Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 93
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Nat Mater ; 22(12): 1470-1477, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38012388

RESUMEN

Three-dimensional (3D) hetero-integration technology is poised to revolutionize the field of electronics by stacking functional layers vertically, thereby creating novel 3D circuity architectures with high integration density and unparalleled multifunctionality. However, the conventional 3D integration technique involves complex wafer processing and intricate interlayer wiring. Here we demonstrate monolithic 3D integration of two-dimensional, material-based artificial intelligence (AI)-processing hardware with ultimate integrability and multifunctionality. A total of six layers of transistor and memristor arrays were vertically integrated into a 3D nanosystem to perform AI tasks, by peeling and stacking of AI processing layers made from bottom-up synthesized two-dimensional materials. This fully monolithic-3D-integrated AI system substantially reduces processing time, voltage drops, latency and footprint due to its densely packed AI processing layers with dense interlayer connectivity. The successful demonstration of this monolithic-3D-integrated AI system will not only provide a material-level solution for hetero-integration of electronics, but also pave the way for unprecedented multifunctional computing hardware with ultimate parallelism.

2.
EMBO Rep ; 22(12): e51503, 2021 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-34585824

RESUMEN

ß-Catenin is a multifunctional protein and participates in numerous processes required for embryonic development, cell proliferation, and homeostasis through various molecular interactions and signaling pathways. To date, however, there is no direct evidence that ß-catenin contributes to cytokinesis. Here, we identify a novel p-S60 epitope on ß-catenin generated by Plk1 kinase activity, which can be found at the actomyosin contractile ring of early telophase cells and at the midbody of late telophase cells. Depletion of ß-catenin leads to cytokinesis-defective phenotypes, which eventually result in apoptotic cell death. In addition, phosphorylation of ß-catenin Ser60 by Plk1 is essential for the recruitment of Ect2 to the midbody, activation of RhoA, and interaction between ß-catenin, Plk1, and Ect2. Time-lapse image analysis confirmed the importance of ß-catenin phospho-Ser60 in furrow ingression and the completion of cytokinesis. Taken together, we propose that phosphorylation of ß-catenin Ser60 by Plk1 in cooperation with Ect2 is essential for the completion of cytokinesis. These findings may provide fundamental knowledge for the research of cytokinesis failure-derived human diseases.


Asunto(s)
Actomiosina , Citocinesis , Actomiosina/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células HeLa , Humanos , Fosforilación , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/metabolismo , Huso Acromático/metabolismo , beta Catenina/metabolismo , Quinasa Tipo Polo 1
3.
Biochem Biophys Res Commun ; 635: 1-11, 2022 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-36252331

RESUMEN

Primary cilia, antenna-like cellular sensor structures, are generated from the mother centriole in the G0/G1 cell-cycle phase under control by cellular signaling pathways involving Wnt, hedgehog, and platelet-derived growth factor. Although primary ciliary dynamics have been reported to be closely related to ciliopathy and tumorigenesis, the molecular basis for the role of primary cilia in human disease is lacking. To clarify how Wnt3a affects primary ciliogenesis in anticancer drug-resistant cells, we derived specific drug-resistant subcell lines from A549 human lung cancer cells using anticancer drugs doxorubicin, dasatinib, and paclitaxel (A549/Dox, A549/Das, and A549/Pac, respectively). The primary cilia-containing cell population and primary cilia length increased in the A549/Dox and A549/Pac subcell lines under increased MDR1 expression, when compared to those in the parental A549 cells. In the A549/Das subcell line, primary cilia length increased but the cell population was not affected. In addition, Wnt3a increased primary cilia-containing cell population and primary cilia length in A549/Dox, A549/Das, and A549/Pac cells, without change of cell growth. Abnormal shapes of primary cilia were frequently observed by anticancer drug resistance and Wnt3a stimulation. Taken together, our results indicate that anticancer drug resistance and Wnt3a affect primary ciliogenesis synergistically, suggesting a potential new strategy for overcoming anticancer drug resistance.


Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Humanos , Células A549 , Antineoplásicos/uso terapéutico , Doxorrubicina/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Paclitaxel/uso terapéutico , Cilios/metabolismo , Proteína Wnt3A/metabolismo
4.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-34299191

RESUMEN

Primary cilia are nonmotile cellular signal-sensing antenna-like structures composed of microtubule-based structures that distinguish them from motile cilia in structure and function. Primary ciliogenesis is regulated by various cellular signals, such as Wnt, hedgehog (Hh), and platelet-derived growth factor (PDGF). The abnormal regulation of ciliogenesis is closely related to developing various human diseases, including ciliopathies and cancer. This study identified a novel primary ciliogenesis factor Cullin 1 (CUL1), a core component of Skp1-Cullin-F-box (SCF) E3 ubiquitin ligase complex, which regulates the proteolysis of dishevelled 2 (Dvl2) through the ubiquitin-proteasome system. Through immunoprecipitation-tandem mass spectrometry analysis, 176 Dvl2 interacting candidates were identified, of which CUL1 is a novel Dvl2 modulator that induces Dvl2 ubiquitination-dependent degradation. Neddylation-dependent CUL1 activity at the centrosomes was essential for centrosomal Dvl2 degradation and primary ciliogenesis. Therefore, this study provides a new mechanism of Dvl2 degradation by CUL1, which ultimately leads to primary ciliogenesis, and suggest a novel target for primary cilia-related human diseases.


Asunto(s)
Cilios/fisiología , Proteínas Cullin/metabolismo , Proteínas Dishevelled/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Ligasas SKP Cullina F-box/metabolismo , Ubiquitina/metabolismo , Células Cultivadas , Humanos , Unión Proteica , Proteolisis , Transducción de Señal , Ubiquitinación
5.
BMC Gastroenterol ; 20(1): 123, 2020 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-32316932

RESUMEN

BACKGROUND: The association between Helicobacter pylori and reflux esophagitis (RE) remains controversial. This study aimed to prospectively evaluate the effect of H. pylori eradication on RE and gastroesophageal reflux (GERD) symptoms in H. pylori-positive patients who underwent endoscopic resection of gastric neoplasm. METHODS: Of the 244 patients enrolled in this study, 173 H. pylori-positive patients underwent follow-up at least once. We evaluated the prevalence of RE and GERD symptoms in these patients following H. pylori eradication. RESULTS: There were 75.7% (131/173), 78.6% (125/159), and 78.9% (105/133) subjects who were successfully eradicated after 6, 12, and 18-24 months, respectively. During the 2-year follow-up period, the eradication of H. pylori did not increase the incidence of RE (OR 0.93; 95% CI, 0.49-1.77, p = 0.828). H. pylori status was also not associated with the development of GERD symptoms (OR 1.12; 95% CI, 0.47-2.95, p = 0.721). In the univariate analysis for RE, present smoking history (OR 4.79; 95% CI 1.98-11.60, p = 0.001), present alcohol consumption history (OR 2.18; 95% CI 1.03-4.63, p = 0.041), and diabetes mellitus (OR 2.44; 95% CI 1.02-5.86, p = 0.045) were found to be associated with RE. Multivariate analysis showed that present smoking history (OR 4.54; 95% CI 1.84-11.02, p = 0.001) was a significant risk factor for RE. CONCLUSIONS: H. pylori eradication did not increase the incidence of RE or GERD symptoms in patients who underwent endoscopic resection of gastric neoplasm.


Asunto(s)
Esofagitis Péptica/tratamiento farmacológico , Reflujo Gastroesofágico/tratamiento farmacológico , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Neoplasias Gástricas/cirugía , Adulto , Anciano , Resección Endoscópica de la Mucosa , Esofagitis Péptica/microbiología , Femenino , Reflujo Gastroesofágico/microbiología , Gastroscopía , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias Gástricas/microbiología , Resultado del Tratamiento , Adulto Joven
6.
Int J Mol Sci ; 21(13)2020 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-32645923

RESUMEN

In the past, several microtubule targeting agents (MTAs) have been developed into successful anticancer drugs. However, the usage of these drugs has been limited by the acquisition of drug resistance in many cancers. Therefore, there is a constant demand for the development of new therapeutic drugs. Here we report the discovery of 5-5 (3-cchlorophenyl)-N-(3-pyridinyl)-2-furamide (CPPF), a novel microtubule targeting anticancer agent. Using both 2D and 3D culture systems, we showed that CPPF was able to suppress the proliferation of diverse cancer cell lines. In addition, CPPF was able to inhibit the growth of multidrug-resistant cell lines that are resistant to other MTAs, such as paclitaxel and colchicine. Our results showed that CPPF inhibited growth by depolymerizing microtubules leading to mitotic arrest and apoptosis. We also confirmed CPPF anticancer effects in vivo using both a mouse xenograft and a two-step skin cancer mouse model. Using established zebrafish models, we showed that CPPF has low toxicity in vivo. Overall, our study proves that CPPF has the potential to become a successful anticancer chemotherapeutic drug.


Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Microtúbulos/metabolismo , Neoplasias/tratamiento farmacológico , Células A549 , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Colchicina/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Células HeLa , Células Hep G2 , Humanos , Células Jurkat , Células K562 , Células MCF-7 , Masculino , Ratones , Mitosis/efectos de los fármacos , Neoplasias/metabolismo , Células PC-3 , Paclitaxel/farmacología , Células U937 , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Pez Cebra
7.
J Biol Chem ; 293(3): 847-862, 2018 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-29191835

RESUMEN

Elevated expression of human enhancer filamentation 1 (HEF1; also known as NEDD9 or Cas-L) is an essential stimulus for the metastatic process of various solid tumors. This process requires HEF1 localization to focal adhesions (FAs). Although the association of HEF1 with FAs is considered to play a role in cancer cell migration, the mechanism targeting HEF1 to FAs remains unclear. Moreover, up-regulation of Polo-like kinase 1 (Plk1) positively correlates with human cancer metastasis, yet how Plk1 deregulation promotes metastasis remains elusive. Here, we report that casein kinase 1δ (CK1δ) phosphorylates HEF1 at Ser-780 and Thr-804 and that these phosphorylation events promote a physical interaction between Plk1 and HEF1. We found that this interaction is critical for HEF1 translocation to FAs and for inducing migration of HeLa cells. Plk1-docking phosphoepitopes were mapped/confirmed in HEF1 by various methods, including X-ray crystallography, and mutated for functional analysis in HeLa cells. In summary, our results reveal the role of a phosphorylation-dependent HEF1-Plk1 complex in HEF1 translocation to FAs to induce cell migration. Our findings provide critical mechanistic insights into the HEF1-Plk1 complex-dependent localization of HEF1 to FAs underlying the metastatic process and may therefore contribute to the development of new cancer therapies.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Ciclo Celular/metabolismo , Adhesiones Focales/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas de Ciclo Celular/genética , Línea Celular , Proliferación Celular/genética , Proliferación Celular/fisiología , Adhesiones Focales/genética , Células HeLa , Humanos , Immunoblotting , Inmunoprecipitación , Fosfoproteínas/genética , Fosforilación/genética , Fosforilación/fisiología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Quinasa Tipo Polo 1
8.
Biochim Biophys Acta ; 1862(6): 1228-35, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26912411

RESUMEN

HIV protease inhibitors are key components of HIV antiretroviral therapies, which are fundamental in the treatment of HIV infection. However, the protease inhibitors are well-known to induce metabolic dysfunction which can in turn escalate the complications of HIV, including HIV associated neurocognitive disorders. As experimental and epidemiological data support a therapeutic role for adiponectin in both metabolic and neurologic homeostasis, this study was designed to determine if increased adiponectin could prevent the detrimental effects of protease inhibitors in mice. Adult male wild type (WT) and adiponectin-overexpressing (ADTg) mice were thus subjected to a 4-week regimen of lopinavir/ritonavir, followed by comprehensive metabolic, neurobehavioral, and neurochemical analyses. Data show that lopinavir/ritonavir-induced lipodystrophy, hypoadiponectinemia, hyperglycemia, hyperinsulinemia, and hypertriglyceridemia were attenuated in ADTg mice. Furthermore, cognitive function and blood-brain barrier integrity were preserved, while loss of cerebrovascular markers and white matter injury were prevented in ADTg mice. Finally, lopinavir/ritonavir caused significant increases in expression of markers of brain inflammation and decreases in synaptic markers in WT, but not in ADTg mice. Collectively, these data reinforce the pathophysiologic link from metabolic dysfunction to loss of cerebrovascular and cognitive homeostasis; and suggest that preservation and/or replacement of adiponectin could prevent these key aspects of HIV protease inhibitor-induced toxicity in clinical settings.


Asunto(s)
Adiponectina/metabolismo , Lesiones Encefálicas/inducido químicamente , Encéfalo/irrigación sanguínea , Inhibidores de la Proteasa del VIH/efectos adversos , Lopinavir/efectos adversos , Ritonavir/efectos adversos , Adiponectina/genética , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Cognición/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Homeostasis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Regulación hacia Arriba
9.
J Biol Chem ; 288(36): 25924-25937, 2013 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-23888052

RESUMEN

Chrysin (5,7-dihydroxyflavone), a natural flavonoid widely distributed in plants, reportedly has chemopreventive properties against various cancers. However, the anticancer activity of chrysin observed in in vivo studies has been disappointing. Here, we report that a chrysin derivative, referred to as compound 69407, more strongly inhibited EGF-induced neoplastic transformation of JB6 P(+) cells compared with chrysin. It attenuated cell cycle progression of EGF-stimulated cells at the G1 phase and inhibited the G1/S transition. It caused loss of retinoblastoma phosphorylation at both Ser-795 and Ser-807/811, the preferred sites phosphorylated by Cdk4/6 and Cdk2, respectively. It also suppressed anchorage-dependent and -independent growth of A431 human epidermoid carcinoma cells. Compound 69407 reduced tumor growth in the A431 mouse xenograft model and retinoblastoma phosphorylation at Ser-795 and Ser-807/811. Immunoprecipitation kinase assay results showed that compound 69407 attenuated endogenous Cdk4 and Cdk2 kinase activities in EGF-stimulated JB6 P(+) cells. Pulldown and in vitro kinase assay results indicated that compound 69407 directly binds with Cdk2 and Cdk4 in an ATP-independent manner and inhibited their kinase activities. A binding model between compound 69407 and a crystal structure of Cdk2 predicted that compound 69407 was located inside the Cdk2 allosteric binding site. The binding was further verified by a point mutation binding assay. Overall results indicated that compound 69407 is an ATP-noncompetitive cyclin-dependent kinase inhibitor with anti-tumor effects, which acts by binding inside the Cdk2 allosteric pocket. This study provides new insights for creating a general pharmacophore model to design and develop novel ATP-noncompetitive agents with chemopreventive or chemotherapeutic potency.


Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Flavonoides/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Regulación Alostérica/efectos de los fármacos , Animales , Sitios de Unión , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Cristalografía por Rayos X , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Factor de Crecimiento Epidérmico/genética , Factor de Crecimiento Epidérmico/metabolismo , Flavonoides/química , Fase G1/efectos de los fármacos , Fase G1/genética , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Trasplante de Neoplasias , Inhibidores de Proteínas Quinasas/química , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Fase S/efectos de los fármacos , Fase S/genética , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología
10.
Biochim Biophys Acta ; 1832(9): 1456-62, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23313575

RESUMEN

Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aß levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1ß and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aß in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aß pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aß pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.


Asunto(s)
Enfermedad de Alzheimer/complicaciones , Encéfalo/patología , Angiopatía Amiloide Cerebral/etiología , Dieta/efectos adversos , Modelos Animales de Enfermedad , Gliosis/etiología , Obesidad/etiología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Western Blotting , Encéfalo/metabolismo , Angiopatía Amiloide Cerebral/patología , Femenino , Gliosis/patología , Humanos , Técnicas para Inmunoenzimas , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/patología , Obesidad/patología , Placa Amiloide/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
11.
Eur Radiol ; 24(6): 1410-20, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24647823

RESUMEN

OBJECTIVES: To investigate the diagnostic performance of 15-min delayed contrast-enhanced computed tomography (15-DECT) compared with that of chemical shift magnetic resonance (CSMR) imaging in differentiating hyperattenuating adrenal masses and to perform subgroup analysis in underlying malignancy and non-malignancy. METHODS: This study included 478 adrenal masses in 453 patients examined with 15-DECT and 235 masses in 217 patients examined with CSMR. Relative percentage washout (RPW) and absolute percentage washout (APW) on 15-DECT, and signal intensity index (SII) and adrenal-to-spleen ratio (ASR) on CSMR were measured. Sensitivity, specificity and accuracy of 15-DECT and CSMR were analysed for characterisation of adrenal adenoma. Subgroup analyses were performed in patients with and without underlying malignancy. Attenuation and size of the masses on unenhanced CT correlated with the risk of non-adenoma. RESULTS: RPW calculated from 15-DECT showed the highest diagnostic performance for characterising hyperattenuating adrenal masses regardless of underlying malignancy, and the sensitivity, specificity and accuracy were 91.7 %, 74.8 % and 88.1 %, respectively in all patients. The risk of non-adenoma increased approximately threefold as mass size increased 1 cm or as its attenuation value increased by 10 Hounsfield units. CONCLUSIONS: 15-DECT was more accurate than CSMR in characterising hyperattenuating adrenal masses regardless of underlying malignancy. KEY POINTS: Delayed contrast-enhanced CT and chemical shift magnetic resonance (CSMR) characterise adrenal lesions. 15-min DECT is more accurate than CSMR in characterising hyperattenuating adrenal masses. Sensitivity of CSMR decreases as the CT attenuation of adenomas increases. Risk of non-adenoma is increased 2.9-fold as size increased by 1 cm. Risk of non-adenoma is increased 2.9-fold as attenuation increased by 10 HU.


Asunto(s)
Adenoma/diagnóstico por imagen , Adenoma/patología , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/patología , Imagen por Resonancia Magnética/métodos , Tomografía Computarizada por Rayos X/métodos , Enfermedades de las Glándulas Suprarrenales/diagnóstico por imagen , Enfermedades de las Glándulas Suprarrenales/patología , Adenoma Corticosuprarrenal/diagnóstico por imagen , Adenoma Corticosuprarrenal/patología , Adulto , Anciano , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/patología , Medios de Contraste , Femenino , Humanos , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/patología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Feocromocitoma/diagnóstico por imagen , Feocromocitoma/patología , Estudios Retrospectivos , Sensibilidad y Especificidad , Factores de Tiempo
12.
Bioorg Med Chem Lett ; 24(7): 1802-4, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24613164

RESUMEN

Three new pyrrolobenzodiazepine derivatives, boseongazepines A-C (1-3), were isolated from a culture broth of Streptomyces sp. 11A057, together with the known compound usabamycin B (4). The structures of 1-4 were determined through the analysis of spectroscopic data including extensive 1D-, 2D-NMR, and MS techniques. Cell growth inhibition effects of these compounds were evaluated against Jurkat, K-562, HL-60, and HepG2 cell lines.


Asunto(s)
Antineoplásicos/farmacología , Benzodiazepinas/farmacología , Benzodiazepinonas/farmacología , Pirroles/farmacología , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Benzodiazepinas/química , Benzodiazepinas/aislamiento & purificación , Benzodiazepinonas/química , Benzodiazepinonas/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Células Hep G2 , Humanos , Células Jurkat , Células K562 , Conformación Molecular , Pirroles/química , Pirroles/aislamiento & purificación , Relación Estructura-Actividad
13.
J Nat Prod ; 77(4): 744-50, 2014 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-24597820

RESUMEN

The secondary metabolites illudins C2 (1) and C3 (2), obtained from the culture broth of Coprinus atramentarius, have been shown to possess antimicrobial activity. In the present study, we discovered novel biological activities of 1 and 2 in lipolysis of differentiated 3T3-L1 adipocytes and adipogenesis of 3T3-L1 preadipocytes. Compounds 1 and 2 exhibit a dose-dependent increase in glycerol release and thereby reduce intracellular lipid accumulation. The stimulatory effects of 1 and 2 on lipolysis are prevented by cAMP-dependent protein kinase (PKA) and extracellular signal-regulated kinase (ERK) inhibitors. Compounds 1 and 2 down-regulated perilipin and also affected the mRNA and protein levels of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). However, 1 and 2 treatment leads to a significant increase in PKA-mediated phosphorylation of HSL at S563 and S660. In addition, 1 and 2 treatment in 3T3-L1 preadipocytes induces down-regulation of the critical transcription factors, CCAAT/enhancer binding protein α and ß (C/EBPα and C/EBPß), and peroxisome proliferator activated receptor γ (PPARγ), which are required for adipogenesis, and accordingly inhibits adipogenesis. These results suggest that 1 and 2 might be useful for treating obesity due to their modulatory effects on fat by affecting adipocyte differentiation and fat mobilization.


Asunto(s)
Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Proteína beta Potenciadora de Unión a CCAAT/efectos de los fármacos , Coprinus/química , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Lipasa/metabolismo , Lipólisis/efectos de los fármacos , PPAR gamma/metabolismo , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Células 3T3-L1 , Adipocitos/metabolismo , Adipogénesis/fisiología , Animales , Proteína alfa Potenciadora de Unión a CCAAT , Relación Dosis-Respuesta a Droga , Glicerol/análisis , Glicerol/metabolismo , Lipasa/análisis , Lipólisis/fisiología , Ratones , Estructura Molecular , Obesidad/tratamiento farmacológico , Sesquiterpenos Policíclicos , Sesquiterpenos/química
14.
Xenobiotica ; 44(12): 1099-107, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24933530

RESUMEN

1. BST204, a purified ginseng dry extract containing a high concentration of racemic Rh2 and Rg3 mixtures, is being developed for supportive care use in cancer patients in Korea. This study investigates the pharmacokinetics and tissue distribution of BST204 in rats. 2. After oral administration of BST204, only the S epimers, S-Rh2 and S-Rg3, could be determined in rat plasma. The poor absorption of the R-epimers, R-Rh2 and R-Rg3, may be attributed to lower membrane permeability and extensive intestinal oxygenation and/or deglycosylation into metabolites. The AUC and Cmax values of both S-Rh2 and S-Rg3 after BST204 oral administration were proportional to the administered BST204 doses ranged from 400 mg/kg to 2000 mg/kg, which suggested linear pharmacokinetic properties. 3. There were no statistically significant differences in the pharmacokinetics of S-Rh2 and S-Rg3 after oral administration of pure S-Rh2 (31.5 mg/kg) and S-Rg3 (68 mg/kg) compared with oral administration of BST204, 1000 mg/kg. These indicated that the presence of other components of BST204 extract did not influence the pharmacokinetic behavior of S-Rh2 and S-Rg3. 4. After oral dosing of BST204, S-Rh2 and S-Rg3 were distributed mainly to the liver and gastrointestinal tract in rats. 5. Our finding may help to understand pharmacokinetic characteristics of S-Rh2, R-Rh2, S-Rg3, and R-Rg3, comprehensively, and provide useful information in clinical application of BST204.


Asunto(s)
Ginsenósidos/farmacocinética , Extractos Vegetales/administración & dosificación , Administración Oral , Animales , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Ginsenósidos/administración & dosificación , Ginsenósidos/química , Ginsenósidos/metabolismo , Masculino , Estructura Molecular , Extractos Vegetales/metabolismo , Ratas , Ratas Sprague-Dawley
15.
Science ; 384(6693): 312-317, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38669572

RESUMEN

Electrostatic capacitors are foundational components of advanced electronics and high-power electrical systems owing to their ultrafast charging-discharging capability. Ferroelectric materials offer high maximum polarization, but high remnant polarization has hindered their effective deployment in energy storage applications. Previous methodologies have encountered problems because of the deteriorated crystallinity of the ferroelectric materials. We introduce an approach to control the relaxation time using two-dimensional (2D) materials while minimizing energy loss by using 2D/3D/2D heterostructures and preserving the crystallinity of ferroelectric 3D materials. Using this approach, we were able to achieve an energy density of 191.7 joules per cubic centimeter with an efficiency greater than 90%. This precise control over relaxation time holds promise for a wide array of applications and has the potential to accelerate the development of highly efficient energy storage systems.

16.
Biochim Biophys Acta ; 1822(8): 1230-7, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22542511

RESUMEN

The fruit fly Drosophila melanogaster is increasingly utilized as an alternative to costly rodent models to study human diseases. Fly models exist for a wide variety of human conditions, such as Alzheimer's and Parkinson's Disease, or cardiac function. Advantages of the fly system are its rapid generation time and its low cost. However, the greatest strength of the fly system are the powerful genetic tools that allow for rapid dissection of molecular disease mechanisms. Here, we describe the diet-dependent development of metabolic phenotypes in adult fruit flies. Depending on the specific type of nutrient, as well as its relative quantity in the diet, flies show weight gain and changes in the levels of storage macromolecules. Furthermore, the activity of insulin-signaling in the major metabolic organ of the fly, the fat body, decreases upon overfeeding. This decrease in insulin-signaling activity in overfed flies is moreover observed when flies are challenged with an acute food stimulus, suggesting that overfeeding leads to insulin resistance. Similar changes were observed in aging flies, with the development of the insulin resistance-like phenotype beginning at early middle ages. Taken together, these data demonstrate that imbalanced diet disrupts metabolic homeostasis in adult D. melanogaster and promotes insulin-resistant phenotypes. Therefore, the fly system may be a useful alternative tool in the investigation of molecular mechanisms of insulin resistance and the development of pharmacologic treatment options.


Asunto(s)
Drosophila melanogaster/metabolismo , Resistencia a la Insulina/fisiología , Factores de Edad , Animales , Grasas de la Dieta/metabolismo , Proteínas en la Dieta/metabolismo , Modelos Animales de Enfermedad , Insulina/metabolismo , Transducción de Señal , Sacarosa/metabolismo
17.
J Sep Sci ; 36(12): 1904-12, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23559579

RESUMEN

We developed and validated an accurate and sensitive LC-MS/MS method for the simultaneous quantitation of ginsenoside Rg3 and Rh2 epimers (R-Rg3, S-Rg3, R-Rh2, and S-Rh2) in rat plasma. Analytes were extracted from 0.1 mL aliquots of rat plasma by liquid-liquid extraction, using 2 mL of ethyl acetate. In this assay, dioscin (500 ng/mL) was used as an internal standard. Chromatographic separation was conducted using an Acclaim RSLC C18 column (150 × 2.1 mm, 2.2 µm) at 40°C, with a gradient mobile phase consisting of 0.1% formic acid in distilled water and in acetonitrile, a flow rate of 0.35 mL/min, and a total run time of 20 min. Detection and quantification were performed using a mass spectrometer in selected reaction-monitoring mode with negative electrospray ionization at m/z 783.4 → 161.1 for R-Rg3 and S-Rg3, m/z 621.3 → 161.1 for R-Rh2 and S-Rh2, and m/z 867.2 → 761.5 for the internal standard. For R-Rg3 and S-Rg3, the lower limit of quantification was 5 ng/mL, with a linear range up to 500 ng/mL; for R-Rh2 and S-Rh2, the lower limit of quantification was 150 ng/mL, with a linear range up to 6000 ng/mL. The coefficient of variation for assay precision was less than 10.5%, with an accuracy of 86.4-112%. No relevant cross-talk or matrix effect was observed. The method was successfully applied to a pharmacokinetic study after oral administration of 400 mg/kg and 2000 mg/kg of BST204, a fermented ginseng extract, to rats. We found that the S epimers exhibited significantly higher plasma concentrations and area under curve values for both Rg3 and Rh2. This is the first report on the separation and simultaneous quantification of R-Rg3, S-Rg3, R-Rh2, and S-Rh2 in rat plasma by LC-MS/MS. The method should be useful in the clinical use of ginseng or its derivatives.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Ginsenósidos/sangre , Ginsenósidos/farmacocinética , Espectrometría de Masas en Tándem/métodos , Animales , Ginsenósidos/química , Masculino , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa por Ionización de Electrospray/métodos , Estereoisomerismo
18.
Technol Health Care ; 31(3): 943-954, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36442161

RESUMEN

BACKGROUND: An electric bed can easily change posture from a lying position and was effective in preventing pressure ulcer. OBJECTIVE: This study aimed to identify the optimal posture for the prevention of pressure ulcers by analyzing pressure changes applied to the pelvic region. METHODS: Pressure changes resulting from lateral rotations of the body using an electronic adjustable bed and changes in the posture and angles of the trunk and knees were assessed. Twelve conditions with varying angles of the trunk and knees (15-35∘ in 5∘ increments) and varying lateral angles (20-35∘ in 5∘ increments) were tested. The pressure (maximum and average) and contact area in the pelvic region of 20 individuals without disabilities were calculated. RESULTS: The conditions in which the average and maximum pressures did not increase according to the increase in angle were 25∘ for the upper body and knee angles and 35∘ for the side. CONCLUSIONS: The body pressure changed according to the posture rather than according to physical characteristics. Lateral rotation combined with changes in the angles of the trunk and knees effectively prevented pressure ulcers. Changes in the posture at various angles prevented an increased pressure on the body.


Asunto(s)
Úlcera por Presión , Humanos , Úlcera por Presión/prevención & control , Postura , Articulación de la Rodilla , Pelvis , Examen Físico , Fenómenos Biomecánicos
19.
J Sci Food Agric ; 92(15): 2975-82, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22522592

RESUMEN

BACKGROUND: The conventional method of processing ginseng (Panax ginseng) roots into red ginseng involves mainly heating and drying processes. In the present study, this method was modified by using high hydrostatic pressure (HHP) to improve the physicochemical characteristics of red ginseng. RESULTS: The HHP process (600 MPa for 1 min) significantly improved the histological properties of red ginseng by increasing cellular disruption and release of cell contents. The total reducing sugar content was significantly (P < 0.05) higher (increased from 10.67 to 15.25 mg g(-1)) in red ginseng processed at 600 MPa for 1 min. Similarly, the total free amino acid content also increased significantly (from 2.81 to 7.77 mg g(-1)). The HHP process resulted in superior and more even colouration and gave an attractive visual appearance to red ginseng. The optical density at 420 nm and Hunter's colour a value (redness) of extracts prepared from red ginseng increased significantly (P < 0.05) with the application of HHP. CONCLUSION: HHP-processed red ginseng has significantly higher reducing sugar and free amino acid contents together with a more compact cell structure and superior visual quality (brighter red colour). Hence the application of HHP in red ginseng processing can result in ginseng products of improved quality compared with those obtained by the conventional method.


Asunto(s)
Color , Manipulación de Alimentos/métodos , Panax , Raíces de Plantas/química , Raíces de Plantas/ultraestructura , Aminoácidos/análisis , Carbohidratos/análisis , Desecación , Calor , Presión Hidrostática , Reacción de Maillard , Microscopía Electrónica de Rastreo
20.
J Exp Anal Behav ; 117(3): 346-362, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35275426

RESUMEN

Single-case experimental designs (SCEDs) are rarely used in behavioral neuroscience despite their potential benefits. The current study used a SCED to evaluate the effects of dietary protein restriction in C57BL/6J and Fgf21-knockout (KO) mice on body weight, food consumption, and protein preference and changes in those outcome measures were quantified using multilevel linear models. In C57BL/6J mice, rate of weight gain was lower and food consumption and protein preference higher during periods of low (4% kcal) protein diet feeding compared to periods of normal (18% kcal) protein diet feeding. In Fgf21-KO mice, who do not produce the liver-derived hormone FGF21, rate of weight gain and protein preference were not substantially affected by diet although food consumption was slightly higher during periods of low protein diet than periods of normal protein diet. These results demonstrate that protein restriction dynamically regulates physiological and behavioral responses at the individual mouse level and that FGF21 is necessary for those responses. Further, the current results demonstrate how a SCED can be used in behavioral neuroscience research, which entails both scientific and practical benefits.


Asunto(s)
Dieta con Restricción de Proteínas , Aumento de Peso , Animales , Peso Corporal , Factores de Crecimiento de Fibroblastos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA