RESUMEN
BACKGROUND: Music therapy is demonstrated to be effective to relieve the agitation among people with dementia, but the comparative effectiveness of methods of music engagement for people with dementia is uncertain. OBJECTIVE: To evaluate the effects on cognitive functions and behavioral symptoms between interactive and receptive music therapies for people with dementia. METHODS: Prospective studies evaluating interactive and receptive music therapies were identified from the OVID databases, included MEDLINE, EMBASE, PsycINFO, and CINAHL. Supplementary search was conducted in Google Scholar. The primary outcome focused on cognitive function; the secondary outcomes were apathy, anxiety, depressive symptoms, agitation, and other behavioral problems. All outcomes were measured by the standard assessment tools. The heterogeneity of studies was examined, and the effects were pooled by meta-analysis. Quality of studies and risk of bias were assessed. RESULTS: Thirty-eight trials involving 1418 participants with dementia were included. The mean age ranged from 75 to 90 years, and the percentage of male participants ranged from 6% to 83%. No significant difference was found between participants receiving interactive or receptive music therapy and usual care in cognitive function; the mean difference (MD) of Mini-Mental State Examination was 0.18 [95% confidence interval (CI) -1.34 to 1.69], and -0.15 (95% CI -0.55 to 0.25), respectively. Participants with receptive music therapy had significant decrease in agitation (Cohen-Mansfield Agitation Inventory: MD = -7.99, 95% CI -5.11 to -0.87) and behavioral problems (Neuropsychiatric Inventory: MD = -3.02 95% CI -5.90 to -0.15) compared to usual care, while no significant difference was found between interactive music therapy and usual care in behavioral problems and psychiatric symptoms. CONCLUSIONS: This study demonstrated that receptive music therapy could reduce agitation, behavioral problems, and anxiety in older people with dementia, and appears to be more effective than interactive music therapy. It is easy and convenient to implement receptive music therapy; therefore, we recommended the use of receptive music therapy in nursing homes, day care centers, and client homes.
Asunto(s)
Síntomas Conductuales/terapia , Demencia/psicología , Demencia/terapia , Musicoterapia/métodos , Ansiedad/terapia , Terapia Conductista/métodos , Humanos , Agitación PsicomotoraRESUMEN
PIN1 is a peptidyl-prolyl isomerase that catalyzes the cis/trans isomerization of peptide bonds between proline and phosphorylated serine/threonine residues. By changing the conformation of its protein substrates, PIN1 increases the activities of key proteins that promote cell cycle progression and oncogenesis. Moreover, it has been shown that PIN1 stabilizes and increases the level of the cyclin-dependent kinase (CDK) inhibitor p27, which inhibits cell cycle progression by binding cyclin A- and cyclin E-CDK2. Notwithstanding the associated increase in the p27 level, PIN1 expression promotes rather than retards cell proliferation. To explain the paradoxical effects of PIN1 on p27 levels and cell cycle progression, we hypothesized that PIN1 relieves CDK2 inhibition by suppressing the CDK inhibitory activity of p27. Here, we confirmed that PIN1-expressing cells exhibit higher p27 levels but have increased CDK2 activities and higher proliferation rates in the S-phase compared with Pin1-null fibroblasts or PIN1-depleted hepatoma cells. Using co-immunoprecipitation and CDK kinase activity assays, we found that PIN1 binds the phosphorylated Thr187-Pro motif in p27 and reduces p27's interaction with cyclin A- or cyclin E-CDK2, leading to increased CDK2 kinase activity. In conclusion, our results indicate that although PIN1 increases p27 levels, it also attenuates p27's inhibitory activity on CDK2 and thereby contributes to increased G1-S phase transitions and cell proliferation.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Ciclo Celular/fisiología , División Celular/fisiología , Ciclina A/metabolismo , Ciclina E/metabolismo , Ciclinas/metabolismo , Fase G1/fisiología , Humanos , FosforilaciónRESUMEN
In mitotic cells, the cyclin-dependent kinase (CDK) subunit protein CKS1 regulates S phase entry by mediating degradation of the CDK inhibitor p27. Although mature neurons lack mitotic CDKs, we found that CKS1 was actively expressed in post-mitotic neurons of the adult hippocampus. Interestingly, Cks1 knockout (Cks1-/-) mice exhibited poor long-term memory, and diminished maintenance of long-term potentiation in the hippocampal circuits. Furthermore, there was neuronal accumulation of cofilin-actin rods or cofilin aggregates, which are associated with defective dendritic spine maturation and synaptic loss. We further demonstrated that it was the increased p27 level that activated cofilin by suppressing the RhoA kinase-mediated inhibitory phosphorylation of cofilin, resulting in the formation of cofilin aggregates in the Cks1-/- neuronal cells. Consistent with reports that the peptidyl-prolyl-isomerase PIN1 competes with CKS1 for p27 binding, we found that inhibition of PIN1 diminished the formation of cofilin aggregates through decreasing p27 levels, thereby activating RhoA and increasing cofilin phosphorylation. Our results revealed that CKS1 is involved in normal glutamatergic synapse development and dendritic spine maturation in adult hippocampus through modulating p27 stability.
Asunto(s)
Factores Despolimerizantes de la Actina/metabolismo , Quinasas CDC2-CDC28/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Hipocampo/metabolismo , Trastornos de la Memoria/metabolismo , Memoria a Largo Plazo , Neuronas/metabolismo , Animales , Quinasas CDC2-CDC28/genética , Ciclo Celular , Espinas Dendríticas , Hipocampo/patología , Potenciación a Largo Plazo , Masculino , Trastornos de la Memoria/patología , Ratones , Ratones Noqueados , Agregado de Proteínas , Aprendizaje EspacialRESUMEN
Germline mutations in the cyclin-dependent kinase inhibitor, CDKN1B, have been described in patients with multiple endocrine neoplasia (MEN), a cancer predisposition syndrome with adult onset neoplasia and no additional phenotypes. Here, we describe the first human case of CDKN1B deficiency, which recapitulates features of the murine CDKN1B knockout mouse model, including gigantism and neurodevelopmental defects. Decreased mRNA and protein expression of CDKN1B were confirmed in the proband's peripheral blood, which is not seen in MEN syndrome patients. We ascribed the decreased protein level to a maternally derived deletion on chromosome 12p13 encompassing the CDKN1B locus (which reduced mRNA expression) and a de novo allelic variant (c.-73G>A) in the CDKN1B promoter (which reduced protein translation). We propose a recessive model where decreased dosage of CDKN1B during development in humans results in a neuronal phenotype akin to that described in mice, placing CDKN1B as a candidate gene involved in developmental delay.
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Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Discapacidades del Desarrollo/genética , Trastorno Autístico/genética , Preescolar , Hibridación Genómica Comparativa , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/deficiencia , Discapacidades del Desarrollo/diagnóstico , Femenino , Expresión Génica , Humanos , Masculino , Mutación , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
Ribosome-inactivating proteins (RIPs) inactivate prokaryotic or eukaryotic ribosomes by removing a single adenine in the large ribosomal RNA. Here we show maize RIP (MOD), an atypical RIP with an internal inactivation loop, interacts with the ribosomal stalk protein P2 via Lys158-Lys161, which is located in the N-terminal domain and at the base of its internal loop. Due to subtle differences in the structure of maize RIP, hydrophobic interaction with the 'FGLFD' motif of P2 is not as evidenced in MOD-P2 interaction. As a result, interaction of P2 with MOD was weaker than those with trichosanthin and shiga toxin A as reflected by the dissociation constants (K(D)) of their interaction, which are 1037.50 ± 65.75 µM, 611.70 ± 28.13 µM and 194.84 ± 9.47 µM respectively.Despite MOD and TCS target at the same ribosomal protein P2, MOD was found 48 and 10 folds less potent than trichosanthin in ribosome depurination and cytotoxicity to 293T cells respectively, implicating the strength of interaction between RIPs and ribosomal proteins is important for the biological activity of RIPs. Our work illustrates the flexibility on the docking of RIPs on ribosomal proteins for targeting the sarcin-ricin loop and the importance of protein-protein interaction for ribosome-inactivating activity.
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Fosfoproteínas/metabolismo , Proteínas Ribosómicas/metabolismo , Proteínas Inactivadoras de Ribosomas/metabolismo , Ribosomas/metabolismo , Zea mays/metabolismo , Animales , Hígado/efectos de los fármacos , Hígado/metabolismo , Fosfoproteínas/genética , ARN Ribosómico/metabolismo , Ratas , Proteínas Ribosómicas/genética , Proteínas Inactivadoras de Ribosomas/genética , Proteínas Inactivadoras de Ribosomas/farmacología , Ribosomas/efectos de los fármacos , Toxina Shiga/genética , Toxina Shiga/metabolismo , Tricosantina/genética , Tricosantina/metabolismo , Zea mays/genéticaRESUMEN
CKS proteins are evolutionarily conserved cyclin-dependent kinase (CDK) subunits whose functions are incompletely understood. Mammals have two CKS proteins. CKS1 acts as a cofactor to the ubiquitin ligase complex SCF(SKP2) to promote degradation of CDK inhibitors, such as p27. Little is known about the role of the closely related CKS2. Using a Cks2(-/-) knockout mouse model, we show that CKS2 counteracts CKS1 and stabilizes p27. Unopposed CKS1 activity in Cks2(-/-) cells leads to loss of p27. The resulting unrestricted cyclin A/CDK2 activity is accompanied by shortening of the cell cycle, increased replication fork velocity, and DNA damage. In vivo, Cks2(-/-) cortical progenitor cells are limited in their capacity to differentiate into mature neurons, a phenotype akin to animals lacking p27. We propose that the balance between CKS2 and CKS1 modulates p27 degradation, and with it cyclin A/CDK2 activity, to safeguard replicative fidelity and control neuronal differentiation.
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Quinasas CDC2-CDC28/metabolismo , Proteína Quinasa CDC28 de Saccharomyces cerevisiae/metabolismo , Ciclina A/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Neuronas/metabolismo , Animales , Proteína Quinasa CDC28 de Saccharomyces cerevisiae/genética , Puntos de Control del Ciclo Celular , Proteínas de Ciclo Celular , Diferenciación Celular , Células Cultivadas , Daño del ADN , Activación Enzimática , Ratones , Ratones Noqueados , Neuronas/citologíaRESUMEN
Luffin P1, the smallest ribosome-inactivating peptide from the seeds of Luffa cylindrica was found to have anti-HIV-1 activity in HIV-1 infected C8166 T-cell lines and be able to bind with HIV Rev Response Element. Nuclear magnetic resonance spectroscopy revealed that the Luffin P1 comprises a helix-loop-helix motif, with the two alpha helices tightly associated by two disulfide bonds. Based on our findings, we conclude that unlike the well-studied ribosome-inactivating proteins, which exert their action through N-glycosidase activities, Luffin P1 demonstrates a novel inactivation mechanism probably through the charge complementation with viral or cellular proteins. Our work also provides a new scaffold for the design of novel inhibitors from a simple helical motif.