RESUMEN
Despite growing clinical use of genomic information, patient perceptions of genomic-based care are poorly understood. We prospectively studied patient-physician pairs who participated in an institutional pharmacogenomic implementation program. Trust/privacy/empathy/medical decision-making (MDM)/personalized care dimensions were assessed through patient surveys after clinic visits at which physicians had access to preemptive pharmacogenomic results (Likert scale, 1 = minimum/5 = maximum; mean [SD]). From 2012-2015, 1,261 surveys were issued to 507 patients, with 792 (62.8%) returned. Privacy, empathy, MDM, and personalized care scores were significantly higher after visits when physicians considered pharmacogenomic results. Importantly, personalized care scores were significantly higher after physicians used pharmacogenomic information to guide medication changes (4.0 [1.4] vs. 3.0 [1.6]; P < 0.001) compared with prescribing visits without genomic guidance. Multivariable modeling controlling for clinical factors confirmed personalized care scores were more favorable after visits with genomic-influenced prescribing (odds ratio [OR] = 3.26; 95% confidence interval [CI] = (1.31-8.14); P < 0.05). Physicians seem to individualize care when utilizing pharmacogenomic results and this decision-making augmentation is perceived positively by patients.
Asunto(s)
Toma de Decisiones Clínicas/métodos , Farmacogenética/métodos , Pruebas de Farmacogenómica/métodos , Relaciones Médico-Paciente , Pautas de la Práctica en Medicina , Medicina de Precisión/psicología , Actitud Frente a la Salud , Sistemas de Apoyo a Decisiones Clínicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Percepción Social , Estados UnidosRESUMEN
We investigated the roles of peroxisome proliferator-activated receptor δ (PPARδ) in Porphyromonas gingivalis-derived lipopolysaccharide (Pg-LPS)-induced activation of matrix metalloproteinase 2 (MMP-2). In human gingival fibroblasts (HGFs), activation of PPARδ by GW501516, a specific ligand of PPARδ, inhibited Pg-LPS-induced activation of MMP-2 and generation of reactive oxygen species (ROS), which was associated with reduced expression of NADPH oxidase 4 (Nox4). These effects were significantly smaller in the presence of small interfering RNA targeting PPARδ or the specific PPARδ inhibitor GSK0660, indicating that PPARδ is involved in these events. In addition, modulation of Nox4 expression by small interfering RNA influenced the effect of PPARδ on MMP-2 activity, suggesting a mechanism in which Nox4-derived ROS modulates MMP-2 activity. Furthermore, c-Jun N-terminal kinase and p38, but not extracellular signal-regulated kinase, mediated PPARδ-dependent inhibition of MMP-2 activity in HGFs treated with Pg-LPS. Concomitantly, PPARδ-mediated inhibition of MMP-2 activity was associated with the restoration of types I and III collagen to levels approaching those in HGFs not treated with Pg-LPS. These results indicate that PPARδ-mediated downregulation of Nox4 modulates cellular redox status, which in turn plays a critical role in extracellular matrix homeostasis through ROS-dependent regulation of MMP-2 activity.
Asunto(s)
Fibroblastos/microbiología , Lipopolisacáridos/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , NADPH Oxidasas/genética , PPAR delta/metabolismo , Porphyromonas gingivalis/metabolismo , Células Cultivadas , Colágeno/genética , Colágeno/metabolismo , Regulación hacia Abajo , Activación Enzimática , Fibroblastos/efectos de los fármacos , Encía/citología , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Lipopolisacáridos/farmacología , NADPH Oxidasa 4 , PPAR delta/antagonistas & inhibidores , PPAR delta/genética , Porphyromonas gingivalis/efectos de los fármacos , Porphyromonas gingivalis/patogenicidad , ARN Interferente Pequeño , Especies Reactivas de Oxígeno/metabolismo , Sulfonas/farmacología , Tiazoles/farmacología , Tiofenos/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Peroxisome proliferator-activated receptors (PPARs) inhibit lipopolysaccharide (LPS)-primed release of high mobility group box 1 (HMGB1), a late proinflammatory mediator, but the underlying molecular mechanism is not completely understood. In this study, we demonstrated that the inhibition of HMGB1 release by PPAR-δ and -γ is associated with the deacetylase activity of SIRT1. Ligand-activated PPAR-δ and -γ inhibited LPS-primed release of HMGB1, concomitant with elevation in SIRT1 expression and promoter activity. These effects were significantly reduced in the presence of small interfering (si)RNAs against PPAR, indicating that PPAR-δ and -γ are involved in both HMGB1 release and SIRT1 expression. In addition, modulation of SIRT1 expression and activity by siRNA or chemicals correspondingly influenced the effects of PPARs on HMGB1 release, suggesting a mechanism in which SIRT1 modulates HMGB1 release. Furthermore, we showed for the first time that HMGB1 acetylated in response to LPS or p300/CBP-associated factor (PCAF) is an effective substrate for SIRT1, and that deacetylation of HMGB1 is responsible for blockade of HMGB1 release in macrophages. Finally, acetylation of HMGB1 was elevated in mouse embryonic fibroblasts from SIRT1-knockout mice, whereas this increase was completely reversed by ectopic expression of SIRT1. These results indicate that PPAR-mediated upregulation of SIRT1 modulates the status of HMGB1 acetylation, which, in turn, has a critical role in the cellular response to inflammation through deacetylation-mediated regulation of HMGB1 release.
Asunto(s)
Proteína HMGB1/metabolismo , Lipopolisacáridos/metabolismo , PPAR delta/metabolismo , PPAR gamma/metabolismo , Sirtuina 1/genética , Animales , Línea Celular , Regulación hacia Abajo , Proteína HMGB1/genética , Humanos , Macrófagos/enzimología , Macrófagos/metabolismo , Ratones , Ratones Noqueados , PPAR delta/genética , PPAR gamma/genética , Sirtuina 1/metabolismo , Regulación hacia Arriba , Factores de Transcripción p300-CBP/genética , Factores de Transcripción p300-CBP/metabolismoRESUMEN
The omega-6 fatty acid derivative 15-Deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) is believed to play a role in cellular protection against oxidative stress in diverse cell systems. However, the cellular mechanisms by which protection is afforded by 15d-PGJ2 are not fully elucidated in vascular smooth muscle cells (VSMCs). In this study, we report the finding that 15d-PGJ2 elicited a time and concentration- dependent increase in aldose reductase (AR) expression. This induction was independent of the activation of peroxisome proliferator- activated receptor γ. Inhibition of phosphatidylinositol 3-kinase (PI3K) significantly suppressed the increase in expression and promoter activity of AR induced by 15d-PGJ2. Luciferase reporter assays demonstrated that 15d-PGJ2 targets the multiple stress response regions comprising the antioxidant response element in the promoter of the AR gene. 15d-PGJ2-mediated induction of AR promoter activity was potentiated in the presence of nuclear factor-erythroid 2-related factor 2 (Nrf2), but not in cells expressing dominant negative Nrf2. Cells treated with 15d-PGJ2 were resistant to oxidant-induced apoptotic cell death by inhibiting production of reactive oxygen species. These effects were significantly attenuated in the presence of an AR inhibitor or small interfering RNA against AR, indicating that AR plays a protective role against oxidative injury. Taken together, these findings demonstrate that activation of PI3K by 15d-PGJ2 increases the expression of AR through Nrf2, and increased AR activity may function as an important cellular response against oxidative injury.
Asunto(s)
Aldehído Reductasa/metabolismo , Miocitos del Músculo Liso/enzimología , Prostaglandina D2/análogos & derivados , Regulación hacia Arriba/efectos de los fármacos , Aldehído Reductasa/genética , Animales , Elementos de Respuesta Antioxidante , Secuencia de Bases , Células Cultivadas , Cromanos/farmacología , Inducción Enzimática/efectos de los fármacos , Glucosa Oxidasa/fisiología , Masculino , Ratones , Datos de Secuencia Molecular , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Fosfatidilinositol 3-Quinasas/metabolismo , Prostaglandina D2/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Rosiglitazona , Transducción de Señal , Tiazolidinedionas/farmacología , TroglitazonaRESUMEN
OBJECTIVES: This study explored the limitations of identifying sedentary individuals via an existing screening question in a state-based surveillance system. METHODS: A national sample (n = 7529) of adults, selected by random-digit dialing between November 1999 and May 2000, responded about participation in leisure-time physical activity. RESULTS: Of those who initially reported no leisure-time physical activity (25%), 85% were engaging in at least some activity, and 20% were engaging in enough moderate- or vigorous-intensity activity to meet health-related recommendations. CONCLUSIONS: Public health programs that use only 1 screening question to identify sedentary behavior may not be able to target physical activity messages effectively, especially if physical activity is defined to include a broad range of activities beyond sports.