RESUMEN
Monitoring neural activity in the central nervous system often utilizes silicon-based microelectromechanical system (MEMS) probes. Despite their effectiveness in monitoring, these probes have a fragility issue, limiting their application across various fields. This study introduces flexible printed circuit board (FPCB) neural probes characterized by robust mechanical and electrical properties. The probes demonstrate low impedance after platinum coating, making them suitable for multiunit recordings in awake animals. This capability allows for the simultaneous monitoring of a large population of neurons in the brain, including cluster data. Additionally, these probes exhibit no fractures, mechanical failures, or electrical issues during repeated-bending tests, both during handling and monitoring. Despite the possibility of using this neural probe for signal measurement in awake animals, simply applying a platinum coating may encounter difficulties in chronic tests and other applications. Furthermore, this suggests that FPCB probes can be advanced by any method and serve as an appropriate type of tailorable neural probes for monitoring neural systems in awake animals.
RESUMEN
PURPOSE: The purpose of this study was to compare the midterm outcomes between fixed and mobile ultra-congruent (UC) bearings in total knee arthroplasty (TKA). METHODS: This is a retrospective matched-pairs case-control study of patients who underwent primary navigation-assisted TKA with a minimum 5-year follow-up. A total of 182 cases involved the fixed UC bearing system as Group 1 and 101 cases involved mobile UC bearing system group as Group 2. After 1:1 matching, 73 knees in each group were enrolled. Clinical and radiographic outcomes were evaluated. RESULTS: The overall survival was 143 of 146 cases (97.9 %) at final follow-up, and 72 of 73 cases (96.3 %) in Group 1 and 71 of 73 cases (95.8 %) in Group 2 at final follow-up based on an endpoint of revision surgery. The reasons of revision TKA were periprosthetic fracture in Group 1, infection and bearing dislocation in Group 2. There was no statistical difference in Hospital for Special Surgery (HSS) scores, Knee Society Scores (KSS), WOMAC index score evaluations between groups. CONCLUSIONS: This study demonstrated that the fixed-bearing UC prosthesis could provide satisfactory performance compared with that of the mobile-bearing UC prosthesis with minimum 5-year follow-up. The fixed-bearing UC prosthesis could be considered in navigation-assisted TKA with theoretical advantages of UC design. LEVEL OF EVIDENCE: IV.
Asunto(s)
Artroplastia de Reemplazo de Rodilla/métodos , Prótesis de la Rodilla , Osteoartritis de la Rodilla/cirugía , Diseño de Prótesis , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Articulación de la Rodilla/cirugía , Masculino , Persona de Mediana Edad , Fracturas Periprotésicas/epidemiología , Complicaciones Posoperatorias/epidemiología , Rango del Movimiento Articular , Reoperación/estadística & datos numéricos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Blood monocytes are recruited to injured tissue sites and differentiate into macrophages, which protect against pathogens and repair damaged tissues. Reactive oxygen species (ROS) are known to be an important contributor to monocytes' differentiation and macrophages' function. NF-E2-related factor 2 (NRF2), a transcription factor regulating cellular redox homeostasis, is known to be a critical modulator of inflammatory responses. We herein investigated the role of NRF2 in macrophage differentiation using the human monocytic U937 cell line and phorbol-12-myristate-13-acetate (PMA). In U937 cells with NRF2 silencing, PMA-stimulated cell adherence was significantly facilitated when compared to control U937 cells. Both transcript and protein levels for pro-inflammatory cytokines, including interleukine-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNFα) were highly elevated in PMA-stimulated NRF2-silenced U937 compared to the control. In addition, PMA-inducible secretion of monocyte chemotactic protein 1 (MCP-1) was significantly high in NRF2-silenced U937. As an underlying mechanism, we showed that NRF2-knockdown U937 retained high levels of cellular ROS and endoplasmic reticulum (ER) stress markers expression; and subsequently, PMA-stimulated levels of Ca2+ and PKCα were greater in NRF2-knockdown U937 cells, which caused enhanced nuclear accumulation of nuclear factor-Ò¡B (NFÒ¡B) p50 and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation. Whereas the treatment of NRF2-silenced U937 cells with pharmacological inhibitors of NFÒ¡B or ERK1/2 largely blocked PMA-induced IL-1ß and IL-6 expression, indicating that these pathways are associated with cell differentiation. Taken together, our results suggest that the NRF2 system functions to suppress PMA-stimulated U937 cell differentiation into pro-inflammatory macrophages and provide evidence that the ROS-PKCα-ERK-NFÒ¡B axis is involved in PMA-facilitated differentiation of NRF2-silenced U937 cells.
Asunto(s)
Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Calcio/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Citocinas/metabolismo , Estrés del Retículo Endoplásmico , Técnicas de Silenciamiento del Gen , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Macrófagos/inmunología , Monocitos/inmunología , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/genética , Subunidad p50 de NF-kappa B/metabolismo , Proteína Quinasa C-alfa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Acetato de Tetradecanoilforbol/farmacología , Células U937RESUMEN
Transcription factor NF-E2-related factor 2 (NRF2) plays a crucial role in the cellular defense against oxidative/electrophilic stress by up-regulating multiple antioxidant genes. Numerous studies with genetically modified animals have demonstrated that Nrf2 is a sensitivity determining factor upon the exposure to environmental chemicals including carcinogens. Moreover, recent studies have demonstrated that polymorphism in the human NRF2 promoter is associated with higher risks for developing acute lung injury, gastric mucosal inflammation, and nephritis. Therefore, the identification of reliable and effective human target genes of NRF2 may allow the monitoring of NRF2 activity and to predict individual sensitivity to environmental stress-induced damage. For this purpose, we investigated genes that are tightly controlled by NRF2 to establish markers for NRF2 activity in human cells. Firstly, in the normal human renal epithelial HK-2 cells, the measurement of the expression of 30 previously reported NRF2 target genes in response to NRF2 inducers (sulforaphane, tert-butylhydroquinone, cinnamic aldehyde, and hydrogen peroxide) showed that the aldo-keto reductase (AKR) 1C1 is highly inducible by all treatments. Accordantly, the basal and inducible expressions of AKRs were significantly attenuated in NRF2-silenced HK-2 cells. Whereas, cells with stable KEAP1 knockdown, which causes a modest NRF2 activation, demonstrated substantially increased levels of AKR1A1, 1B1, 1B10, 1C1, 1C2, and 1C3. Secondly, the linkage between NRF2 and the AKRs was confirmed in human monocytic leukemia cell line U937, which can be a model of peripherally available blood cells. The treatment of U937 cells with NRF2 inducers including sulforaphane effectively elevated the expression of AKR1B1, 1B10, 1C1, 1C2, and 1C3. Whereas, the levels of both the basal and sulforaphane-inducible expression of AKR1C1 were significantly reduced in NRF2-silenced stable U937 cells compared to the control cells. Similarly, the inducible expression of AKR1C1 was observed in another human monocytic leukemia cell line THP-1 as well as in human primary blood CD14(+) monocytes. In conclusion, together with the high inducibility and NRF2 dependency shown in renal epithelial cells as well as in peripherally available blood cells, current findings suggest that AKRs can be utilized as a marker of NRF2 activity in human cells.
Asunto(s)
Aldehído Reductasa/genética , Regulación de la Expresión Génica/fisiología , Túbulos Renales Proximales/enzimología , Factor 2 Relacionado con NF-E2/genética , 20-Hidroxiesteroide Deshidrogenasas/biosíntesis , 20-Hidroxiesteroide Deshidrogenasas/efectos de los fármacos , Acroleína/análogos & derivados , Acroleína/farmacología , Aldehído Reductasa/metabolismo , Biomarcadores/metabolismo , Inducción Enzimática/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Marcadores Genéticos , Humanos , Peróxido de Hidrógeno/farmacología , Hidroquinonas/farmacología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Isotiocianatos , Proteína 1 Asociada A ECH Tipo Kelch , Túbulos Renales Proximales/efectos de los fármacos , Leucemia Monocítica Aguda/enzimología , Leucemia Monocítica Aguda/genética , Monocitos/enzimología , Monocitos/patología , Factor 2 Relacionado con NF-E2/biosíntesis , Estrés Oxidativo/fisiología , Sulfóxidos , Tiocianatos/farmacología , Células U937RESUMEN
NF-E2-related factor 2 (NRF2) is a transcription factor that regulates the expression of various antioxidant and detoxifying enzymes. Although the benefit of NRF2 in cancer prevention is well established, its role in cancer pathobiology was recently discovered. In this study, the role of NRF2 in tumor growth and docetaxel sensitivity was investigated in ErbB2-overexpressing ovarian carcinoma SKOV3 cells. Interfering RNA-mediated stable inhibition of NRF2 in SKOV3 cells repressed NRF2 signaling, resulting in cell growth arrest at G(0)/G(1) phase and tumor growth retardation in mouse xenografts. Microarray analysis revealed that ErbB2 expression is substantially reduced in NRF2-inhibited SKOV3 and this was further confirmed by RT-PCR and immunoblot analysis. Repression of ErbB2 led to a decrease in phospho-AKT and enhanced p27 protein, reinforcing the effect of NRF2 knockdown on SKOV3 growth. Furthermore, NRF2 inhibition-mediated ErbB2 repression increases the sensitivity of these cells to docetaxel cytotoxicity and apoptosis. The linkage between NRF2 and ErbB2 was confirmed in the ErbB2-positive breast cancer cell line BT-474: NRF2 knockdown suppressed ErbB2 expression and enhanced docetaxel sensitivity. Our results provide insight into the coordinated regulation of signaling molecules responding to environmental stress and suggest that NRF2 modulation might be a therapeutic strategy to limit tumor growth and enhance sensitivity to taxane-based chemotherapy.