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Altered production of reactive oxygen species (ROS), causing lipid peroxidation and DNA damage, contributes to the progression of atherosclerosis and cancer. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a lectin-like receptor for oxidized low-density lipoproteins (ox-LDL) primarily expressed in endothelial cells and vasculature-rich organs. LOX-1 receptors is a marker for atherosclerosis, and once activated by ox-LDL or other ligands, stimulates the expression of adhesion molecules, pro-inflammatory signaling pathways and proangiogenic proteins, including NF-kB and VEGF, in vascular endothelial cells and macrophages. Several different types of cancer reported LOX-1 gene upregulation, and numerous interplays exist concerning LOX-1 in atherosclerosis, metabolic diseases and cancer. One of them involves NF-kB, an oncogenic protein that regulates the transcription of several inflammatory genes response. In a model of cellular transformation, the MCF10A ER-Src, inhibition of LOX-1 gene reduces NF-kB activation and the inflammatory and hypoxia pathways, suggesting a mechanistic connection between cellular transformation and atherosclerosis. The remodeling proteins MMP-2 and MMP-9 have been found increased in angiogenesis in atherosclerotic plaque and also in human prostate cancer cells. In this review, we outlined the role of LOX-1 in atherogenesis and tumorigenesis as a potential link in these diseases, suggesting that LOX-1 inhibition could represent a promising strategy in the treatment of atherosclerosis and tumors.

Thyroid hormones (TH) play an important role in heart vascular system, and both hyperthyroidism and hypothyroidism are associated with altered cardiovascular system. Moreover, several evidences suggest that heart diseases trigger a reduction in cardiac tissue thyroid hormone levels.

Studies from human and animal models with metabolic disease and hypertension highlight atrophic remodeling, reduced lumen size and thinner vascular walls of microvessels with profound density reduction. This impaired vascular response limits the perfusion of peripheral tissues inducing organ damage. These conditions are strongly associated with oxidative stress and in particular with the up-regulation of lectin-like oxidized low density lipoprotein receptor-1 (LOX-1). Several factors such as cytokines, shear stress, and advanced glycation end-products, especially oxLDL, can up-regulate LOX-1. The activation of this receptor induces the production of adhesion molecules, cytokines and the release of reactive oxygen species via NADPH oxidase. LOX-1 is considered a potent mediator of endothelial dysfunction and it is significantly associated with reduced microvascular endothelium NO-dependent vasodilation in hypercholesterolemia and hypertension. Microvascular endothelial cells increased the expression of IL-6 in association with the increased concentration of LDL and its degree of oxidation. Moreover, increased IL-6 levels are associated with up-regulation of LOX-1 in a dose-dependent manner. Another consequence of microvascular inflammation is the generation of small amounts of ROS, similar to those induced by low concentration of oxLDL (

This study dealt with the effect of sourdough fermentation on antinutrients, phytochemicals, and antioxidant activities of flours from three Phaseoulus vulgaris L. genotypes with differing composition of lectins. Specifically, cultivar Lady Joy (LJ) devoid of phytohemagglutinin (PHA) and enriched in alfa-amylase inhibitor (αAI), breeding line P500 low in PHA and devoid of αAI, and Taylor's horticultivar, containing normal levels of both proteins. Sourdough fermentation positively affects the nutritional values of all bean flours by reducing some antinutrients, for example, phytic acid while preserving αAI activity. It significantly increased total polyphenols, flavonols, and ascorbic acid content, while reducing flavonoids. No significant differences in antioxidant activity, measured by in vitro and ex vivo assays on human erythrocytes, were found. The kinetic profiles of conjugated dienes analysis showed a strong inhibitory effect on low-density lipoproteins oxidation of all tested powders, with unfermented flours displaying the best antioxidant activity. Among bean powders, unfermented and fermented LJ showed the highest polyphenols level (4.21 ± 0.18 and 4.96 ± 0.15 mg GAE/g dw, respectively), oxygen radical absorbance capacity (ORAC) values (24.17 ± 0.14 and 24.02 ± 0.93 µmol TE/100g dw, respectively) and cellular antioxidant activity (71.6 ± 7.05 and 62.7 ± 3.3 units, respectively). Finally, since fermentation drastically reduces phytic acid content while preserving αAI activity, fermented LJ represents an important natural slimming supplement.

In the study of new drug molecules for the treatment of cancer, nitric oxide has received much attention for its tumoricidal role. In addition to its direct cytotoxic effect, NO may enhance the efficiency of classical chemotherapeutic drugs, resulting in a promising strategy against tumorigenesis and tumor progression. However, the clinical therapeutic potential of NO is limited by the short half-life, the concentration, and the biological microenvironment with which it interacts. Particular attention should be paid to the concentrations, as according to some authors, low NO levels could promote the growth of cancer cells. The development of a nanoparticle-based delivery system is aimed to the selective release of NO and drugs at the target tumor site, increasing their stability and biodistribution and preserving their therapeutic dosage. This review summarizes the current knowledge of NO-based anticancer treatments and their association with chemotherapy, focusing on the benefit of using nanotechnology.

The aim of this study was to determine to what extent thromboxane A2 (TP) receptor mediates the effect of oxidated low-density lipoprotein (LDL) on nitric oxide (NO), interleukin (IL)- 6, and endothelin-1 (ET-1) release by microvascular endothelial cells.Endothelial nitric oxide synthase (eNOS), nitrites and nitrates (NO2/NO3), ET-1, and IL-6 production were measured following human microvascular endothelial cell 1 exposure to isoprostane-8-epi-PGF2alpha (F2IP), a natural agonist of the TP receptor present in oxidized LDL, or native, low-, or medium-oxidized LDL either with the TP-receptor blocker, SQ29.548, or its vehicle.F2IP and both native and oxidized LDL enhanced NO2/NO3. F2IP through the TP receptor stimulated eNOS (eight-fold), while the oxidized LDL effect (two- to five-fold) was only partially prevented by SQ29.548. While LDL concentration and degree of oxidation synergistically and independent of SQ29.548 stimulated IL-6, F2IP had no effect. F2IP induced a modest (+50%) increase in ET-1. LDL, independent of concentration or degree of oxidation, stimulated (+120%) ET-1 production, and this effect was only partially attenuated by SQ29.548.In microvascular endothelial cells, LDL concentration and degree of oxidation synergistically stimulate NO and IL-6 production, but only NO release is largely mediated by the TP receptor. LDL facilitates ET-1 release independent of concentration and degree of oxidation; TP-receptor stimulation is only partially responsible for this effect.

Background and aim The effect of low-density lipoproteins (LDLs) on endothelial nitric oxide synthase (eNOS) is debated. By coupling in viva and in vitro experiments we evaluated the role of oxidized lipid substrates in the modulation of eNOS activity by LDLs. Materials and methods Plasma lipids, nitrite/nitrates (NO 2 /NO 3 ), and malondialdehyde (MDA) were measured in 14 controls, and in 13 patients with familial hypercholesterolemia (FH) before and after 12 weeks of treatment with atorvastatin (20 mg u.i.d.). Nitric oxide synthase in cell lysate and NO 2 /NO 3 into the medium were measured in human microvascular (HMEC-1) and umbilical vein (HUVEC) endothelial cells after 24 h of incubation with increasing concentrations of mildly oxidized LDLs with and without atorvastatin and in HMEC-1 with and without vitamin C. In HMEC-1, NO 2 /NO 3 was also determined after exposure to more intensively oxidized LDLs. Results At baseline, plasma NO 2 /NO 3 (56 ± 7 vs. 35 ± 3 μM) and MDA (5.6 ± 0.7 vs. 2.9 ± 0.3 μM), were significantly (P < 0.02 for both) higher in the FH patients. In the whole study group, NO 2 /NO 3 was more strongly correlated with plasma MDA (Rho = 0.70) than LDL-cholesterol (Rho = 0.57). In the FH patients, atorvastatin induced a significant decline in plasma total and LDL-cholesterol (-3.1 ± 0.5 and -2.9 ± 0.5 mM, respectively), NO 2 / NO 3 (-35 ± 8 μM) and MDA (-3.4 ± 0.7 μM) (P < 0.001 for all). Changes in plasma NO 2 / NO 3 were related to the concomitant changes in plasma MDA (Rho = 0.79, P < 0.006) and not to changes in LDL-cholesterol. In HMEC-1 and in HUVEC, mildly oxidized LDLs stimulated both e-NOS and NO 2 /NO 3 accumulation; the effect on e-NOS was potentiated by vitamin C in HMEC-1. Atorvastatin had no effect in HMEC-1 while it stimulated eNOS but not NO 2 /NO 3 in HUVEC. The accumulation of NO 2 /NO 3 in HMEC exposed to increasing concentrations of more intensively oxidized-LDLs showed a nonlinear dose-response curve. Conclusions In uncomplicated patients with FH, plasma NO 2 /NO 3 concentrations are elevated; the cross-sectional data, intervention study and in vitro experiments indicate that oxidized lipids exert a tonic stimulatory action on e-NOS and NO 2 /NO 3 generation not mediated through superoxide anion formation. Atorvastatin amplify this eNOS response in HUVEC, but not in HMEC, and this effect is not associated with a parallel increased NO 2 / NO 3 generation.

Nitric oxide (NO) and cyclooxygenase (COX) derived prostaglandins (PGs) are involved in vascular homeostasis. Contradictory results have been obtained in previous studies on the putative ‘cross-talk’ between these two pathways. Our aim was to evaluate the interaction between NO and PG release in human microvascular endothelial cells (HMEC-1) and in umbilical vein endothelial cells (HUVEC). Methods: Medium samples were assayed for nitrite/nitrate (NOx) and L-citrulline levels while lysed cells were assayed for endothelial NO synthase (eNOS), as markers of NO production. Prostaglandin E2 (PGE2) and 6-keto-prostaglandin F1α (6-keto-PGF1α) were assessed as indicators of COX activity. Results: The NO donor sodium nitroprusside and L-arginine increased PGs levels in both cell types. NG-monomethyl-L-arginine (L-NMMA) significantly inhibited 6-keto-PGF1α release without significantly reducing PGE2 levels. Indomethacin increased both NOx, eNOS and L-citrulline levels. PGE2 treatment did not modify NOx values. Conclusion: The stimulation of PGs by NO may represent an additional pathway used by exogenous nitrovasodilators to elicit vasodilation. Reduction of PGs by inhibition of COX was compensated by enhanced NO. Conversely, PGsdid not compensatedecreased NO following L-NMMA treatment. Treatment with the vasodilatator prostaglandin E2 did not modifyNOx levels.

Direct measurement of oxidative stress in biological fluids requires complex laboratory instruments and extraction procedures. Aim of the study was to analyse a new colorimetric assay and to evaluate its utility in the clinical setting. Forty-four unselected outpatients were studied. Stress oxidative levels were analysed with a colorimetric determination of oxygen free radicals, the dROMs test while serum total antioxidant capability was determined by OXY-adsorbent assay. In nine patients, ELISA 8-iso-PGF 2α plasma level determinations were obtained. The lower limit of sensitivity of dROMs test resulted 4.96 mg % H 2 O 2 . The assay was found to be linear over the range of oxidative stress levels 0–500 mg % H 2 O 2 , with correlation coefficients greater than 0.99. According to dROMs, the exposition to oxygen radical in the studied population was of moderate entity. Variation on replicate samples within or between days were lower than 5.5% and free radical levels were directly correlated with serum glucose concentration. A high significant inverse correlation between oxidative stress and total serum antioxidant levels was observed. 8-iso-PGF 2α plasma levels were positively correlated with serum free radical levels and inversely with serum concentration of antioxidant. The present data indicate that the analysis of serum free radicals with d-ROMs test is a rapid, no expensive method with good sensitivity and reproducibility.

Previous studies evidenced a significant reduction in serum cholesterol levels during an episode of acute inflammation. The aim of the present study was to verify the hypothesis of a regulatory role of cytokines through an in vitro model that simulates a situation of vascular inflammation and high levels of LDL or lipoperoxides.Human microvascular endothelial cells-1 were used in all experiments. The cells were exposed for 24 h to increasing doses of LDL, oxidized lipoprotein, and 8-isoprostane (in the absence or presence of SQ29.548, a TXA2 receptor antagonist). Moreover, LDL receptor and oxidized lipoprotein receptor expression analyzed after endothelial cells’ incubation with increasing doses of interleukin-6. The ELISA test and quantitative real-time PCR were performed. Endothelial cells showed a significant increase in interleukin-6 medium levels associated with LDL, oxidized LDL and with the degree of oxidation (absence or presence of SQ29.548), while 8-isoprostane did not. Treatment of human microvascular endothelial cells-1 for 24 h with increasing doses of interleukin-6 significantly enhanced LDL receptor and oxidized lipoprotein receptor-1 mRNA expression.Our data suggest the presence of a compensatory mechanism. The induction of a significant increase of IL-6 does not seem to be caused by the presence of the biological activity of 8-isoprostane.

Lectin-like oxidized low-density lipoprotein (LOX-1) has been identified in endothelial cells as the main receptor of oxidized low-density lipoprotein (OxLDL). LOX-1 is upregulated in the presence of pathological conditions including atherosclerosis, hypertension, and diabetes because it acts as a mediator of "endothelial dysfunction". It promotes the generation of superoxide anion (O2(-)), the inhibition of nitric oxide (NO) production and the increment of endothelial adhesiveness to monocytes. Recently, it was reported that OxLDL, binding to LOX-1, determined a significant increase in the generation of reactive oxygen species (ROS), suggesting the involvement of signaling pathways such as mitogen-activated protein kinases (MAPKs). It is now generally accepted that ROS act indirectly on the modulation of LOX-1 expression because ROS oxidize native LDL. Moreover, LOX-1 activation per se may stimulate ROS generation. Accordingly, our findings showed that high levels of ROS can directly increase LOX-1 production in microvascular endothelial cells (HMEC-1). It has been reported that OxLDL, usually > 20 μg protein/ml, induced apoptosis in a variety of cell types. At low concentrations (< 5 μg protein/ml) OxLDL appears to be associated with cell proliferation and low levels of ROS-induced capillary tube formation in endothelial cells. Our data and those of the literature indicate the existence of a direct control of LOX-1 by ROS. Although ROS in large amounts clearly have detrimental effects on cell biology, small amounts of ROS could have a beneficial effect, suggesting its therapeutic potential for reducing ischemic tissue.

Nitrates act as donors of nitric oxide (NO), a molecule with a recognized potential for genotoxicity. In order to assess whether chronic long-term nitrate therapy may increase genotoxicity, we evaluated chromosomal damage in peripheral lymphocytes of 27 ischaemic patients undergoing chronic nitrate treatment for vertical line4 years (7.9 +/- 3.1, mean +/- SD) and 18 age- and sex-matched subjects without any previous nitrate treatment. At the same time, after treatment in vitro with 0-20 microM sodium nitroprusside as NO donor, micronucleus induction and cell proliferation were also evaluated using blood from six different healthy donors. The results showed that the frequency of structural chromosomal aberrations was not significantly higher in the drug-treated group than the control [2.1 +/- 1.4 versus 1.6 +/- 1.2 (mean +/- SD); P = 0.23]. The frequency of micronucleated lymphocytes was higher in the nitrate group than in the control group (6.5 +/- 4.6 versus 3.5 +/- 2.9, P=0.01). In vitro treatment indicated a dose-dependent increase in the frequency of micronucleated lymphocytes with increasing SNP concentrations. Cytotoxicity and cell cycle delay, with a statistically significant difference with respect to control culture, were also observed. Our results suggest a possible genotoxic activity of nitrate therapy. Further studies focusing on the possible link between nitrate therapy and genotoxicity are warranted at this point.

Angiogenesis, the process involving the growth of new blood vessels from pre-existing vessels, may be a target for combating diseases characterized by either poor vascularisation or abnormal vasculature as in cardiovascular diseases. Thyroid hormones (THs) are strong proangiogenic factors whose action starts at the plasma membrane integrin αvβ3 protein transducing rapid nongenomic signals on tumor thyroid cells. The tetraiodothyroacetic acid (Tetrac) inhibits the binding of TH to integrin receptor αVs3 blocking angiogenesis. Growing evidences suggest that, also in heart, Triiodothyronine (T3) and Thyroxine (T4) triggered nongenomic pathways through their binding to integrin receptor αVβ3 inducing capillary proliferation. The angiogenic activity of T3 and T4 has been studied by the chick choriallontoic endothelial cell microtubule assay and the human dermal microvascular endothelial cells microtubule assay. The aim of this work was to evaluate the direct stimulative activity of T3 and T4 on human cardiac microvascular endothelial cell (HMVEC-C) proliferation, migration and tube formation, employing Tetrac as inhibitor. Our in vitro study indicates that T3 and T4 directly stimulate angiogenesis in HMVEC-C observed as capillary density, cell proliferation and cell migration. In all models, Tetrac (5 μM) inhibited the proangiogenic effect of T3 and T4 suggesting its integrin-mediated action. Sq RT-PCR assay revealed that T3, and in less extent T4, increased the expression of angiogenic genes such as angiopoietin-1 (Angpt-1), angio-associated migratory cell protein (AAMP) and vascular endothelial growth factor (VEGF), whereas when the cells were pre-incubated with Tetrac this effect was abolished. In conclusion, our results show that THs stimulate angiogenesis, suggesting a potential therapeutic role aimed at increasing capillary density in cardiac diseases.

The protective effect of a powder of grain (Lisosan G) against cisplatin-induced toxicity in rats was studied. Male rats were fed with Lisosan G before injection of cisplatin and four days later they were killed and blood was collected along with hepatic, renal and testicular tissues. The results showed that cisplatin treatment increased plasma blood urea nitrogen, creatinine and hydrogen peroxide and decreased cytochrome P450 content in renal and hepatic tissues. It also reduced the plasmatic testosterone level and caused a depletion of testicular 17α-progesterone hydroxylase activity. In the group fed with Lisosan G and treated with cisplatin blood urea nitrogen and creatinine returned to the control level indicating a protective effect of Lisosan G. It was also observed that the ones fed with Lisosan G were able to attenuate the decrease in the P450-dependent activities and the activities of antioxidant enzymes as well. Lisosan G protected the testicular 17α-progesterone hydroxylase activity and increased the plasma testosterone level compared to animals treated only with cisplatin. Our results showed a protective effect of Lisosan G against the cisplatin induced toxicity. The protective effect of Lisosan G could be associated mainly with the attenuation of the oxidative stress and the preservation in antioxidant enzymes.

Among flavonoids, chalcones have been identified as interesting compounds having antioxidant, antimutagenic and antitumour properties. In this study we have evaluated the clastogenicity of plicatin B on human lymphocytes (whole blood and isolated lymphocytes) and its anticlastogenic activity, in the same cellular systems, using mitomycin C (MMC), radio-mimetic bleomycin (BL) and hydrogen peroxide (H 2 O 2 ) as reference clastogens. Plicatin B per se resulted cytotoxic at high dose but non-clastogenic. The clastogenic effects induced by MMC and BL were significantly reduced (−33%) whereas with H 2 O 2 the protective effect of plicatin B was observed (−62%) only at the greater H 2 O 2 dose. The anticlastogen effects of plicatin B were effective when the chalcone was introduced in the culture,1 h before the reference clastogens.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) can be associated with severe adverse digestive effects. In clinical settings, proton pump inhibitors have proven to be effective in preventing and healing NSAID-induced gastroduodenal lesions. The present study investigates the mechanisms of protection afforded by pantoprazole against gastric injury induced by different NSAIDs in rats. Animals were orally treated with indomethacin (100 micromol/kg), diclofenac (60 micromol/kg), piroxicam (150 micromol/kg) or ketoprofen (150 micromol/kg). Thirty minutes before NSAIDs, animals received pantoprazole 6 or 60 micromol/kg orally. Four hours after NSAIDs, the following parameters were assessed: histomorphometric evaluation of gastric mucosal damage; gastric mucosal levels of myeloperoxidase (MPO), malondialdehyde (MDA), reduced glutathione as an index of non-proteic sulfhydryl compounds (GSH), and prostaglandin E2 (PGE2); mucosal cyclooxygenase-1 and -2 (COX-1, COX-2) mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). Separate experiments were carried out to assay the effects of pantoprazole on gastric acid secretion in pylorus-ligated rats. The in vitro influence of pantoprazole (1-10 microM) on the oxidation of low density lipoproteins (LDLs) induced by copper sulphate was also examined. All NSAIDs elicited mucosal necrotic lesions associated with neutrophil infiltration and reduction of PGE2 levels. Increments of MPO and MDA contents, as well as a decrease in GSH levels, were detected in the gastric mucosa of indomethacin-, piroxicam- or ketoprofen-treated animals. Indomethacin enhanced mucosal COX-2 expression, while not affecting COX-1. At the oral dose of 6 micromol/kg pantoprazole did not affect NSAID-induced mucosal damage, whereas at 60 micromol/kg it markedly reduced injuries provoked by all test NSAIDs. Pantoprazole 60 micromol/kg also reversed the effects of NSAIDs on MPO, MDA, and GSH mucosal contents, without interfering with the decrease in PGE2 levels or indomethacin-induced COX-2 expression. However, at both doses, pantoprazole inhibited acid secretion in pylorus-ligated rats. Furthermore, pantoprazole concentration dependently reduced the in vitro oxidation of LDLs. Our results suggest that besides inhibiting acid secretion, the protection afforded by pantoprazole against NSAID-induced gastric damage depends on a reduction in mucosal oxidative injury, which may also account for an increment of sulfhydryl radical mucosal bioavailability. It is also suggested that pantoprazole does not influence the down-regulation of gastric prostaglandin production associated with NSAID treatment.

Sedentary aging is associated with oxidative stress and endothelial dysfunction. The aim of this study was to evaluate the relationship between long-term physical activity, plasma antioxidant status, and conduit artery endothelial function in young and older healthy men.In young (n = 16) and older athletes (n = 16) and in matched healthy sedentary subjects, endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent response to glyceryl trinitrate (GTN), 400 microg, were measured in the brachial artery from high-resolution ultrasonography. Plasma malondialdehyde (MDA) and antioxidant capacity as total oxyradical scavenging capacity (TOSC) were also evaluated.We found that FMD was lower (or =0.01) in sedentary older subjects (2.3% +/- 1.0%) as compared with older athletes (5.3% +/- 3.2%) and both sedentary (5.4% +/- 2.0%) and athletically trained (6.1% +/- 3.2%) young subjects. Sedentary older subjects showed higher (Por = .05) MDA levels and lower (P.0001) plasma antioxidant capacity as compared with the other subgroups, whereas in older athletes MDA levels and antioxidant capacity were similar to those observed in the young subgroups. In the whole group, FMD, but not GTN, was negatively related to age (r = -0.31, P.05) and directly related (Por = .01) to VO2max (r = 0.49) and TOSC against peroxyl (r = 0.69) and hydroxyl radicals (r = 0.53). In the multivariate analysis, TOSC against peroxyl radicals resulted as the most significant predictor of FMD (R2 = 0.60; P = .003).These results suggest that regular physical activity is associated with preserved antioxidant defenses and endothelial function in older individuals.

Previous studies suggested that interleukin-6 (IL-6) affects the reduction of serum lipoprotein LDL cholesterol levels during acute inflammation. We have investigated the association between cytokines and cholesterol levels in normal subjects and moderate hypercholesterolemic patients. Moreover, cultured human microvascular endothelial cells (HMEC-1) were treated with low density lipoproteins (LDL-C) to verify whether IL-6 expression is modulate during the treatment. Blood samples of all subjects were assayed for serum lipid, TNFα and IL-6 levels. HMEC-1 cells were treated for 24 h with increasing concentrations of LDL-C in presence and absence of the TXA2 receptor antagonist SQ29.548. Normal subjects and patients with moderate hypercholesterolemia showed significant difference in IL-6 serum levels ( P P P P

This study investigated the mechanisms involved in the protective actions exerted by lansoprazole against experimental gastric injury. Following the intraluminal injection of ethanol-HCl, the histomorphometric analysis of rat gastric sections demonstrated a pattern of mucosal lesions associated with a significant increase in the mucosal contents of malondialdehyde and 8-iso-prostaglandin F(2alpha) (indices of lipid peroxidation), as well as a decrease in the levels of mucosal sulfhydryl compounds, assayed as reduced glutathione (GSH). Pretreatment with lansoprazole 90 micromol/kg, given intraduodenally as single dose or once daily by intragastric route for 8 days, significantly prevented ethanol-HCl-induced gastric damage. The concomitant changes in the mucosal levels of malondialdehyde, 8-iso-prostaglandin F(2alpha) and GSH elicited by ethanol-HCl were also counteracted by lansoprazole. In separate experiments, performed on animals undergoing 2-h pylorus ligation, lansoprazole did not enhance the concentration of prostaglandin E(2), bicyclo-prostaglandin E(2), or nitric oxide (NO) metabolites into gastric juice. Western blot analysis revealed the expression of both type 1 and 2 cyclooxygenase (COX) isoforms in the gastric mucosa of pylorus-ligated rats. These expression patterns were not significantly modified by single-dose or repeated treatment with lansoprazole. Lansoprazole also exhibited direct antioxidant properties by reducing 8-iso-prostaglandin F(2alpha) generation in an in vitro system where human native low-density lipoproteins were subjected to oxidation upon exposure to CuSO(4). The present results suggest that the protective effects of lansoprazole can be ascribed to a reduction of gastric oxidative injury, resulting in an increased bioavailability of mucosal sulfhydryl compounds. It is also proposed that lansoprazole does not exert modulator effects on the gastric expression of COX isoforms as well as on the activity of NO pathways.

In the present study we assessed the effect of physical training on Laser Doppler skin flux (LDF) and nitric oxide (NO) release, before and after 3 min of brachial artery occlusion. To this end we performed laser Doppler measurements and the venous plasma assay of nitrite/nitrate (NOx) on 10 sedentary healthy subjects and 10 endurance athletes. The sedentary control subjects had lower basal and post reperfusion levels of NOx as compared to athletes (mean +/- SE: 27.8 +/- 3.5 vs. 33.2 +/- 3.4, 48.6 +/- 7.9 vs. 60.1 +/- 10.1 micromol/L; p < 0.05). LDF at baseline was not significantly different in the two groups (157.5 +/- 7.9 and 176.64 +/- 26.7 PU for sedentary subjects and athletes, respectively) while post ischemic LDF was significantly lower in nonathletic subjects than in athletes (209.9 +/- 13 and 343.8 +/- 21.3 PU, p < 0.001). In both groups the hyperaemic stimulus significantly increased LDF and NOx levels (p < 0.01 and p < 0.05, respectively). The flow reserve, estimated as peak/basal LDF, was significantly lower in control subjects than in athletes (1.34 +/- 0.2 and 2.32 +/- 0.9, respectively, p < 0.01). In athletes, as opposed to sedentary subjects, a direct correlation was found between plasma NOx concentration and LDF both in basal conditions (r = 0.92; p < 0.001), and during hyperaemia (r = 0.84; p < 0.01). In conclusion, compared to sedentary subjects, athletes had an enhanced nitric oxide release. Hyperaemia increased LDF and nitric oxide levels both in sedentary subjects and in athletes.

Sedentary aging is associated with endothelial dysfunction and nitric oxide (NO) impairment. The aim of the present study was to assess the effects of regular physical exercise on nitrite/nitrate (NOx) concentrations and microcirculatory function in older men compared with young individuals. We measured NOx plasma concentrations and baseline and stimulated skin blood flow (SBF) by laser Doppler flowmetry in 39 male athletes [range, 22–72 years; maximal oxygen consumption (VO2max), 60.0±4.7 ml·min-1·kg of body weight-1 (mean±S.D.)] and 45 age- and sex-matched sedentary controls (VO2max, 38.0±7.1 ml·min-1·kg of body weight-1). NOx concentrations were higher in athletes than in controls (50.4±16.3 compared with 39.0±15.4 µmol/l; P0.30, P

In biological systems there is a balance between the production and neutralization of reactive oxygen species (ROS). This balance is maintained by the presence of natural antioxidants and antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase. The enhancement of lipid peroxidation or the decrease of antioxidant protection present in metabolic diseases or bad lifestyle can induce endothelial dysfunction and atherosclerosis. Clinical studies have shown that oxidative stress can increase ROS reducing the formation of antioxidant defences, especially in subjects with coronary artery disease (CAD). Some observation indicated that in the early stages of the disease there is a homeostatic up-regulation of the antioxidant enzyme system in response to increased free radicals to prevent vascular damage. As soon as free radicals get to chronically elevated levels, this compensation ceases. Therefore, SOD and the other enzymes may represent a good therapeutic target against ROS, but they are not useful markers for the diagnosis of CAD. In conclusion antioxidant enzymes are reduced in presence of metabolic disease and CAD. However the existence of genes that promote their enzymatic activity could contribute to create new drugs for the treatment of damage caused by metabolic diseases or lifestyle that increases the plasma ROS levels.

The aim of this study was to evaluate the analytical performance and clinical usefulness of spectrophotometric assays for the measurement of the plasma levels of nitrite plus nitrate (NOx), and malondialdehyde (MDA), as an index of nitric oxide release and lipid peroxidation, respectively. We studied 30 healthy sedentary volunteers, 12 endurance athletes and 12 regular heavy smokers. The lower limit of quantification for plasma NOx concentration was 1 µmol/l, and linearity was observed from 1 to 40 µmol/l of NOx concentration. Variation in replicate samples within or between days was always below 5%. NOx levels were significantly higher in athletes compared to both control subjects and smokers (p

AIM: This study investigated the mechanisms of protection afforded by the proton pump inhibitor lansoprazole against gastric injury induced by different non-steroidal anti-inflammatory drugs (NSAIDs) in rats. METHODS: Male Sprague-Dawley rats were orally treated with indomethacin (100 µmol/kg), diclofenac (60 µmol/kg), piroxicam (150 µmol/kg) or ketoprofen (150 µmol/kg). Thirty minutes before NSAIDs, animals were orally treated with lansoprazole 18 or 90 µmol/kg. Four hours after the end of treatments, the following parameters were assessed: gastric mucosal PGE2, malondialdehyde (MDA), myeloperoxidase (MPO) or non-proteic sulfhydryl compounds (GSH) levels; reverse transcription-polymerase chain reaction (RT-PCR) of mucosal COX-2 mRNA; gastric acid secretion in pylorus-ligated animals; in vitro effects of lansoprazole (1-300 µmol/L) on the oxidation of low density lipoproteins (LDLs) induced by copper sulphate. RESULTS: All NSAIDs elicited mucosal necrotic lesions which were associated with neutrophil infiltration and reduction of PGE2 levels. Increments of MPO and MDA contents, as well as a decrease in GSH levels were detected in the gastric mucosa of indomethacin- or piroxicam-treated animals. Indomethacin enhanced mucosal cyclooxygenase-2 expression, while not affecting cyclooxygenase-1. At the oral dose of 18 µmol/kg lansoprazole partly counteracted diclofenac-induced mucosal damage, whereas at 90 µmol/kg it markedly prevented injuries evoked by all test NSAIDs. Lansoprazole at 90 µmol/kg reversed also the effects of NSAIDs on MPO, MDA and GSH mucosal contents, without interfering with the decrease in PGE2 levels or indomethacin-induced cyclooxygenase-2 expression. However, both lansoprazole doses markedly inhibited acid secretion in pylorus-ligated rats. Lansoprazole concentration-dependently reduced the oxidation of LDLs in vitro. CONCLUSION: These results suggest that, besides the inhibition of acid secretion, lansoprazole protection against NSAID-induced gastric damage depends on a reduction in mucosal oxidative injury, which is also responsible for an increment of sulfhydryl radical bioavailability. It is also suggested that lansoprazole does not influence the down-regulation of gastric prostaglandin production associated with NSAID treatment.