ABSTRACT
Background: The aging process promotes a progressive increase in chronic-degenerative diseases. The effect of these diseases on the functional capacity has been well recognized. Another health parameter concerns “quality of life related to health”. Among the elderly population, cardiovascular diseases stand out due to the epidemiological and clinical impact. Usually, these diseases have been associated with others. This set of problems may compromise both independence and quality of life in elderly patients who seek cardiologic treatment. These health parameters have not been well contemplated by cardiologists. Objective: Evaluating, among the elderly population with cardiovascular disease, which are the most relevant clinical determinants regarding dependence and quality of life. Methods: This group was randomly and consecutively selected and four questionnaires were applied: HAQ, SF-36, PRIME-MD e Mini Mental State. Results: The study included 1,020 elderly patients, 63.3% women. The group had been between 60 and 97 years-old (mean: 75.56 ± 6.62 years-old). 61.4% were independent or mild dependence. The quality of life total score was high (HAQ: 88.66 ± 2.68). 87.8% of patients had a SF-36 total score > 66. In the multivariate analysis, the association between diagnoses and high degrees of dependence was significant only for previous stroke (p = 0.014), obesity (p < 0.001), lack of physical activity (p = 0.016), osteoarthritis (p < 0.001), cognitive impairment (p < 0.001), and major depression (p < 0.001). Analyzing the quality of life, major depression and physical illness for depression was significantly associated with all domains of the SF-36. Conclusion: Among an elderly outpatient cardiology population, dependence and quality of life clinical determinants are not cardiovascular comorbidities, especially the depression. .
Fundamento: Com o envelhecimento, a prevalência de doenças crônico-degenerativas sofreu aumento progressivo. A repercussão dessas doenças sobre a capacidade funcional foi reconhecida. Outro parâmetro de saúde é a “qualidade de vida relacionada à saúde”. Na população idosa, as doenças cardiovasculares destacam-se pelo impacto epidemiológico e clínico. Elas, geralmente, vêm associadas a outras afecções. Esse conjunto de problemas pode comprometer a independência e a qualidade de vida do idoso que busca tratamento cardiológico. Objetivo: Avaliar, em uma população de idosos cardiopatas, quais são os determinantes clínicos mais relevantes de dependência e de qualidade de vida. Métodos: O grupo foi selecionado aleatória e consecutivamente, sendo aplicados quatro questionários: HAQ, SF-36, PRIME‑MD e Mini Exame do Estado Mental. Resultados: Incluiu-se 1020 idosos, 63,3% mulheres. O grupo tinha em média 75,56 ± 6,62 anos. 61,4% mostrou-se independente ou com dependência leve. O escore de qualidade de vida foi elevado (HAQ: 88,66 ± 2,68). 87,8% dos pacientes apresentou escore total do SF-36 ≥ 66. À análise multivariada, a associação entre os diagnósticos e graus elevados de dependência foi significante apenas para acidente vascular cerebral prévio (p = 0,014), obesidade (p < 0,001), sedentarismo (p = 0,016), osteoartrite (p < 0,001), déficit cognitivo (p < 0,001), e depressão maior (p < 0,001). Ao analisarmos a qualidade de vida, a depressão maior e a depressão por doença física associou-se significativamente com todos os domínios do SF-36. Conclusão: Em uma população de idosos cardiopatas, os determinantes clínicos mais relevantes de prejuízos para dependência e qualidade de vida foram as comorbidades não cardiovasculares, particularmente a depressão. .
Subject(s)
Humans , Hepatocytes/pathology , Liver Regeneration , Liver Failure, Acute/metabolism , Apoptosis , /physiology , Fas Ligand Protein/physiology , Hepatocytes/metabolism , Liver Failure, Acute/therapy , Necrosis , Receptors, Tumor Necrosis Factor/metabolism , Signal Transduction , TNF-Related Apoptosis-Inducing Ligand/physiology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
This study was designed to investigate the effects of the prenylated flavonoid kurarinone on TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis and its underlying mechanism. A low dose of kurarinone had no significant effect on apoptosis, but this compound markedly promoted tumor cell death through elevation of Bid cleavage, cytochrome c release and caspase activation in HeLa cells treated with TRAIL. Caspase inhibitors inhibited kurarinone-mediated cell death, which indicates that the cytotoxic effect of this compound is mediated by caspase-dependent apoptosis. The cytotoxic effect of kurarinone was not associated with expression levels of Bcl-2 and IAP family proteins, such as Bcl-2, Bcl-xL, Bid, Bad, Bax, XIAP, cIAP-1 and cIAP-2. In addition, this compound did not regulate the death-inducing receptors DR4 and DR5. On the other hand, kurarinone significantly inhibited TRAIL-induced IKK activation, IkappaB degradation and nuclear translocation of NF-kappaB, as well as effectively suppressed cellular FLICE-inhibitory protein long form (cFLIPL) expression. The synergistic effects of kurarinone on TRAIL-induced apoptosis were mimicked when kurarinone was replaced by the NF-kappaB inhibitor withaferin A or following siRNA-mediated knockdown of cFLIPL. Moreover, cFLIP overexpression effectively antagonized kurarinone-mediated TRAIL sensitization. These data suggest that kurarinone sensitizes TRAIL-induced tumor cell apoptosis via suppression of NF-kappaB-dependent cFLIP expression, indicating that this compound can be used as an anti-tumor agent in combination with TRAIL.
Subject(s)
Humans , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , CASP8 and FADD-Like Apoptosis Regulating Protein/genetics , Caspase 3/metabolism , Caspase 8/metabolism , Drug Synergism , Enzyme Activation/drug effects , Flavonoids/pharmacology , Gene Expression/drug effects , Gene Knockdown Techniques , HeLa Cells , NF-kappa B/antagonists & inhibitors , Protein Transport/drug effects , RNA, Small Interfering/genetics , Signal Transduction , TNF-Related Apoptosis-Inducing Ligand/physiology , Up-Regulation/drug effectsABSTRACT
RAC3 pertenece a la familia de coactivadores de receptores nucleares p160, y se encuentra sobreexpresado en varios tumores. Demostramos previamente que RAC3 es coactivador del factor de transcripción anti-apoptótico NF-kB. En este trabajo investigamos su rol en la apoptosis inducida por H2O2 en una línea celular no tumoral derivada de riñón embrionario humano (HEK293), y por el ligando inductor de apoptosis relacionado a TNF (TRAIL) en una línea de leucemia mieloide crónica humana (K562), naturalmente resistente a la muerte por este estímulo. Observamos que las células tumorales K562 poseen niveles altos de RAC3 comparados con las células no tumorales HEK293. La sobreexpresión normal de coactivador o por transfección, inhibe la apoptosis mediante una disminución de la activación de caspasas, translocación del factor inductor de apoptosis (AIF) al núcleo, aumento de la actividad de NF-kB y las quinasas AKT y p38 y disminución de la quinasa ERK. Lo opuesto fue observado por disminución de RAC3 mediante la técnica de ARN interferente (RNAi) en K562, aumentando así la apoptosis inducida por TRAIL. Estas evidencias sugieren que una sobreexpresión de RAC3 contribuye al desarrollo de tumores, participando en las cascadas que controlan la muerte celular por mecanismos no estrictamente dependientes de hormonas esteroideas y/o de acetilación, constituyendo esto un posible blanco de ataque para el tratamiento de tumores.
RAC3 belongs to the family of p160 nuclear receptors coactivators and it is over-expressed in several tumors. We have previously shown that RAC3 is a NF-kB coactivator. In this paper, we investigated the role of RAC3 in cell-sensitivity to apoptosis, using H2O2 in the human embryonic kidney cell line (HEK293), and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in a human chronic myeloid leukemia cell line (K562) naturally resistant to TRAIL. We observed that the tumoral K562 cells have high levels of RAC3 if compared with the non-tumoral HEK293 cells. The normal or transfected coactivator over-expression inhibits apoptosis through a diminished caspase activity and AIF nuclear translocation, increased NF-kB, AKT and p38, and decreased ERK activities. In contrast, inhibition of RAC3 by siRNA induced sensitivity of K562 to TRAIL-induced apoptosis. Such results suggest that over-expression of RAC3 contributes to tumor development through molecular mechanisms that do not depend strictly on acetylation and/or steroid hormones, which control cell death. This could be a possible target for future tumor therapies.