chloride (TMA) and trisodium citrate (TSC). The prepared AgNPs were well characterized in terms of their morphological, spectroscopic and functional properties and biological activities. The implementation of several complementary techniques allowed not only the estimation of the average particle size (from 3 to 40 nm depending on the synthesis procedure used) but also the confirmation of the crystalline nature of the NPs and their round shape. To prove the usefulness of these materials in biological systems, cellular uptake and cytotoxicity in microbial and mammalian cells were determined. Positively charged 10 nm Ag@TMA2 revealed antimicrobial activity against Gram-negative bacteria with a minimum inhibitory concentration (MIC) value of 0.17 µg/mL and complete eradication of Escherichia coli (7 logs) for Ag@TMA2 at a concentration of 0.50 µg/mL, whereas negatively charged 10 nm Ag@TSC1 was effective against Gram-positive bacteria (MIC = 0.05 µg/mL), leading to inactivation of Staphylococcus aureus at relatively low concentrations. In addition, the largest 40 nm Ag@TSC2 was shown to exhibit pronounced anticancer activity against murine colon carcinoma (CT26) and murine mammary gland carcinoma (4T1) cells cultured as 2D and 3D tumor models and reduced toxicity against human HaCaT keratinocytes. Among the possible mechanisms of AgNPs are their ability to generate reactive oxygen species, which was further evaluated in vitro and correlates well with cellular accumulation and overall activity of AgNPs. Furthermore, we confirmed the anticancer efficacy of the most potent Ag@TSC2 in hiPSC-derived colonic organoids and demonstrated that the NPs are biocompatible and applicable in vivo. A pilot study in BALB/c mice evidenced that the treatment with Ag@TSC2 resulted in temporary (>60 days) remission of CT26 tumors.
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Nanopartículas del Metal , Plata , Animales , Antibacterianos/química , Antibacterianos/farmacología , Mamíferos , Nanopartículas del Metal/química , Ratones , Pruebas de Sensibilidad Microbiana , Proyectos Piloto , Plata/química , Plata/farmacologíaRESUMEN
Huntington disease (HD) is a devastating and presently untreatable neurodegenerative disease characterized by progressively disabling motor and mental manifestations. The sigma-1 receptor (σ1R) is a protein expressed in the central nervous system, whose 3D structure has been recently determined by X-ray crystallography and whose agonists have been shown to have neuroprotective activity in neurodegenerative diseases. To identify therapeutic agents against HD, we have implemented a drug repositioning strategy consisting of: (i) Prediction of the ability of the FDA-approved drugs publicly available through the ZINC database to interact with σ1R by virtual screening, followed by computational docking and visual examination of the 20 highest scoring drugs; and (ii) Assessment of the ability of the six drugs selected by computational analyses to directly bind purified σ1R in vitro by Surface Plasmon Resonance and improve the growth of fibroblasts obtained from HD patients, which is significantly impaired with respect to control cells. All six of the selected drugs proved able to directly bind purified σ1R in vitro and improve the growth of HD cells from both or one HD patient. These results support the validity of the drug repositioning procedure implemented herein for the identification of new therapeutic tools against HD.
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Fibroblastos/citología , Enfermedad de Huntington/metabolismo , Preparaciones Farmacéuticas/química , Receptores sigma/metabolismo , Adulto , Proliferación Celular , Células Cultivadas , Simulación por Computador , Bases de Datos Farmacéuticas , Evaluación Preclínica de Medicamentos , Reposicionamiento de Medicamentos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Enfermedad de Huntington/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Modelos Moleculares , Simulación del Acoplamiento Molecular , Conformación Proteica , Receptores sigma/química , Relación Estructura-Actividad , Resonancia por Plasmón de Superficie , Receptor Sigma-1RESUMEN
Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.
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Galactosemias/genética , Galactosemias/fisiopatología , Animales , Modelos Animales de Enfermedad , Galactoquinasa/genética , Galactoquinasa/metabolismo , Galactosa/metabolismo , Galactosemias/metabolismo , Galactosemias/terapia , Genotipo , Humanos , Estrés Oxidativo , Fenotipo , UDPglucosa 4-Epimerasa/genética , UDPglucosa 4-Epimerasa/metabolismo , UTP-Hexosa-1-Fosfato Uridililtransferasa/genética , UTP-Hexosa-1-Fosfato Uridililtransferasa/metabolismoRESUMEN
Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are highly expressed in tumor cells, as well as in organs involved in absorption and secretion processes, mediating the ATP-dependent efflux of compounds, both endogenous substances and xenobiotics, including drugs. Their expression and activity levels are modulated by the presence of inhibitors, inducers and/or activators. In vitro, ex vivo and in vivo studies with both known and newly synthesized P-glycoprotein (P-gp) inducers and/or activators have shown the usefulness of these transport mechanisms in reducing the systemic exposure and specific tissue access of potentially harmful compounds. This article focuses on the main ABC transporters involved in multidrug resistance [P-gp, multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP)] expressed in tissues of toxicological relevance, such as the blood-brain barrier, cardiovascular system, liver, kidney and intestine. Moreover, it provides a review of the available cellular models, in vitro and ex vivo assays for the screening and selection of safe and specific inducers and activators of these membrane transporters. The available cellular models and in vitro assays have been proposed as high throughput and low-cost alternatives to excessive animal testing, allowing the evaluation of a large number of compounds.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Descubrimiento de Drogas , Resistencia a Medicamentos/efectos de los fármacos , Modelos Biológicos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/química , Animales , Evaluación Preclínica de Medicamentos/métodos , Humanos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/química , Especificidad de Órganos , Relación Estructura-ActividadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Gelsemium sempervirens L. is a traditional medicinal plant mainly distributed in the southeastern of the United States, employed in phytotheraphy and homeopathy as nervous system relaxant to treat various types of anxiety, pain, headache and other ailments. Although animal models showed its effectiveness, the mechanisms by which it might operate on the nervous system are largely unknown. This study investigated for the first time by a real-time PCR technique (RT-PCR Array) the gene expression of a panel of human neurotransmitter receptors and regulators, involved in neuronal excitatory signaling, on a neurocyte cell line. MATERIALS AND METHODS: Human SH-SY5Y neuroblastoma cells were exposed for 24h to Gelsemium sempervirens at 2c and 9c dilutions (i.e. 2 and 9-fold centesimal dilutions from mother tincture) and the gene expression profile compared to that of cells treated with control vehicle solutions. RESULTS: Exposure to the Gelsemium sempervirens 2c dilution, containing a nanomolar concentration of active principle gelsemine, induced a down-regulation of most genes of this array. In particular, the treated cells showed a statistically significant decrease of the prokineticin receptor 2, whose ligand is a neuropeptide involved in nociception, anxiety and depression-like behavior. CONCLUSIONS: Overall, the results indicate a negative modulation trend in neuronal excitatory signaling, which can suggest new working hypotheses on the anxiolytic and analgesic action of this plant.