BACKGROUND/AIMS: Ozone is an environmentally reactive oxidant, and pycnogenol is a mixture of flavonoid compounds extracted from pine tree bark that have antioxidant activity. We investigated the effects of pycnogenol on reactive nitrogen species, antioxidant responses, and airway responsiveness in BALB/c mice exposed to ozone. METHODS: Antioxidant levels were determined using high performance liquid chromatography with electrochemical detection. Nitric oxide (NO) metabolites in bronchoalveolar lavage (BAL) fluid from BALB/c mice in filtered air and 2 ppm ozone with pycnogenol pretreatment before ozone exposure (n = 6) were quantified colorimetrically using the Griess reaction. RESULTS: Uric acid and ascorbic acid concentrations were significantly higher in BAL fluid following pretreatment with pycnogenol, whereas gamma-tocopherol concentrations were higher in the ozone exposed group but were similar in the ozone and pycnogenol pretreatment groups. Retinol and gamma-tocopherol concentrations tended to increase in the ozone exposure group but were similar in the ozone and pycnogenol pretreatment groups following ozone exposure. Malonylaldehyde concentrations increased in the ozone exposure group but were similar in the ozone and pycnogenol plus ozone groups. The nitrite and total NO metabolite concentrations in BAL fluid, which parallel the in vivo generation of NO in the airways, were significantly greater in the ozone exposed group than the group exposed to filtered air, but decreased with pycnogenol pretreatment. CONCLUSIONS: Pycnogenol may increase levels of antioxidant enzymes and decrease levels of nitrogen species, suggesting that antioxidants minimize the effects of acute ozone exposure via a protective mechanism.
Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/metabolism ; Bronchial Hyperreactivity/chemically induced/metabolism/*prevention & control ; Bronchoalveolar Lavage Fluid/chemistry ; Bronchoconstriction/drug effects ; Disease Models, Animal ; Female ; Flavonoids/*pharmacology ; Inhalation Exposure ; Lung/*drug effects/enzymology/physiopathology ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred BALB C ; Nitric Oxide/metabolism ; Oxidative Stress/*drug effects ; *Ozone ; Uric Acid/metabolism ; Vitamin A/metabolism ; alpha-Tocopherol/metabolism

Paclitaxel is one of the chemotheraputic drugs widely used for the treatment of nonsmall cell lung cancer (NSCLC) patients. Here, we tested the ability of alpha-tocopheryl succinate (TOS), another promising anticancer agent, to enhance the paclitaxel response in NSCLC cells. We found that sub-apoptotic doses of TOS greatly enhanced paclitaxel-induced growth suppression and apoptosis in the human H460 NSCLC cell lines. Our data revealed that this was accounted for primarily by an augmented cleavage of poly(ADP-ribose) polymerase (PARP) and enhanced activation of caspase-8. Pretreatment with z-VAD-FMK (a pan-caspase inhibitor) or z-IETD-FMK (a caspase-8 inhibitor) blocked TOS/paclitaxel cotreatment-induced PARP cleavage and apoptosis, suggesting that TOS potentiates the paclitaxel-induced apoptosis through enforced caspase 8 activation in H460 cells. Furthermore, the growth suppression effect of TOS/paclitaxel combination on human H460, A549 and H358 NSCLC cell lines were synergistic. Our observations indicate that combination of paclitaxel and TOS may offer a novel therapeutic strategy for improving paclitaxel drug efficacy in NSCLC patient therapy as well as for potentially lowering the toxic side effects of paclitaxel through reduced drug dosage.
Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism/pathology ; Caspase 8/metabolism ; Cell Growth Processes/drug effects ; Cell Line, Tumor ; Drug Synergism ; Drug Therapy, Combination ; Humans ; Neoplastic Stem Cells ; Paclitaxel/pharmacology ; alpha-Tocopherol/*pharmacology

OBJECTIVETo investigate the role of reactive oxygen species (ROS) and the effect of vitamin E on proliferation of vascular smooth muscle cells (VSMCs) induced by homocysteine.

METHODSDNA synthesis in the VSMCs cells was measured using [3H]-thymidine incorporation assay, and the cell number determined by trypan blue method. The level of ROS in the cells was determined using DCF-DA as the fluorescence probe.

RESULTSHomocysteine promoted VSMC DNA synthesis, proliferation, and ROS production. Cysteine resulted in increased ROS production in VSMCs, but had no significant effect on DNA synthesis and cell proliferation. Catalase significantly inhibited ROS production induced by homocysteine, but did not significantly inhibited homocysteine-mediated proliferation of VSMCs. While alpha-tocopherol and beta-tocopherol both suppressed increased ROS production induced by homocysteine in VSMCs, only alpha-tocopherol significantly inhibited homocysteine-mediated VSMC proliferation.

CONCLUSIONROS is not associated with VSMC proliferation, and vitamin E-induced suppression of VSMC proliferation is probably related to protein kinase C inhibition.

Animals ; Antioxidants ; pharmacology ; Cell Proliferation ; drug effects ; Cells, Cultured ; Homocysteine ; pharmacology ; Muscle, Smooth ; cytology ; drug effects ; metabolism ; Muscle, Smooth, Vascular ; cytology ; drug effects ; metabolism ; Rats ; Reactive Oxygen Species ; metabolism ; Vitamin E ; pharmacology ; alpha-Tocopherol ; pharmacology ; beta-Tocopherol ; pharmacology

Cadmium is known to exert toxic effects on multiple organs, including the testes. To determine if alpha-tocopherol, an antioxidant, could protect testicular tissues and spermatogenesis from the toxic effects of cadmium, six-week old male Sprague-Dawley rats were randomized to receive cadmium at doses of 0 (control), 1, 2, 4 or 8 mg/kg by the intraperitoneal route (Group A) or alpha-tocopherol for 5 days before being challenged with cadmium (Group B) in an identical dose-dependent manner. When both groups received cadmium at 1 mg/kg, there were no changes in testicular histology relative to controls. When Group A received cadmium at 2 mg/kg, undifferentiated spermatids and dead Sertoli cells increased in the seminiferous tubules while interstitial cells decreased and inflammatory cells increased in the interstitial tissues. On flow cytometric analysis, the numbers of elongated spermatids (M1) and round spermatids (M2) decreased while 2c stage cells (M3, diploid) increased. In contrast, when Group B received cadmium at 2 mg/kg, the histological insults were reduced and the distribution of the germ cell population remained comparable to controls. However, alpha-tocopherol had no protective effects with higher cadmium doses of 4 and 8 mg/kg. These findings indicate that alpha-tocopherol treatment can protect testicular tissue and preserve spermatogenesis from the detrimental effects of cadmium but its effectiveness is dependent on the dose of cadmium exposed.
alpha-Tocopherol/*pharmacology ; Testis/*drug effects/pathology ; Spermatogenesis/*drug effects ; Rats, Sprague-Dawley ; Rats ; Male ; Inflammation ; Flow Cytometry ; Dose-Response Relationship, Drug ; Cadmium Poisoning/*pathology ; Cadmium/metabolism/*pharmacology ; Antioxidants/pharmacology ; Animals