RESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoma. MIC-A and MIC-B are the natural ligands for NKG2D, a receptor expressed in NK cells. MIC-A soluble isoforms (sMICA) have been described in different malignancies. OBJECTIVES: To analyze lymphocyte subsets and sMIC-A in germinal center DLBCL. MATERIALS AND METHODS: sMICA, sMICB, and peripheral blood lymphocyte subsets (CD4+, CD8+, NK, NKT, γδ T cells, and dendritic cells) were analyzed in 59 patients and 60 healthy donors. RESULTS: Patients had decreased numbers of type 1 and type 2 dendritic cells, NK, iNKT, CD4 T, and CD8 T cells, and higher levels of sMIC-A. The 2-year PFS for high IPI scores and high sMIC-A was 24% and 28%, respectively. The 2-year OS for high IPI scores and high sMIC-A was 42% and 33%. The 2-year PFS and OS for patients not achieving response to treatment were 0% and 10%, respectively. The MICPI score (one point each for high IPI score and high sMIC-A) showed that those patients summing two points had worse PSF and OS. CONCLUSIONS: Patients with DLBCL have decreased numbers of peripheral lymphocyte subsets and high levels of sMIC-A. The addition of sMIC-A to IPI could improve its prognostic relevance.
Assuntos
Centro Germinativo , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Prognóstico , Centro Germinativo/patologia , Centro Germinativo/metabolismo , Adulto , Subpopulações de Linfócitos/metabolismo , Subpopulações de Linfócitos/imunologia , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do Tratamento , Estadiamento de Neoplasias , Imunofenotipagem , Biomarcadores TumoraisRESUMO
Glioblastoma multiforme (GBM) represents the most malignant type of astrocytoma, with a life expectancy of two years. It has been shown that Poly (ADP-ribose) polymerase 1 (PARP-1) protein is over-expressed in GBM cells, while its expression in healthy tissue is low. In addition, perezone, a phyto-compound, is a PARP-1 inhibitor with anti-neoplastic activity. As a consequence, in the present study, both in vitro and computational evaluations of perezone and its chemically related compound, perezone angelate, as anti-GBM agents were performed. Hence, the anti-proliferative assay showed that perezone angelate induces higher cytotoxicity in the GBM cell line (U373 IC50 = 6.44 µM) than perezone (U373 IC50 = 51.20 µM) by induction of apoptosis. In addition, perezone angelate showed low cytotoxic activity in rat glial cells (IC50 = 173.66 µM). PARP-1 inhibitory activity (IC50 = 5.25 µM) and oxidative stress induction by perezone angelate were corroborated employing in vitro studies. In the other hand, the performed docking studies allowed explaining the PARP-1 inhibitory activity of perezone angelate, and ADMET studies showed its probability to permeate cell membranes and the blood-brain barrier, which is an essential characteristic of drugs to treat neurological diseases. Finally, it is essential to highlight that the results confirm perezone angelate as a potential anti-GBM agent.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Sesquiterpenos , Animais , Apoptose , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ratos , Sesquiterpenos/farmacologiaRESUMO
Cancer is one of the leading causes of morbidity and mortality worldwide. This disease is characterized by uncontrolled growth and proliferation of abnormal cells with a high probability to develop metastasis. Recently, it was demonstrated that perezone, a sesquiterpene quinone, is capable to induce cell death in leukemia (K562), prostate (PC-3), colorectal (HCT-15) and lung (SKLU-1) cancer cell lines; however, its mechanism of action is unknown. Therefore, in this study, in vitro and computational studies were performed to determine the mechanism of action of perezone. Firstly, changes in K562â¯cell viability, as well as changes in the redox status of the cell in response to treatment with several concentrations of perezone were analyzed. The type of cell death induced, and the modification of the cell cycle were determined. In addition, MD simulations and docking studies were performed to investigate the interaction of perezone with seven regulators of the apoptotic process. Finally, the ability of perezone to inhibit PARP-1 was evaluated by in vitro studies. K562 cells treated with perezone exhibited decreased viability and more oxidized status, being this effect concentration-dependent. In addition, the increase of G0/G1 phase of cell cycle and apoptosis were observed. According to the performed computational studies conducted, perezone showed the highest affinity to PARP-1 enzyme being this complex the most stable due to the presence of a small and deep cavity in the active site, which allows perezone to fit deeply by forming hydrogen bonds and hydrophobic interactions, which drive this interaction. The activity of perezone as PARP-1 inhibitor was corroborated with an IC50â¯=â¯181.5⯵M. The pro-apoptotic action of perezone may be related to PARP-1 inhibition and changes in the redox state of the cell. The obtained results allowed to understand the biological effect of perezone and, consequently, these could be employed to develop novel PARP-1 inhibitors.
Assuntos
Oxirredução/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Sesquiterpenos/farmacologia , Apoptose/efeitos dos fármacos , Asteraceae/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células K562 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/isolamento & purificação , Sesquiterpenos/isolamento & purificaçãoRESUMO
Background: Recent studies have shown that osteocalcin (OC) is related to not only bone metabolism but also energy metabolism. The aim of the present study was to investigate whether OC was associated with metabolic factors and bone mineral density (BMD) in elderly men. Methods: A cross-sectional study was done including 122 healthy men aged 60 years or older. Serum glucose, lipids, insulin, adiponectin and OC were measured and BMD was estimated using dual energy X-ray absorptiometry. Results: 42.8% of men had metabolic syndrome (MetS). OC levels were not significantly different between men with and without MetS. OC concentrations were inversely associated with body mass index (BMI) (r = −0.226, p = 0.04), waist circumference (r = −0.261, p = 0.02), glucose (r = −0.245, p = 0.03), insulin (r = −0.235, p = 0.03), and HOMA-IR (r = −0.211, p = 0.04). In addition, OC levels were higher in patients with diminished BMD compared with those with normal BMD. Conclusions: OC levels correlate negatively with BMI, waist circumference, glucose, insulin and HOMA-IR in elderly men, which suggests a connection between bone and energy metabolism.
Introducción: diversos estudios sugieren que la osteocalcina (OC) contribuye no solo a la regulación del metabolismo óseo, sino también al metabolismo energético. El objetivo del trabajo fue evaluar la relación entre la concentración sérica de OC y los parámetros metabólicos y la densidad mineral ósea (DMO) en adultos mayores. Métodos: estudio transversal descriptivo en 122 hombres sanos mayores de 60 años. Se les determinó glucosa, lípidos, insulina, adiponectina y OC. La DMO se analizó por absorciometría de doble fotón. Resultados: el 42.8% de la muestra presentó síndrome metabólico (SM). Los niveles de OC no difirieron entre el grupo de pacientes con y sin SM. Se observó una correlación negativa entre la concentración de OC y el índice de masa corporal (IMC) (r = −0.226, p = 0.04), circunferencia de cintura (r = −0.261, p = 0.02), glucosa (r = −0.245, p = 0.03), insulina (r = −0.235, p = 0.03) y HOMA-IR (r = −0.211, p = 0.04). Los pacientes con DMO disminuida mostraron una concentración significativamente mayor de OC en comparación con aquellos con DMO normal. Conclusiones: la OC se asoció inversamente con el IMC, la obesidad abdominal, la glucosa, la insulina y la resistencia a la insulina en hombres mayores de 60 años. Lo anterior confirma la conexión que existe entre el tejido óseo y el metabolismo.