RESUMEN
In the present study it was shown that resveratrol (3,4,5-trihydroxystilbene), an efficient light-absorbing molecule, during its transition from trans to cis configuration under UV light, transfers its energy of excitation to triplet oxygen to produce singlet oxygen ((1)O(2)). This transition is prevented by Trolox, a quencher of singlet oxygen. In the presence of a stable amount of nitrosoglutathione, UV-irradiated resveratrol reacts with nitric oxide (NO) originating from the nitrosoglutathione to produce peroxynitrite (ONOO(-)). Beta-carotene, acting as a quencher of (1)O(2), prevents the transition of resveratrol from trans to cis. Beta-carotene also prevents DNA damage induced by the (1)O(2). NO synthase (NOS) activity in synaptosomes isolated from rabbit brain increased approximately three-fold by resveratrol and the NO released was converted to ONOO(-). Resveratrol increased the lipid fluidity of synaptosomal plasma membranes. These changes suggest that the incorporation of resveratrol into synaptosomal plasma membranes causes an up-regulation of NO synthase. On the other hand, the simultaneous ONOO(-) and (1)O(2) formation may cause disturbances in transmembrane signal transduction leading to neurotoxicity. The present study concerning the behavior of resveratrol with respect to its structure and potential prooxidant-antioxidant function provides important new clues as to the role of this fascinating molecule in pathophysiology.
Asunto(s)
Antioxidantes/farmacología , Óxido Nítrico Sintasa de Tipo I/biosíntesis , Oxígeno Singlete/metabolismo , Estilbenos/farmacología , Sinaptosomas/efectos de los fármacos , Animales , Antioxidantes/análisis , Antioxidantes/efectos de la radiación , Cromatografía Líquida de Alta Presión , Daño del ADN/efectos de los fármacos , Membranas Intracelulares/efectos de los fármacos , Membranas Intracelulares/metabolismo , Luminiscencia , Fluidez de la Membrana/efectos de los fármacos , Nitratos/metabolismo , Estrés Oxidativo , Conejos , Resveratrol , S-Nitrosoglutatión/metabolismo , Estilbenos/análisis , Estilbenos/efectos de la radiación , Sinaptosomas/enzimología , Regulación hacia Arriba , beta Caroteno/farmacologíaRESUMEN
AIM: To investigate the risk of pelvic lymph node metastasis in patients with a preoperative diagnosis of early endometrial cancer with favorable histological characteristics, assessed by complete pelvic lymphadenectomy. PATIENTS AND METHODS: A total of 108 patients with clinical early endometrioid grade I or II endometrial carcinoma underwent complete pelvic lymphadenectomy between 2001-2007. Only cases with at least 15 nodes histologically examined were included. All operations were performed by the same team. The preoperative tumor histology was compared with the final pathological findings. The incidence of pelvic nodal involvement was estimated in relation to the final grade and depth of myometrial invasion in halves. RESULTS: The median age of patients was 63 years. In the final histology, 10 tumors (9.3%) of non-endometrioid histology were found. The discordance between pre- and postoperative tumor grade was 32.4%, with 24.1% being upgraded. Nine patients (8.3%) had poorly differentiated tumors and 23 (21.3%) deep (>50%) myometrial invasion in the final pathology. A total of 11 patients (10.2%) had pelvic nodal metastasis. The rate of lymph node metastasis in relation to final grade I and II and myometrial invasion was as follows: grade I, 1.8% (inner half 0%, outer half 14.3%); grade II, 15.9% (inner half 12.1% outer half 27.3%). Overall 19.4% of patients were upstaged at surgery. CONCLUSION: A significant proportion of patients presenting with early endometrial cancer of optimal characteristics will have a more advanced disease at surgical staging. Complete pelvic lymphadenectomy may increase the possibility of detecting metastatic disease in the lymph nodes.
Asunto(s)
Neoplasias Endometriales/cirugía , Escisión del Ganglio Linfático/métodos , Metástasis Linfática/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Endometriales/patología , Femenino , Humanos , Persona de Mediana EdadRESUMEN
Ultraviolet C (UVC)-irradiated microvessels isolated from rat skin release free nitrogen radicals, i.e. nitric oxide (NO), peroxynitrite (ONOO-) and nitrosocompounds formed from L-arginine. During UVC radiation of microvessels, heme (Fe3+) is released from hemoglobin and reacts with NO to form nitrosyl-heme (Fe2+-NO). The hydroxyl radical (OH*) produced is attached to heme-iron (Fe3+) to form hematin. ONOO- then binds to Fe(OH) and the complex Fe[(OH)ONOO-]2- is formed. Thus, in cases of increased oxidative stress, the free heme can act as an endogenous scavenger of OH* and ONOO-. Furthermore, Fe-NO and Fe[(OH)ONOO-]2- can act as NO donor and as antioxidant in redox cyclic iron-centered heme reactions, respectively. The scavenging-antioxidant properties of heme complexes, which allow it to protect the cells from the cytotoxic effects of the oxygen and/or nitrogen free radicals, were verified by estimating the changes in membrane fluidity of microvessels after UVC radiation. The present study indicates that UVC radiation of the skin acts as a potent stimulator for the formation of Fe-NO and Fe[(OH)ONOO-]2- in microvasculature with cytoprotective effects.
Asunto(s)
Hemo/química , Hierro/química , Óxido Nítrico/farmacología , Ácido Peroxinitroso/farmacología , Piel/metabolismo , Piel/efectos de la radiación , Animales , Antioxidantes/metabolismo , Arginina/metabolismo , Hemo/análogos & derivados , Hemina/química , Microcirculación , Óxido Nítrico/química , Oxidación-Reducción , Estrés Oxidativo , Ácido Peroxinitroso/química , Ratas , Rayos UltravioletaRESUMEN
BACKGROUND: We determined the alterations of nitric oxide (NO) and oxygen free radicals during orthotopic liver transplantation (OLT) in healthy pigs and investigated their relationship to pulmonary hemodynamics. MATERIALS AND METHODS: Fourteen pigs served as donors and recipients for 7 OLT, under general anesthesia. Hemodynamic monitoring included: systemic and mean pulmonary arterial pressure, pulmonary capillary wedge pressure, cardiac output, cardiac index, pulmonary (PVR) and systemic vascular resistance. Serum NO concentration and serum total antioxidant capacity (TAC), which indirectly quantifies the oxygen free radicals in the serum were determined by spectroscopic method of luminol-dependent chemiluminescence, before laparotomy, before reperfusion, 30 and 60 min postreperfusion. RESULTS: PVR increased significantly during the anhepatic phase and remained at high levels at 30 and 60 min postreperfusion (P = 0.046). NO concentration decreased significantly until 60 min postreperfusion (P = 0.009). TAC decreased throughout the whole period of our measurements (P = 0.002). A significant positive correlation was found between NO concentration, TAC, and PVR (P = 0.026 and P < 0.01, respectively, Spearman correlation). CONCLUSIONS: Our study showed a significant correlation between increased PVR, reduced NO concentration, and increased serum oxygen free radicals levels in the early reperfusion period in healthy pigs undergoing OLT.
Asunto(s)
Trasplante de Hígado , Óxido Nítrico/sangre , Circulación Pulmonar , Especies Reactivas de Oxígeno/sangre , Porcinos/cirugía , Animales , HemodinámicaRESUMEN
Lipoplatin, a new liposomal cisplatin formulation, is formed from cisplatin and liposomes composed of dipalmitoyl phosphatidyl glycerol (DPPG), soy phosphatidyl choline (SPC-3), cholesterol and methoxy-polyethylene glycol-distearoyl phosphatidylethanolamine (mPEG2000-DSPE). Following intravenous infusion, the nanoparticles (110 nm) are distributed into tissues and concentrate preferentially at tumor sites supposedly via extravasation through the leaky tumor vasculature. This study was designed to investigate the pharmacokinetics and the toxicity of this new liposomal cisplatin in patients with pretreated advanced malignant tumors. The drug was infused for 8 h every 14 days at escalating doses. Twenty-seven patients were included and 3-5 patients were selected for each dosage level; levels started at 25 mg/m2 and were increased by 25 to 125 mg/m2. Three patients were also treated at higher dose levels, one each at 200, 250 and 300 mg/m2. Blood was taken at certain time intervals in order to estimate total platinum plasma levels. At level 5 (125 mg/m2), grades 1 and 2 GI tract and hematological toxicities were detected. No nephrotoxicity was observed. Seven additional patients were added at the 4th level (100 mg/m2) for further pharmacokinetic evaluation. Measurement of platinum levels in the plasma of patients as a function of time showed that a maximum platinum level is attained at 6-8 h. The half-life of Lipoplatin was 60-117 h depending on the dose. Urine excretion reached about 40% of the infused dose in 3 days. The data demonstrate that Lipoplatin up to a dose of 125 mg/m2 every 14 days has no nephrotoxicity and it lacks the serious side effects of cisplatin.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Escamosas/tratamiento farmacológico , Cisplatino/efectos adversos , Cisplatino/farmacocinética , Neoplasias Renales/tratamiento farmacológico , Liposomas/química , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Área Bajo la Curva , Colesterol/química , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Cinética , Lípidos/química , Masculino , Persona de Mediana Edad , Nanotecnología , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Fosfatidilgliceroles/química , Polietilenglicoles/química , Factores de TiempoRESUMEN
PURPOSE: Aging is associated with increased oxidative stress, whereas systematic exercise training has been shown to improve quality of life and functional performance of the aged. This study aimed to evaluate responses of selected markers of oxidative stress and antioxidant status in inactive older men during endurance training and detraining. METHODS: Nineteen older men (65-78 yr) were randomly assigned into either a control (C, N = 8) or an endurance-training (ET, N = 11, three training sessions per week, 16 wk, walking/jogging at 50-80% of HR(max)) group. Before, immediately posttraining, and after 4 months of detraining, subjects performed a progressive diagnostic treadmill test to exhaustion (GXT). Plasma samples, collected before and immediately post-GXT, were analyzed for malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) levels, total antioxidant capacity (TAC), and glutathione peroxidase activity (GPX). RESULTS: ET caused a 40% increase in running time and a 20% increase in maximal oxygen consumption (VO(2max)) (P < 0.05). ET lowered MDA (9% at rest, P < 0.01; and 16% postexercise, P < 0.05) and 3-NT levels (20% postexercise, P < 0.05), whereas it increased TAC (6% at rest, P < 0.01; and 14% postexercise, P < 0.05) and GPX (12% postexercise, P < 0.05). However, detraining abolished these adaptations. CONCLUSIONS: ET may attenuate basal and exercise-induced lipid peroxidation and increase protection against oxidative stress by increasing TAC and GPX activity. However, training cessation may reverse these training-induced adaptations.
Asunto(s)
Envejecimiento/fisiología , Terapia por Ejercicio , Ejercicio Físico/fisiología , Estrés Oxidativo , Anciano , Antioxidantes/análisis , Prueba de Esfuerzo , Humanos , Peroxidación de Lípido , Masculino , Resistencia FísicaRESUMEN
Interferon-alpha2b (IFN-alpha2b) is being used intravesically for preventing recurrence and progression of superficial transitional cell carcinoma of the bladder. However, its mechanism of action when instilled intravesically is not yet elucidated. We monitored end products of nitric oxide (NO) in urine in 12 bladder cancer patients undergoing intravesical instillations of IFN-alpha2b. Urine end products of NO levels rose gradually after each instillation, reaching a peak value after the third instillation. Although the patients continued their treatment for 5 more weeks, no further alteration was observed. Inducible nitric oxide synthase (iNOS) expression was immunohistochemically evaluated in urinary bladder biopsy specimens before and after IFN-alpha2b instillations. It was shown that IFN-alpha2b induced urothelial iNOS expression, with subsequent oxidative stress. The peroxynitrite (ONOO-) formed from the combination of NO with superoxide (O2-) provides important clues in the role of ONOO- as a causative factor in the antineoplastic action of IFN-alpha2b.
Asunto(s)
Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/metabolismo , Interferón-alfa/administración & dosificación , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico/orina , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Vejiga Urinaria/metabolismo , Administración Intravesical , Antineoplásicos/administración & dosificación , Carcinoma de Células Transicionales/patología , Humanos , Inmunohistoquímica , Interferón alfa-2 , Óxido Nítrico Sintasa de Tipo II , Ácido Peroxinitroso/orina , Proteínas Recombinantes , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/enzimología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
This experimental animal study of 12-weeks' duration, involving Wistar rats, tested the possible chemoprotection of Doxorubicin (adriamycin), cardiomyopathy and other toxicities by Amifostine. One hundred and five animals were divided into 3 groups: Groups A, B and C, which had Doxorubicin, simultaneous Doxorubicin and Amifostine treatment and normal saline for control, respectively. Treatment was administered once weekly for 12 consecutive weeks. The doses of each drug were appropriately calculated on the basis of other experiments in the literature and given in analogous dosage to human kilograms of body weight. Euthanasias and autopsies of six animals at a time from each animal group were performed on weeks 3, 6, 8, 10 and 12. The blood, heart, lung, liver, aorta, thymus, spleen, kidneys, adrenals, testis and ovaries and muscle and lipoid tissue were examined macroscopically and microscopically. Biochemical liver and kidney examinations, full blood count and serum lipids were examined before and during the weeks of treatment and autopsies. Increased cholesterol and triglycerides from the 6th week towards the end of the experiment and a gradual increase in cardiomyopathy were found, particularly in Group A. The findings were similar in Group B, except for the timing (the increase of serum lipids and the serious cardiac lesions were delayed by two weeks). No abnormalities were detected in the controls, Group C. In conclusion, Amifostine does not seem to be cardioprotective when administered with Doxorubicin, since it only delays the onset of cardiac lesions. In in vitro testing, Amifostine was found to be a scavenger of the oxygen-free radicals which are produced by Doxorubicin.
Asunto(s)
Amifostina/farmacología , Antibióticos Antineoplásicos/toxicidad , Cardiomiopatías/prevención & control , Doxorrubicina/toxicidad , Animales , Cardiomiopatías/inducido químicamente , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Colesterol/sangre , Interacciones Farmacológicas , Femenino , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Triglicéridos/sangreRESUMEN
This experimental study compares the toxic effect of the two cytotoxic drugs, doxorubicin and mitoxantrone, on cardiac muscle and on serum lipids. The cardiotoxicity of doxorubicin due to the cumulative effect of repeated administration is known. A relative compound, mitoxantrone, is a member of the androstenedione class of synthetic antitumor agents and its chemical structure, based on a quinone ring, is similar to that of doxorubicin. Doxorubicin has wide application in cancer medicine but its dose-limited cardiac effect creates the need for a substitute compound. Mitoxantrone, also an effective agent, may be able to cover this need. Three groups of 35 Wistar rats were used during this experimental study of 12 weeks' duration. Drugs at a certain calculated dose were administered once weekly. Group A animals were treated with doxorubicin, Group B with mitoxantrone and Group C, the controls, with normal saline. Six animals per group were autopsied after euthanasia in the 3rd, 6th, 8th, 10th and 12th weeks. Cardiac muscle, liver and other organs, plus blood, were removed for macro- and microscopical, and biochemical tests. Our results showed that there was a cumulative toxic effect of doxorubicin (adriamycin) on cardiac muscle starting in the 6th week which gradually increased to Grade III lesions by the 10th and 12th weeks. In parallel, an increase in serum lipids, mainly cholesterol and triglycerides was observed. Mitoxantrone-treated animals showed moderate cardiotoxic lesions (but not cumulative) and no increase in serum lipids. In vitro testing of oxygen-free radical production showed high production by doxorubicin and very low production by mitoxantrone. Thus, mitoxantrone appears to be safer than doxorubicin.
Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Antineoplásicos/toxicidad , Doxorrubicina/toxicidad , Corazón/efectos de los fármacos , Lípidos/sangre , Mitoxantrona/toxicidad , Animales , Femenino , Masculino , Miocardio/metabolismo , Miocardio/patología , Estrés Oxidativo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Se infectaron células linfoblastoides humanas (HSB2) con el virus herpes humano-6 y se determinaron los efectos citopáticos por la infección viral en razón de los cambios de la permeabilidad de la membrana celular, la explosión oxidativa y la apoptosis. La bicapa lipídica de la membrana celular tanto de las células infectadas como de las no infectadas, se marcó con ácido 5-doxil-esteático y fue sometida a resonancia electrónica acelerada (REA) para medir la fluidez de los lípidos de membrana. Se determinó la producción intracelular de especies reactivas al oxígeno mediante quemiluminiscencia en presencia de luminol. Las células que sufrieron apoptosis se identificaron mediante la técnica de marcaje terminal in situ (ISEL). Los resultados confirman, en parte, datos previos como rigidez de membrana celular coincidente con producción de radicales de oxígeno y muerte celular programada (apoptosis), secundaria a la infección con el virus herpes. Los posibles mecanismos patogénicos se señalan en la discusión