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1.
Nat Rev Neurosci ; 21(11): 611-624, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32929261

RESUMEN

Renewed interest in the use of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. After a hiatus of about 50 years, state-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing. In addition, functional studies have shown that changes in self-experience, emotional processing and social cognition may contribute to the potential therapeutic effects of psychedelics. These discoveries provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.


Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Alucinógenos/administración & dosificación , Trastornos Mentales/tratamiento farmacológico , Animales , Cateninas/efectos de los fármacos , Cateninas/fisiología , Emociones/efectos de los fármacos , Emociones/fisiología , Humanos , Trastornos Mentales/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Receptores de Serotonina/fisiología , Autoimagen , Catenina delta
2.
Pharmacol Res ; 97: 70-8, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25917209

RESUMEN

Human bone marrow derived mesenchymal stem cells (BM-MSCs) are a novel cell source used in stem cell therapy to treat bone diseases owing to their high potential to differentiate into osteoblasts. Effective induction of osteogenic differentiation from human BM-MSCs is critical to fulfill their therapeutic potential. In this study, Ginkgo biloba extract (GBE), a traditional herbal medicine, was used to stimulate the proliferation and osteogenic differentiation of human BM-MSCs. The present study revealed that GBE improved the proliferation and osteogenesis of human BM-MSCs in a dose-dependent manner in the range 25-75 mg/l, as indicated by alkaline phosphatase (ALP) activity and calcium content. However, such effect was decreased or inhibited at 100mg/l or higher. The dose-dependent improvement in osteogenesis of human BM-MSCs by GBE was further confirmed by the dose-dependent upregulation of marker genes, osteopontin (OPN) and Collagen I. The increased osteoprotegerin (OPG) expression and minimal expression of receptor activator of nuclear factor-κB ligand (RANKL) suggested that GBE also inhibited osteoclastogenesis of human BM-MSCs. Further mechanistic study demonstrated that the transcriptional levels of bone morphogenetic protein 4 (BMP4) and runt-related transcription factor 2 (RUNX2) in the BMP signaling, ß-catenin and Cyclin D1 in the Wnt/ß-catenin signaling, increased significantly during GBE-promoted osteogenesis. Meanwhile, loss-of-function assay with the signaling inhibitor(s) confirmed that the BMP and Wnt/ß-catenin signaling pathways were indispensable during the GBE-promoted osteogenesis, suggesting that GBE improved osteogenesis via upregulation of the BMP and Wnt/ß-catenin signaling. The present study proposed GBE to be used to upregulate the osteogenic differentiation of human BM-MSCs for new bone formation in BM-MSC-based cell therapy, which could provide an attractive and promising treatment for bone disorders.


Asunto(s)
Células de la Médula Ósea/efectos de los fármacos , Cateninas/efectos de los fármacos , Ginkgo biloba/química , Células Madre Mesenquimatosas/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Extractos Vegetales/farmacología , Proteínas Wnt/efectos de los fármacos , Fosfatasa Alcalina/metabolismo , Proteína Morfogenética Ósea 4/efectos de los fármacos , Calcio/metabolismo , Colágeno Tipo I/biosíntesis , Subunidad alfa 1 del Factor de Unión al Sitio Principal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Osteopontina/biosíntesis , Ligando RANK/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
3.
Toxicol Appl Pharmacol ; 256(2): 114-21, 2011 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-21854796

RESUMEN

Long term exposure to arsenic can increase incidence of human cancers, such as skin, lung, and colon rectum. The mechanism of arsenic induced carcinogenesis is still unclear. It is generally believed that reactive oxygen species (ROS) may play an important role in this process. In the present study, we investigate the possible linkage between ROS, ß-catenin and arsenic induced transformation and tumorigenesis in human colorectal adenocarcinoma cell line, DLD1 cells. Our results show that arsenic was able to activate p47(phox) and p67(phox), two key proteins for activation of NADPH oxidase. Arsenic was also able to generate ROS in DLD1 cells. Arsenic increased ß-catenin expression level and its promoter activity. ROS played a major role in arsenic-induced ß-catenin activation. Treatment of DLD1 cells by arsenic enhanced both transformation and tumorigenesis of these cells. The tumor volumes of arsenic treated group were much larger than those without arsenic treatment. Addition of either superoxide dismutase (SOD) or catalase reduced arsenic induced cell transformation and tumor formation. The results indicate that ROS are involved in arsenic induced cell transformation and tumor formation possible through Wnt/ß-catenin pathway in human colorectal adenocarcinoma cell line DLD1 cells.


Asunto(s)
Adenocarcinoma/fisiopatología , Arsenicales/farmacología , Cateninas/fisiología , Transformación Celular Neoplásica/efectos de los fármacos , Neoplasias Colorrectales/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Wnt/fisiología , Adenocarcinoma/metabolismo , Animales , Western Blotting , Pruebas de Carcinogenicidad , Cateninas/efectos de los fármacos , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/metabolismo , Espectroscopía de Resonancia por Spin del Electrón , Activación Enzimática/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Desnudos , NADPH Oxidasas/metabolismo , Transducción de Señal/fisiología , Proteínas Wnt/efectos de los fármacos , beta Catenina/metabolismo
4.
J Neurosci Res ; 88(16): 3621-34, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20936696

RESUMEN

Atorvastatin (ATV), a 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, exerts beneficial effects on stroke through several pleiotropic mechanisms. However, its role following cerebral ischemia is not completely understood yet. We evaluated the effect of ATV treatment on the synaptic adhesion proteins after a transient middle cerebral artery occlusion (t-MCAO) model in rats. Ischemic male Wistar rats were treated with 10 mg/kg ATV. The first dose was 6 hr after reperfusion, then every 24 hr for 3days. Our findings showed that ATV treatment produced an increase in pAkt ser473 and a decrease in pMAPK 44/42 protein levels 12 and 24 hr postischemia in the cerebral cortex and the hippocampus. However, p120 catenin and αN-catenin became drastically increased throughout the temporal course of postischemia treatment (12-72 hr), mainly in the hippocampus. Neurological recovery was observed at 48 and 72 hr, supported by a significant reduction of infarct volume, neuronal loss, and glial hyperreactivity after 72 hr of postischemia treatment with ATV. ATV treatment also up-regulated the association of p120(ctn) , αN-catenin to PSD-95, accompanied by a reduction of RhoA activation and the recovery of MAP2 immunoreactivity, these being significantly affected by the focal cerebral ischemia. Our findings suggested that p120(ctn) and αN-catenin synaptic adhesion proteins are crucial molecular targets in ATV-mediated neuroprotection and neuronal plasticity after focal cerebral ischemia.


Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Proteínas del Tejido Nervioso/efectos de los fármacos , Pirroles/farmacología , Sinapsis/efectos de los fármacos , alfa Catenina/efectos de los fármacos , Análisis de Varianza , Animales , Atorvastatina , Isquemia Encefálica/etiología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Cateninas/efectos de los fármacos , Cateninas/metabolismo , Moléculas de Adhesión Celular , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Regulación de la Expresión Génica , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Estudios Longitudinales , Masculino , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Fármacos Neuroprotectores/farmacología , Isoformas de Proteínas , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Sinapsis/metabolismo , alfa Catenina/metabolismo , Catenina delta
5.
Biofactors ; 46(3): 411-420, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31960520

RESUMEN

Diabetic neuropathy is a peripheral nervous system disorder affecting both somatic and autonomic components of nervous system. A growing body of evidence have depicted that high glucose levels can induce activation of the Wnt/ß-catenin pathway, however there are no studies targeting this pathway in DN. The intent of the present study was to investigate the effects of isoquercitrin (ISQ), a Wnt/ß-catenin signaling pathway inhibitor, in diabetic neuropathy. Streptozotocin (50 mg/kg, i.p.) was used to induce diabetes in rats. 6-week diabetic rats were treated intrathecally with ISQ at 10 and 30 µM doses for 3 days. Furthermore, to confirm the results of the intrathecal study, a 2-week intraperitoneal treatment of ISQ was given to diabetic rats. After 6 weeks, diabetic rats developed neuropathy which was evident from reduced thermal and mechanical hyperalgesia thresholds and significant deterioration in motor nerve conduction velocity (MNCV), nerve blood flow (NBF). Sciatic nerves of diabetic neuropathy rats showed increased expression of Wnt pathway proteins namely ß-catenin, c-myc and MMP2. Treatment with ISQ, both intrathecally (10 and 30 µM) and intraperitoneally (10 mg/kg), significantly ameliorated the alterations in behavioral pain thresholds and improved functional parameters in diabetic rats. Moreover, ISQ also downregulated the expression of Wnt/ß-catenin pathway proteins significantly in diabetic rats as compared to vehicle-treated diabetic rats. Results of the present study suggest the neuroprotective potential of ISQ in the treatment of DN via inhibition of Wnt/ß-catenin signaling pathway.


Asunto(s)
Antioxidantes/farmacología , Neuropatías Diabéticas/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Quercetina/análogos & derivados , Vía de Señalización Wnt/efectos de los fármacos , Animales , Cateninas/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Neuropatías Diabéticas/etiología , Modelos Animales de Enfermedad , Masculino , Quercetina/farmacología , Ratas , Ratas Sprague-Dawley
6.
Shock ; 45(6): 626-33, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26717103

RESUMEN

INTRODUCTION: Lipopolysaccharide (LPS) is known to induce vascular derangements. The pathophysiology involved therein is unknown, but matrix metalloproteinases (MMPs) may be an important mediator. We hypothesized that in vitro LPS provokes vascular permeability, damages endothelial structural proteins, and increases MMP activity; that in vivo LPS increases permeability and fluid requirements; and that the MMP inhibitor doxycycline mitigates such changes. METHODS: Rat lung microvascular endothelial cells were divided into four groups: control, LPS, LPS plus doxycycline, and doxycycline. Permeability, structural proteins ß-catenin and Filamentous-actin, and MMP-9 activity were examined. Sprauge Dawley rats were divided into sham, IV LPS, and IV LPS plus IV doxycycline groups. Mesenteric postcapillary venules were observed. Blood pressure was measured as animals were resuscitated and fluid requirements were compared. Statistical analysis was conducted using Student's t-test and ANOVA. RESULTS: In vitro LPS increased permeability, damaged adherens junctions, induced actin stress fiber formation, and increased MMP-9 enzyme activity. In vivo, IV LPS administration induced vascular permeability. During resuscitation, significantly more fluid was necessary to maintain normotension in the IV LPS group. Doxycycline mitigated all derangements observed. CONCLUSIONS: We conclude that LPS increases permeability, damages structural proteins, and increases MMP-9 activity in endothelial cells. Additionally, endotoxemia induces hyperpermeability and increases the amount of IV fluid required to maintain normotension in vivo. Doxycycline mitigates such changes both in vitro and in vivo. Our findings illuminate the possible role of matrix metalloproteinases in the pathophysiology of lipopolysaccharide-induced microvascular hyperpermeability and pave the way for better understanding and treatment of this process.


Asunto(s)
Antibacterianos/farmacología , Doxiciclina/farmacología , Endotelio Vascular/metabolismo , Lipopolisacáridos/metabolismo , Metaloproteinasas de la Matriz/efectos de los fármacos , Actinas/efectos de los fármacos , Animales , Permeabilidad Capilar/efectos de los fármacos , Cateninas/efectos de los fármacos , Células Endoteliales/metabolismo , Técnicas In Vitro , Masculino , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Ratas , Ratas Sprague-Dawley
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