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OBJECTIVES: To compare the effects of conventional core stabilization and dynamic neuromuscular stabilization (DNS) on anticipatory postural adjustment (APA) time, balance performance, and fear of falls in chronic hemiparetic stroke. DESIGN: Two-group randomized controlled trial with pretest-posttest design. SETTING: Hospital rehabilitation center. PARTICIPANTS: Adults with chronic hemiparetic stroke (N=28). INTERVENTIONS: Participants were randomly divided into either conventional core stabilization (n=14) or DNS (n=14) groups. Both groups received a total of 20 sessions of conventional core stabilization or DNS training for 30 minutes per session 5 times a week during the 4-week period. MAIN OUTCOME MEASURES: Electromyography was used to measure the APA time for bilateral external oblique (EO), transverse abdominis (TrA)/internal oblique (IO), and erector spinae (ES) activation during rapid shoulder flexion. Trunk Impairment Scale (TIS), Berg Balance Scale (BBS), and Falls Efficacy Scale (FES) were used to measure trunk movement control, balance performance, and fear of falling. RESULTS: Baseline APA times were delayed and fear of falling was moderately high in both the conventional core stabilization and DNS groups. After the interventions, the APA times for EO, TrA/IO, and ES were shorter in the DNS group than in the conventional core stabilization group (P<.008). The BBS and TIS scores (P<.008) and the FES score (P<.003) were improved compared with baseline in both groups, but FES remained stable through the 2-year follow-up period only in the DNS group (P<.003). CONCLUSIONS: This is the first clinical evidence highlighting the importance of core stabilization exercises for improving APA control, balance, and fear of falls in individuals with hemiparetic stroke.
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Accidentes por Caídas/prevención & control , Terapia por Ejercicio/métodos , Paresia/rehabilitación , Equilibrio Postural/fisiología , Rehabilitación de Accidente Cerebrovascular/métodos , Músculos Abdominales/fisiopatología , Músculos Oblicuos del Abdomen/fisiopatología , Anciano , Anticipación Psicológica , Enfermedad Crónica , Electromiografía , Miedo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ejercicios de Estiramiento Muscular/métodos , Músculos Paraespinales/fisiopatología , Paresia/fisiopatología , Paresia/psicología , Método Simple Ciego , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/psicología , Torso/fisiopatología , Resultado del TratamientoRESUMEN
The inhibitors of apoptosis proteins (IAP), which include cIAP1, cIAP2 and XIAP, suppress apoptosis through the inhibition of caspases, and the activity of IAPs is regulated by a variety of IAP-binding proteins. Herein, we report the identification of a Vestigial-like 4 (Vgl-4), which functions as a transcription cofactor in cardiac myocytes, as a new IAP binding protein. Vgl-4 is expressed predominantly in the nucleus and its overexpression triggers a relocalization of IAPs from the cytoplasm to the nucleus. cIAP1/2-interacting protein TRAF2 (TNF receptor-associated factor 2) prevented the Vgl-4-driven nuclear localization of cIAP2. Accordingly, the forced relocation of IAPs to the nucleus by Vgl-4 significantly reduced their ability to prevent Bax- and TNFα-induced apoptosis, which can be recovered by co-expression with TRAF2. Our results suggest that Vgl-4 may play a role in the apoptotic pathways by regulating translocation of IAPs between different cell compartments.
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Apoptosis , Núcleo Celular/metabolismo , Proteínas Inhibidoras de la Apoptosis/metabolismo , Factores de Transcripción/metabolismo , Transporte Activo de Núcleo Celular , Células HEK293 , Células HeLa , Humanos , Factor 2 Asociado a Receptor de TNF/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a XRESUMEN
The pharmacokinetics of SP-8203, a potential protective agent for the treatment of cerebral infarction, were evaluated after its intravenous (10, 20 and 30 mg/kg) and oral (10, 20, 30 and 100 mg/kg) administration in rats. After the intravenous administration of SP-8203, the AUCs of SP-8203 were dose-dependent; the dose-normalized AUCs were significantly greater with increasing doses. After the oral administration of SP-8203, plasma concentrations of SP-8203 were much lower than those after intravenous administration. This could be due to considerable hepatic and intestinal metabolism and the high percent of the dose recovered from the gastrointestinal tract (including its contents and feces) at 24 h as unchanged drug.
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Fármacos Neuroprotectores/farmacocinética , Quinazolinonas/administración & dosificación , Quinazolinonas/farmacocinética , Acetamidas , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Infusiones Intravenosas , Masculino , Fármacos Neuroprotectores/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
The pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphomas is associated with independent chromosomal translocations that lead to the upregulation of either BCL10 or MALT1 or the generation of a fusion protein, cIAP2-MALT1. While both BCL10 and MALT1 are critically involved in antigen receptor-mediated NF-kappaB activation, the role of cIAP2 is not clear. Here we show that cIAP2 is a ubiquitin ligase (E3) of BCL10 and targets it for degradation, inhibiting antigen receptor-mediated cytokine production. cIAP2-MALT1 lacks E3 activity, and concomitantly, the BCL10 protein is stabilized in MALT lymphomas harboring this fusion. Furthermore, BCL10 and cIAP2-MALT1 synergistically activate NF-kappaB. These results reveal cIAP2 as an inhibitor of antigenic signaling and implicate its dysfunction in MALT lymphomas.
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Citocinas/inmunología , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Linfoma de Células B de la Zona Marginal/enzimología , Proteínas de Neoplasias/metabolismo , Caspasas , Línea Celular , Fusión Génica , Humanos , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B de la Zona Marginal/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Proteínas de Neoplasias/genética , Proteínas Recombinantes de Fusión/metabolismo , Translocación GenéticaRESUMEN
A dental implant is a unique structure which can be used with a noninvasive method because it is inserted into the bone in part and extended extracorporally. This study presents an electronic device that is temporarily connected with the dental implant, and reports its effect on accelerating bone formation in the surrounding tissues in a canine mandibular model. A small sized and low power consumption biphasic electrical current (BEC) stimulator ASIC was developed and the surrounding tissue was exposed to continuous BEC stimulation for 7 days with the parameters of 20 microA/cm(2), 125 micros duration, and 100 pulses/s. After 2 (n = 5) and 5 weeks (n = 5), animals were sacrificed and the specimens were histomorphometrically evaluated. The newly formed bone area (BA) was 1.30 times (3 weeks, P < 0.05) and 1.35 times (5 weeks, P < 0.05) higher in the experimental group compared to the control group, respectively. Bone-implant contact (BIC) in 3-week specimens was 1.62 times (P < 0.05) greater in the experimental group, while there was no statistically significant difference in 5-week specimens. Based on these results showing accelerated bone formation on and around the dental implant, it could be suggested that the latent time for osseointegration in dental implants can be reduced, and the success rate of implants in poor quality bone can be increased by using our device with BEC.
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Implantes Dentales , Electrónica Médica/instrumentación , Osteogénesis , Animales , Perros , Conductividad Eléctrica , Electroquímica , Mandíbula/fisiologíaRESUMEN
BACKGROUND: Death-Associated Protein Kinase 1 (DAPK1) plays an important role in apoptosis, tumor suppression and neurodegeneration including Alzheimer's Disease (AD). OBJECTIVE: This review will describe the diverse roles of DAPK1 in the development of cancer and AD, and the current status of drug development targeting DAPK1-based therapies. METHODS: Reports of DAPK1 regulation, function and substrates were analyzed using genetic DAPK1 manipulation and chemical DAPK1 modulators. RESULTS: DAPK1 expression and activity are deregulated in cancer and AD. It is down-regulated and/or inactivated by multiple mechanisms in many human cancers, and elicits a protective effect to counteract numerous death stimuli in cancer, including activation of the master regulator Pin1. Moreover, loss of DAPK1 expression has correlated strongly with tumor recurrence and metastasis, suggesting that lack of sufficient functional DAPK1 might contribute to cancer. In contrast, DAPK1 is highly expressed in the brains of most human AD patients and has been identified as one of the genetic factors affecting susceptibility to late-onset AD. The absence of DAPK1 promotes efficient learning and better memory in mice and prevents the development of AD by acting on many key proteins including Pin1 and its downstream targets tau and APP. Recent patents show that DAPK1 modulation might be used to treat both cancer and AD. CONCLUSION: DAPK1 plays a critical role in diverse physiological processes and importantly, its deregulation is implicated in the pathogenesis of either cancer or AD. Therefore, manipulating DAPK1 activity and/or expression may be a promising therapeutic option for cancer or AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Proteínas Quinasas Asociadas a Muerte Celular/fisiología , Terapia Molecular Dirigida/tendencias , Neoplasias/tratamiento farmacológico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Proteínas Quinasas Asociadas a Muerte Celular/antagonistas & inhibidores , Humanos , Ratones , Terapia Molecular Dirigida/métodos , Patentes como AsuntoRESUMEN
Inhibitor of apoptosis (IAP) proteins are a family of evolutionarily conserved proteins that regulate apoptosis as well as other cellular processes. The functions of many IAPs are defined by their RING domains, which possess E3 ubiquitin ligase activity and promote proteasomal degradation of an increasing number of target proteins. In this chapter, we describe the methods used in our laboratories to study the IAP's E3 activity.
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Proteínas Inhibidoras de la Apoptosis/fisiología , Ubiquitinación/fisiología , Bacterias/metabolismo , Células Cultivadas , HumanosRESUMEN
This paper presents two novel Lyapunov functionals for analyzing the stability of neural networks with time-varying delay. Based on our newly proposed Lyapunov functionals and a relaxed Wirtinger-based integral inequality, new stability criteria are derived in the form of linear matrix inequalities. A comprehensive comparison of results is given to illustrate the newly proposed stability criteria from both the conservative and computational complexity point of views.
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cIAP2 (cellular inhibitor of apoptosis protein 2) is induced by NF-kappaB (nuclear factor kappaB) when cells need to respond quickly to different apoptotic stimuli. A recent study using cDNA microarray technology has suggested that cIAP2 transcription is regulated in a cell cycle-dependent manner, although the mechanism for such regulation is unknown. In this study, we confirmed the cell cycle-dependent regulation of cIAP2 expression at both the mRNA and protein levels. Additionally, we found that a bipartite CDE (cell cycle-dependent element)/CHR (cell cycle gene homology region) element in the cIAP2 promoter mediates cIAP2 gene activation in G2/M phase. Cell cycle-dependent G2/M-phase-specific cIAP2 expression is enhanced by NF-kappaB activation, and selective down-regulation of cIAP2 causes cells blocked in mitosis with nocodazole to become susceptible to apoptosis, indicating that the G2/M-phase-specific expression of cIAP2 contributes to the survival of mitotically arrested cells. Our studies describing the NF-kappaB-independent G2/M-phase-specific expression of cIAP2 will help in further understanding the molecular basis of cIAP2 over-expression in a variety of human cancers.
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Fase G2 , Proteínas Inhibidoras de la Apoptosis/metabolismo , Mitosis , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Secuencia de Bases , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Datos de Secuencia Molecular , Mutación/genética , FN-kappa B/metabolismo , Nocodazol/farmacología , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transcripción Genética/efectos de los fármacos , Activación Transcripcional , Factor de Necrosis Tumoral alfa/metabolismo , Ubiquitina-Proteína LigasasAsunto(s)
Fibrosis Quística , Enfermedades del Íleon , Obstrucción Intestinal , Intususcepción , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Humanos , Enfermedades del Íleon/diagnóstico , Enfermedades del Íleon/etiología , Enfermedades del Íleon/cirugía , Obstrucción Intestinal/diagnóstico por imagen , Obstrucción Intestinal/etiología , Intususcepción/diagnóstico , Intususcepción/etiología , Adulto JovenRESUMEN
Mammalian cells are capable of de novo centriole formation after the removal of existing centrioles. This suggests that de novo centriole assembly is repressed in normally duplicating cells to maintain a constant number of centrioles in the cells. However, neither the mechanism of de novo centriole assembly nor that of its hypothesized repression is understood due to the lack of an experimental system. We found that the heat shock (HS; 42°C, 2 h) of mouse embryonic fibroblasts caused the separation of centriole pairs, a transient increase in polo-like kinase (Plk) 4 expression, and the formation of a complex containing γ-tubulin, pericentrin, HS protein (Hsp) 90, and Plk4, in approximately half of the cells. Subsequently, spindle-assembly abnormal protein (Sas) 6, centrosomal protein (Cep) 135, and centrin localized to the complex, and tubulin consequently became polyglutamylated, indicating de novo centriole assembly in the heat-shocked cells. These results suggested that HS-induced de novo centriole assembly could provide an experimental system for further elucidating the regulation of centrosome number in mammalian cells. © 2016 Wiley Periodicals, Inc.
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Centriolos/metabolismo , Fibroblastos/metabolismo , Cinética , Animales , Calor , RatonesRESUMEN
Heterogeneous nuclear ribonucleoprotein K protein (hnRNP K) has diverse molecular partners implicated in signal transduction pathways, and is tyrosine-phosphorylated in response to growth factors and oxidative stress. Among the structurally distinct domains of hnRNP K, an SH3-binding domain (SH3BD) has been known to promote the association of SH3-containing tyrosine kinases and protooncoprotein Vav, which are involved in B cell receptor (BCR) signalling. In this study, we analyzed proteins of Ramos B cell line that are altered upon BCR activation with anti-IgM antibody, revealing that a certain hnRNP K isoform is up-regulated in response to anti-IgM treatment. We also showed that hnRNP K is tyrosine-phosphorylated after BCR ligation. HnRNP K lacking the SH3BD is shown not to interact with phosphorylated Vav, and Ramos cells stably expressing this mutant protein are less susceptible to anti-IgM-induced apoptosis, indicating that hnRNP K is coupled to BCR-mediated signalling and its SH3BD is required for proper signal propagation. Our results provide the first evidence that hnRNP K is involved in BCR signalling pathway.
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Anticuerpos Antiidiotipos/farmacología , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , Fosfotirosina/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Apoptosis/inmunología , Línea Celular Tumoral , Electroforesis en Gel Bidimensional , Ribonucleoproteína Heterogénea-Nuclear Grupo K/genética , Humanos , Inmunoglobulina M/inmunología , Fosforilación/efectos de los fármacosRESUMEN
Receptor interacting protein (RIP) is recruited to tumor necrosis factor-alpha receptor 1 (TNFR1) complex upon stimulation and plays a crucial role in the receptor-mediated NF-kappaB activation. Among the components of the TNFR1 complex are proteins that possess ubiquitin-protein isopeptide ligase (E3) activities, such as TNFR1-associated factor 2 (TRAF2), cellular inhibitor of apoptosis proteins (c-IAPs) namely, c-IAP1 and c-IAP2. Here, we showed that ectopically expressed RIP is ubiquitinated, and either the intermediate or death domain of RIP is required for this modification. Expression of c-IAP1 and c-IAP2 decreased the steady-state level of RIP, which was blocked by inhibition of the 26S proteasome. RIP degradation requires intact c-IAP2 containing the RING domain. Our in vitro ubiquitination assay revealed that while TRAF2 had no effect, both c-IAP1 and c-IAP2-mediated RIP ubiquitination with similar efficiency, indicating that c-IAPs can function as E3 toward RIP.
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Proteínas/metabolismo , Proteínas/fisiología , Ubiquitina/metabolismo , Animales , Apoptosis , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Línea Celular , Eliminación de Gen , Humanos , Immunoblotting , Proteínas Inhibidoras de la Apoptosis , Ratones , Biosíntesis de Proteínas , Estructura Terciaria de Proteína , Proteínas/química , Proteínas/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Receptores del Factor de Necrosis Tumoral/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transfección , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Follicular dendritic cells (FDCs) play pivotal roles in germinal center (GC) responses in secondary lymphoid follicles, and their functions are influenced by cytokines present in the GC. We investigated the functional effects of interleukin-4 (IL-4) using an established FDC-like line of HK cells. In spite of the activation of ERK1/2 and PI3K/Akt pathways by IL-4, which are implicated in the induction of cell proliferation and survival, IL-4 did not exhibit protective function on anisomycin-induced apoptosis of HK cells, but rather slightly enhanced it. This IL-4 effect correlated with the up-regulation of anisomycin-induced p38 signaling, which is attenuated by inhibition of the PI3K/Akt pathway. Expression of an active form of Akt increased anisomycin-elicited activation of p38 and its upstream kinase MKK3/6. Our data indicate a positive cross-talk between the p38 and PI3K/Akt pathways.
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Anisomicina/farmacología , Células Dendríticas Foliculares/citología , Interleucina-4/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular , Células Dendríticas Foliculares/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Proteínas Quinasas Activadas por Mitógenos/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Proteínas Proto-Oncogénicas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt , Receptor Cross-Talk , Transducción de Señal , Transfección , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Human soluble Fas ligand (sFasL) has an apoptotic activity in contrast to murine sFasL. The physiological function of human sFasL is not known, while the pathological consequence of sFasL overproduction has been reported. To understand the physiological function of (human) sFasL, murine and human lymphocytes were treated with sFasL. sFasL treatment significantly decreased CD45RBlo "memory" CD4+ lymphocyte fraction and increased propidium iodide (PI)+ apoptotic CD45RBloCD4+ lymphocytes among murine peripheral lymphocytes. However, sFasL treatment neither decreased CD45RO+ "memory" CD4+ lymphocyte fraction nor increased PI+ CD45RO+CD4+ lymphocytes among human peripheral lymphocytes, suggesting that the deletion of memory cells by sFasL had already occurred in vivo. Patients with systemic lupus erythematosus had sFasL-susceptible "memory" cell fraction suggesting an incomplete deletion of such "memory" cells. These results suggest that the physiological function of human sFasL is to delete the potentially auto-reactive "memory" lymphocytes, which complements membrane FasL (mFasL)-mediated deletion of auto-reactive cells in human beings but not in mice.
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Autoinmunidad , Memoria Inmunológica , Glicoproteínas de Membrana/metabolismo , Animales , Apoptosis , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Supresión Clonal , Citotoxicidad Inmunológica , Diabetes Mellitus Tipo 1/inmunología , Proteína Ligando Fas , Humanos , Técnicas In Vitro , Antígenos Comunes de Leucocito/metabolismo , Lupus Eritematoso Sistémico/inmunología , Glicoproteínas de Membrana/farmacología , Ratones , Ratones Endogámicos ICR , Ratones Endogámicos NOD , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Solubilidad , Especificidad de la Especie , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunologíaRESUMEN
In this brief, an extended dissipativity analysis was conducted for a neural network with time-varying delays. The concept of the extended dissipativity can be used to solve for the H∞, L2-L∞, passive, and dissipative performance by adjusting the weighting matrices in a new performance index. In addition, the activation function dividing method is modified by introducing a tuning parameter. Examples are provided to show the effectiveness and less conservatism of the proposed method.
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Redes Neurales de la Computación , Dinámicas no Lineales , Reconocimiento de Normas Patrones Automatizadas/métodos , Algoritmos , Simulación por Computador , Humanos , Factores de TiempoRESUMEN
This paper considers the state estimation problem for Markovian jumping genetic regulatory networks (GRNs) with mode-dependent leakage and time-varying delays. In order to approximate the true concentrations of the mRNA and protein, the state estimator is designed using available measurement outputs. The GRNs are composed of N modes. The system switches from one mode to another according to a Markovian chain with known transition probabilities. Based on the Lyapunov functionals, including triple integral terms, some inequalities, and a time-varying delay partitioning approach, delay-dependent criteria which employ all upper bounds of time delays of each mode are obtained in terms of linear matrix inequalities (LMIs). This guarantees that the estimation error dynamics can be globally asymptotically stable from solutions of LMIs. Finally, a numerical example is presented to demonstrate the efficiency of the proposed estimation scheme.
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Biología Computacional/métodos , Simulación por Computador , Redes Reguladoras de Genes/genética , Modelos Genéticos , Modelos Estadísticos , Cadenas de Markov , Proteínas/análisis , Proteínas/genética , Proteínas/metabolismo , ARN Mensajero/análisis , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
This study examines the state estimation problem for neural networks with a time-varying delay. Unlike other studies, the sampled-data with stochastic sampling is used to design the state estimator using a novel approach that divides the bounding of the activation function into two subintervals. To fully use the sawtooth structure characteristics of the sampling input delay, a discontinuous Lyapunov functional is proposed based on the extended Wirtinger inequality. The desired estimator gain can be characterized in terms of the solution to linear matrix inequalities (LMIs). Finally, the proposed method is applied to two numerical examples to show the effectiveness of our result.