RESUMEN
Vessel wall inflammation promotes the destabilization of atherosclerotic plaques. The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) expressed by vascular cells and monocytes. LOX index is calculated by multiplying LOX-1 ligand containing apolipoprotein B level with the soluble LOX-1. A high LOX index reflects an increased risk for stroke and myocardial infarction. However, the change in LOX index after smoking cessation and the relationship between smoking-related variables and LOX index are unknown. Relation of the clinical parameters to the LOX index was examined on 180 subjects (135 males and 45 females) at the first visit to our outpatient clinic for smoking cessation. The impact of smoking cessation on the LOX index was also determined in the 94 subjects (62 males and 32 females) who successfully stopped smoking. Sex-adjusted regression analysis and multivariate analysis identified three independent determinants of the LOX index, namely, low-density lipoprotein-cholesterol (LDL-C; ß = 0.311, p < 0.001), high-sensitivity C-reactive protein (ß = 0.358, p < 0.001), and expired carbon monoxide concentration reflecting smoking heaviness (ß = 0.264, p = 0.003). Body mass index (BMI) significantly increased 3 months after the onset of smoking cessation (p < 0.001). However, the LOX index significantly decreased (p < 0.001), regardless of the rate of increase in BMI post-cessation. The LOX index is closely associated with smoking heaviness as well as dyslipidemia and an inflammation marker. Smoking cessation may induce a decrease in this cardiovascular risk marker, independently of weight gain.
Asunto(s)
Aterosclerosis/sangre , Vasos Sanguíneos/patología , Inflamación/prevención & control , Medición de Riesgo , Receptores Depuradores de Clase E/sangre , Cese del Hábito de Fumar , Fumar/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Aterosclerosis/etiología , Aterosclerosis/patología , Biomarcadores , Vasos Sanguíneos/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Inflamación/sangre , Inflamación/patología , Japón/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Fumar/epidemiologíaRESUMEN
Objective The expression level of monocyte chemoattractant protein-1 (MCP-1) is increased in atherosclerotic regions, inducing monocyte migration to the blood vessel wall. Although the serum MCP-1 concentration is higher in patients with than without cardiovascular disease, the precise correlations between the serum MCP-1 concentration and factors associated with smoking and atherosclerosis are unknown. Methods The serum MCP-1 concentration was measured using an enzyme-linked immunosorbent assay in 207 consecutive smokers who visited our smoking cessation clinic. Results Sex-adjusted analysis of smokers revealed that the MCP-1 concentration was positively correlated with age ( ß = 0.311), smoking duration ( ß = 0.342), systolic blood pressure ( ß = 0.225), and diastolic blood pressure ( ß = 0.137) but not with the body mass index. Multivariate regression analysis showed that smoking duration and systolic blood pressure were independent determinants of the MCP-1 concentration. Conclusions The MCP-1 concentration was positively correlated with blood pressure among smokers. Long-term smokers with high blood pressure may be more susceptible to plaque rupture at atherosclerotic lesion sites.
Asunto(s)
Presión Sanguínea , Quimiocina CCL2/sangre , Fumar Cigarrillos/sangre , Hipertensión/diagnóstico , Cese del Hábito de Fumar , Anciano , Biomarcadores/sangre , Determinación de la Presión Sanguínea , Índice de Masa Corporal , Fumar Cigarrillos/fisiopatología , Femenino , Humanos , Hipertensión/sangre , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
AIM: The α1-antitrypsin-low-density lipoprotein complex (AT-LDL) and serum amyloid A-LDL complex (SAA-LDL) are oxidatively modified LDL complexes that promote atherosclerosis. The serum levels of AT-LDL and SAA-LDL are suggested to be increased by obesity and smoking. We have previously demonstrated that larger weight gain after smoking cessation (SC) perturbs a decrease in the serum level of AT-LDL at 3 months after SC. However, changes of these atherosclerotic makers ï¼3 months after SC are unknown. This study investigated post-SC time-dependent changes in two atherogenic lipoproteins, AT-LDL and SAA-LDL, and in the extent of abdominal obesity. METHODS: In 50 outpatients who had continued SC for 1 year, we measured serum AT-LDL and SAA-LDL levels by the enzyme-linked immunosorbent assay before SC, and at 3 months and 1 year after SC. RESULTS: Both body mass index and waist circumstance significantly increased from pre-SC to 3 months after SC and from 3 months after SC to 1 year after SC. Although the serum levels of AT-LDL and SAA-LDL were unchanged from pre-SC to 3 months after SC, these levels decreased significantly from 3 months after SC to 1 year after SC. CONCLUSIONS: The extent of abdominal obesity and levels of two atherogenic lipoproteins time-dependently change after SC. Although abdominal obesity progressively worsened after SC, the beneficial effect of non-smoking overcomes the potential vascular risks by cessation-associated obesity at 1 year after SC.
Asunto(s)
Aterosclerosis/sangre , Biomarcadores/sangre , Lipoproteínas LDL/sangre , Proteína Amiloide A Sérica/metabolismo , Cese del Hábito de Fumar , Aumento de Peso , alfa 1-Antitripsina/sangre , Adulto , Anciano , Anciano de 80 o más Años , Aterosclerosis/diagnóstico , Aterosclerosis/etiología , Proteína C-Reactiva/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Obesidad/fisiopatología , Pronóstico , Estudios Prospectivos , Factores de TiempoRESUMEN
OBJECTIVES: This study aimed to evaluate influence of ethnic factors on the pharmacokinetics of orally inhaled QMF149, a novel combination of an approved longacting ß2-agonist, indacaterol (Onbrez® Breezhaler® for COPD), and an approved inhaled corticosteroid, mometasone furoate (MF), (Asmanex® Twisthaler® for asthma), following multiple dose administration of QMF149 (indacaterol acetate/MF) 150/80 µg and 150/320 µg via the Breezhaler® device in healthy Japanese and Caucasian subjects. METHODS: This was a single-center, openlabel, multiple-dose, two-period, complete crossover study that randomized healthy Japanese and, age and weight matched Caucasian subjects to QMF149 150/80 µg or 150/320 µg once daily (o.d.) for 14 days in each period. Pharmacokinetics (PK) were assessed up to 24 hours on days 1 and 14. RESULTS: 24 Japanese and 24 Caucasian healthy subjects were enrolled. Indacaterol and MF had similar PK profiles across both the doses and both ethnic groups. The maximum geometric mean ratios (90% confidence interval (CI)) for Japanese vs. Caucasian subjects for Cmax were 1.23 (1.11 - 1.38) and 1.24 (1.11 - 1.38) for indacaterol and MF, respectively. For AUC, the maximum ratios were 1.22 (1.09 - 1.36) and 1.30 (1.18 - 1.44) for indacaterol and MF, respectively. The mild trend towards higher exposure in Japanese subjects could be explained by the fact that the mean body weight was 14% higher for Caucasians compared to their Japanese counterparts. No serious adverse events or discontinuations related to study medication were reported. CONCLUSION: The study demonstrated increase of mean exposure parameters in Japanese subjects vs. Caucasian subjects, which ranged between 19 - 23% and 17 - 30%, for indacaterol and MF components, respectively. Multiple doses of both the QMF149 dose levels were safe and well-tolerated in all subjects. Body weight was considered a key contributory factor for the observed difference in exposure. These results suggest no dose adjustment for QMF149 is required in Asian populations.
Asunto(s)
Antiasmáticos/farmacocinética , Pueblo Asiatico , Indanos/farmacocinética , Pregnadienodioles/farmacocinética , Quinolonas/farmacocinética , Población Blanca , Administración por Inhalación , Adulto , Antiasmáticos/administración & dosificación , Antiasmáticos/efectos adversos , Antiasmáticos/sangre , Área Bajo la Curva , Estudios Cruzados , Combinación de Medicamentos , Monitoreo de Drogas , Humanos , Indanos/administración & dosificación , Indanos/efectos adversos , Indanos/sangre , Japón , Masculino , Nebulizadores y Vaporizadores , Pregnadienodioles/administración & dosificación , Pregnadienodioles/efectos adversos , Pregnadienodioles/sangre , Quinolonas/administración & dosificación , Quinolonas/efectos adversos , Quinolonas/sangre , Adulto JovenRESUMEN
Hypoxia-inducible factor (HIF)-1 is well known as a promising target for cancer chemotherapy. By screening an in-house chemical library using a hypoxia-responsive luciferase reporter gene assay, we identified CLB-016 (1) containing 1-ethylpyrazole-3-carboxamide as a HIF-1 inhibitor (IC50=19.1µM). In a subsequent extensive structure-activity relationship (SAR) study, we developed compound 11Ae with an IC50 value of 8.1µM against HIF-1-driven luciferase activity. Compounds 1 and 11Ae were shown to significantly suppress the HIF-1-mediated hypoxia response, including carbonic anhydrase IX (CAIX) gene expression and migration of human sarcoma HT1080 cells. These results revealed 1-ethylpyrazole-3-carboxamide as a novel scaffold to develop promising anti-cancer drugs targeting the HIF-1 signaling pathway.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Diseño de Fármacos , Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Pirazoles/química , Pirazoles/farmacología , Antineoplásicos/síntesis química , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Pirazoles/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
Although cardiovascular risks decrease after quitting smoking, body weight often increases in the early period after smoking cessation. We have previously reported that the serum level of the α1-antitrypsin-low-density lipoprotein complex (AT-LDL)-an oxidatively modified low-density lipoprotein that accelerates atherosclerosis-is high in current smokers, and that the level rapidly decreases after smoking cessation. However, the effects of weight gain after smoking cessation on this cardiovascular marker are unknown. In 183 outpatients (134 males, 49 females) who had successfully quit smoking, serum AT-LDL levels were measured using an enzyme-linked immunosorbent assay. For all persons who had successfully quit smoking, body mass index (BMI) significantly increased 12 weeks after the first examination (p < 0.01). Among patients with a BMI increase smaller than the median, a significant decrease (p < 0.01) in serum AT-LDL values was found, but no significant changes in serum AT-LDL values were found in patients with a BMI increase greater than the median. The findings suggest that the decrease in serum AT-LDL levels after quitting smoking is influenced by weight gain after smoking cessation.
Asunto(s)
Aterosclerosis/sangre , Lipoproteínas LDL/sangre , Aumento de Peso , alfa 1-Antitripsina/sangre , Adulto , Anciano , Anciano de 80 o más Años , Aterosclerosis/terapia , Biomarcadores , Índice de Masa Corporal , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Fumar/efectos adversos , Adulto JovenRESUMEN
OBJECTIVE: To assess the effects of meal timing on the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin in Japanese patients with Type 2 diabetes. METHODS: In this open-label, single-center crossover study, 12 Japanese patients with Type 2 diabetes were randomized to twice-daily vildagliptin 50 mg, administered 30 min before or immediately before breakfast and dinner for 7 days. After a 7-day washout period, patients received the other regimen. Blood samples were collected for the determination of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1) and glucose. RESULTS: Vildagliptin absorption appeared slower when administered 30 min before rather than immediately before meals (tmax absolute range: 1.00 - 2.00 h vs. 0.33 - 1.58 h). Vildagliptin Cmax and AUC0-8 h were essentially the same irrespective of meal timing (geometric mean ratio: Cmax 1.08 (90% CI; 0.92 - 1.26); AUC0-8 h 0.97 (90% CI; 0.91 - 1.05)). Meal timing did not affect pharmacodynamics; complete DPP-4 inhibition (> 90%) was sustained for 8 h post-dose, and plasma active glucagon-like peptide-1 levels increased 2 - 3-fold from baseline. Fasting plasma glucose (FPG) and postprandial plasma glucose (PPPG) reductions from baseline did not differ significantly with meal timing (30 min before vs. immediately before: FPG, -8.9 vs. -5.8 mg/dl; adjusted AUE0-4 h, -67.0 vs. -51.0 mg×h/dl). Vildagliptin was well tolerated. CONCLUSIONS: Dosing 30 min or immediately before meals did not affect vildagliptin pharmacokinetics or pharmacodynamics in Japanese patients with Type 2 diabetes.
Asunto(s)
Adamantano/análogos & derivados , Pueblo Asiatico , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Ingestión de Alimentos , Conducta Alimentaria , Interacciones Alimento-Droga , Nitrilos/administración & dosificación , Nitrilos/farmacocinética , Pirrolidinas/administración & dosificación , Pirrolidinas/farmacocinética , Adamantano/administración & dosificación , Adamantano/efectos adversos , Adamantano/farmacocinética , Adulto , Análisis de Varianza , Área Bajo la Curva , Biomarcadores/sangre , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etnología , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Esquema de Medicación , Monitoreo de Drogas , Femenino , Péptido 1 Similar al Glucagón/sangre , Humanos , Absorción Intestinal , Japón/epidemiología , Masculino , Persona de Mediana Edad , Nitrilos/efectos adversos , Periodo Posprandial , Pirrolidinas/efectos adversos , Resultado del Tratamiento , VildagliptinaRESUMEN
The genus Megasphaera is relevant to the environment, human health and food, and renewable energy for the future. In this study, a primer set was designed for PCR-restriction fragment length polymorphism (RFLP) analyses to detect and identify the members of Megasphaera. Direct detection and identification were achieved for environmental samples and isolates.
Asunto(s)
Cartilla de ADN/genética , Megasphaera/genética , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Longitud del Fragmento de Restricción , ARN Ribosómico 16S/genética , ADN Bacteriano/análisis , ADN Bacteriano/genética , Megasphaera/aislamiento & purificación , ARN Ribosómico 16S/análisis , Alineación de SecuenciaRESUMEN
BACKGROUND: Cigarette smoking is an independent risk factor for cardiovascular events such as myocardial infarction and stroke. To date, a useful and convenient method of predicting such events in smokers has not been established. The rheological properties of blood assessed by the microchannel method reflect the blood's viscosity and the state of microthrombus formation, which may predict cardiovascular thrombotic events. METHODS AND RESULTS: Blood fluidity was assessed in 74 smoking patients (54 men, 20 women, mean age 57.9 years) by measuring the blood passage time (BPT) in an aliquot (100 µl) of blood using the Micro Channel Array Flow Analyzer. BPT was significantly related with smoking variables such as daily consumption of tobacco (r = 0.236, P = 0.044), Brinkman's index (r = 0.252, P = 0.033), the Fagerstrom Test for Nicotine Dependence (r = 0.257, P = 0.029), and the score of a self-rating depression scale (r = 0.236, P < 0.05). Multivariate regression analysis revealed that an independent BPT determinant was daily consumption of tobacco (r = 0.326, P = 0.045). Furthermore, smoking cessation markedly decreased BPT from 63.0 s to 49.7 s (P = 0.002) at 3 months after the start of therapy. CONCLUSIONS: Unfavorable blood rheology is closely associated with cigarette smoking and may reflect increased cardiovascular risk in smokers. The study results also suggest that such risk can be reduced after only 3 months of smoking cessation.
Asunto(s)
Viscosidad Sanguínea , Enfermedades Cardiovasculares/prevención & control , Cese del Hábito de Fumar , Prevención del Hábito de Fumar , Fumar/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Femenino , Conductas Relacionadas con la Salud , Conocimientos, Actitudes y Práctica en Salud , Hemorreología , Humanos , Japón , Modelos Logísticos , Masculino , Persona de Mediana Edad , Motivación , Medición de Riesgo , Factores de Riesgo , Fumar/efectos adversos , Fumar/psicología , Cese del Hábito de Fumar/psicología , Factores de TiempoRESUMEN
Little information on the relationship between blood rheology and atherosclerosis indicators in obese patients is available. We examined blood rheology as assessed by the blood passage time (BPT) with the microchannel method in 109 obese patients. BPT was correlated well with the extent of each metabolic syndrome component. A multivariate regression analysis revealed that the independent contributors to BPT were pulse-wave velocity, an index of arterial stiffness, body mass index and red blood cell. Furthermore, weight reduction intervention significantly decreased BPT. Assessment of rheology may be associated with pulse-wave velocity, and useful to manage obese patients.
Asunto(s)
Velocidad del Flujo Sanguíneo , Hemorreología/fisiología , Obesidad/fisiopatología , Resistencia Vascular , Enfermedades Cardiovasculares/etiología , Femenino , Humanos , Masculino , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Flujo Pulsátil/fisiología , Factores de RiesgoRESUMEN
HOM/C homeobox (Hox) and forkhead box (Fox) factors are reported to be expressed in the foregut endoderm and are subsequently detected in a spatio-temporal pattern during lung development. Some of these factors were reported to influence the expression of lung marker proteins or to modulate lung development. To clarify the molecular mechanisms for generating functional lung cells from progenitor cell populations, we introduced the forkhead box factors, FoxA1 and FoxA2, and the homeobox factor, HoxB3, into the differentiation process in a multipotent hamster lung epithelial M3E3/C3 cell line. Ectopic expression of FoxA2 promoted differentiation to Clara-like cells with up-regulation of the expression of the lung marker proteins, Clara cell-specific 10-kDa protein and surfactant protein-B. In contrast, FoxA1 repressed the differentiation. HoxB3 transfection induced FoxA2 expression transiently at the pre-differentiation stage. The endogenous HoxB3 expression level decreased at later stages of Clara-like cell differentiation, and the attenuation was enhanced by FoxA2 transfection. HoxB3 is a putative upstream regulator that enhances FoxA2 expression at the pre-differentiation stage. In addition, we found that the expression of HoxA4, HoxA5, and HoxC9 increased differentially during Clara-like cell differentiation. These results suggest that HoxB3 may be a putative positive regulator of FoxA2 expression at the pre-differentiation stage, and those interactions of Fox factors and Hox factors could participate in Clara cell differentiation.