Location of superoxide anion in the human colonic mucosa.
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Colon↗
Biomedical subjects
F Cuccurullo
Publications and source records attributed to F Cuccurullo.
Ambroxol is a scavenger of hypochlorous acid and monochloramine.
Experimental studies have suggested that ambroxol, a drug clinically used to enhance pulmonary surfactant production, may also exert some anti-inflammatory effects, though specific mechanisms are not yet fully understood. Thus, potential scavenging properties of ambroxol towards the most toxic neutrophil-arising prooxidants hypochlorous acid and monochloramine were investigated. We have found that the drug at 25, 50 and 100 mumol/l exerted a significant, concentration-related antagonizing effect on both chlorine species, with a maximal specific activity detected against hypochlorous acid. These new pharmacological properties of ambroxol may play a role in vivo in disease entities characterized by white blood cell activation and uncontrolled oxidant generation, such as inflammatory/ischemic conditions.
Ambroxol↗
Antiproliferative effect of desferrioxamine on vascular smooth muscle cells in vitro and in vivo.
Vascular smooth muscle cell (VSMC) growth is a primary component of accelerated and spontaneous atherosclerosis. Previous studies have shown that iron may be involved in the control of enzymatic activities that modulate DNA synthesis in human cells. In this study the effects of the iron chelator desferrioxamine on in vitro and in vivo VSMC proliferation were tested. Rat VSMCs in culture and a rabbit model of carotid artery balloon injury were used. Desferrioxamine showed a significant inhibitory effect on [3H]thymidine incorporation in cell cultures that was antagonized by iron supplementation. Desferrioxamine also provided effective preventive myointimal VSMC proliferation as assessed by bromodeoxyuridine labeling and morphometric analysis of endoluminal stenosis. These experiments suggested that iron may be involved in the control of VSMC proliferation and that desferrioxamine may have a role in preventing VSMC growth and myointimal proliferative lesions.
Animals↗
Hypochlorous acid-induced zinc release from thiolate bonds: a potential protective mechanism towards biomolecules oxidant damage during inflammation.
It has been proposed that metalloprotein zinc mobilization mediated by hypochlorous acid (HOCl) may induce cell injury (see H. Fliss and M. Ménard (1991), Archives of Biochemistry and Biophysics, 287, 175-179). In the present paper, we have demonstrated using a dimercaptopropanol-zinc complex that, once released from thiolate bonds by HOCl, zinc can exert a significant antioxidant effect on both linolenic acid and deoxyribose oxidation induced by iron. In these experimental conditions, however, the antagonism towards deoxyribose oxidation is notably less than that towards linolenic acid peroxidation, thus suggesting a more specific inhibitory effect of zinc on iron-mediated oxidant damage when polyunsaturated fatty acids represent the oxidizable substrate. The antioxidant effects of zinc are strictly related to the "free" form; indeed, the dimercaptopropanol-zinc complex per se is stimulatory even on biomolecules oxidant damage, apparently as a result of the prooxidant prooxidant interaction of the thiol compound with iron. In light of these results, it may be proposed that the zinc released from thiolate bonds by HOCl could specifically limit tissue oxidative burden in pathological conditions involving neutrophil accumulation and activation, such as inflammation and ischemia-reperfusion.
Animals↗
Myocardial antioxidant defense mechanisms: time related changes after reperfusion of the ischemic rat heart.
It is well known that reperfusion damage of ischemic myocardium may be attributed to alterations in the antioxidant defense system against free radical aggression. In addition, the degree of myocardial damage may depend on the duration and severity of ischemia that precedes reperfusion. We carried out serial ischemic experiments (10, 30, 60 and 120 min) in ex-vivo rat hearts followed by 30 min reperfusion and we assayed the glutathione-dependent enzymatic activities (selenium-dependent glutathione-peroxidase: GSH-Px; selenium-independent glutathione peroxidase: GST-Px; glutathione-transferase: GST and glutathione-reductase: GS-SG-Red), Catalase activity (CAT) and non-proteic thiol compounds (NP-SH) at the end of reperfusion. We found a significant reduction of NP-SH, GSH-Px and CAT in ischemic/reperfused hearts from 30 min on, while GST activity was increased. In addition, we observed the appearance of a selenium-independent glutathione peroxidase activity (GST-Px) belonging to the GST system. In conclusion, we found the longer the duration of ischemia the greater the inbalance between the myocardial antioxidant system especially the GST activation, suggesting in particular for GST-Px, a role in the control of the damage against oxygen toxicity during ischemia/reperfusion.
Animals↗
Bacterial mucosal infiltration in Helicobacter pylori-associated gastritis: histological and clinical consequences.
OBJECTIVES: We wished to demonstrate that gastric epithelial cells infiltration by HP is associated with the active inflammatory response and the severity of gastritis in the gastric antrum of patients harboring the bacterium. METHODS: We studied 129 patients with HP-associated gastritis and 60 HP-negative controls with gastritis of different origin. Gastric mucosal biopsies were obtained from all subjects at endoscopy and were examined for histological features of active inflammation and type of gastritis, as well as for electronmicroscopical features of invasion and damage, according to a four-degree classification (range 0-3). RESULTS: At entry, the presence of acute inflammatory activity, defined according to the presence of a polymorphonuclear cell infiltrate, was significantly greater in HP-positive patients than in controls (p < 0.00001) and was well related to the depth of mucosal invasion (p < 0.001). Accordingly, the prevalence of chronic atrophic gastritis was higher in HP-positive patients (p < 0.02 vs. controls) and at grade 3 of invasion (p < 0.04 vs. grade 1 and 2). Peptic ulcers were more frequent in grade 3 patients (p < 0.04). CONCLUSION: Gastric epithelial cell infiltration and damage by HP, as assessed by electron microscopy, is an important feature of HP-associated gastritis due to its histological and clinical correlates.
Female↗
Five-year maintenance treatment with ranitidine: effects on the natural history of duodenal ulcer disease.
In this study, we assessed the effect of a 5-yr maintenance program with ranitidine on the natural history of duodenal ulcer disease both during treatment and after drug withdrawal. Two groups of patients with duodenal ulcer were studied. In group A patients (n = 40), ranitidine (150 mg/day) was given continuously for 5 yr; group B patients (n = 40), received seasonal, 8-wk prophylactic treatment with ranitidine (300 mg/day), in spring and fall. Routine endoscopy was performed every year and whenever ulcer symptoms recurred. After the 5-yr study, the drug was discontinued in both groups, and patients underwent endoscopy after 3, 6, 12, and 18 months. The probability of duodenal ulcer recurrence was significantly lower in patients continuously receiving ranitidine (p < 0.001), and ulcer complications were significantly lesser in group A patients (p < 0.03). In the 18 months of follow-up after drug discontinuation, only 15% (4/26) of patients of group A relapsed, whereas ulcer recurrence was diagnosed in 84% (26/32) of group B patients (p < 0.001). We conclude that low-dose continuous treatment with ranitidine is preferable to seasonal prophylaxis for its ability to modify the natural history of duodenal ulcer disease.
Adult↗
Heightened free radical activity in angina pectoris.
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Angina Pectoris↗
Effect of interleukin-1 receptor antagonist on vascular smooth muscle cell proliferation.
The development of the atheromatous plaque is largely dependent on vascular smooth muscle cell proliferation and production of biologically active compounds such as cytokines and growth factors. Cytokines such as IL-1 derived from blood vessel wall may contribute to regional defense or pathology. Neutralization of the effects mediated by IL-1 by a receptor antagonist specific for IL-1 alpha and IL-1 beta has been shown to reduce the possible pathologic consequences induced by IL-1 in the regional environment. The effect of human recombinant interleukin-1 receptor antagonist (hrIL-1ra), a new member of the IL-1 family, has been assessed on modulating vascular smooth muscle cell (VSMC) proliferation in the rat. A significant dose- and time-dependent reduction of DNA synthesis was observed when hrIL-1ra was added to the cell cultures. The maximum inhibitory effect was seen using IL-1ra at a concentration of 250 ng/ml and after 48 h incubation with cultured vascular smooth muscle cells. Furthermore, hrIL-1ra inhibited VSMC growth in the presence of exogenous mitogenic doses of IL-1 alpha. The addition of indomethacin to the cultures did not modify the inhibitory events. These data suggest a possible pharmacologic role for IL-1ra in inhibiting VSMC proliferation by possibly interfering with the autocrine regulatory pathway of IL-1.
Animals↗
Protein kinase C pathway and proliferative responses of aged and young rat vascular smooth muscle cells.
Alterations of vascular smooth muscle cell (VSMC) proliferation have been implicated in the age-dependent susceptibility to atherosclerosis. Although it is known that protein kinase C (PKC) is involved in the mechanism of VSMC proliferation, there are no data on the possible involvement of PKC in disregulating VSMC proliferation in aged vascular cells. We evaluated the proliferative pattern, the PKC responsiveness and the effect of phorbol ester (PMA) treatment on vascular cell growth and cell cycle distribution in VSMCs from young and aged rats. The proliferative response was significantly higher in aged than in young cells after serum stimulation (7.5 vs. 2.8 x 10(4), 18 vs. 12 x 10(4), 26 vs. 22 x 10(4) cells/well, aged vs. young at days 2, 4, 6; P < 0.005). On the contrary, aged cells showed a significant inhibition of DNA synthesis at 48 h incubation with PMA concentrations of 1, 10, 100 nM (-47%, -53%, -58%, respectively) compared with controls (fetal calf serum 0.5%) and cell count (average decrease: -38% from 48 h to 96 h) after treatment with PMA 10 nM. The opposite was observed in young cells on [3H]thymidine incorporation with PMA 1, 10, 100 nM (+52%, +100%, +121%, respectively and cell count (average increase +55% from 48 h to 96 h). In addition, inhibition of the cell cycle from G1 to the S phase and reduction of PKC translocation in aged VSMC were observed. Alterations of PKC function could be involved in the disregulation of aged VSMC proliferation, which seems to characterize the increased susceptibility to atherosclerosis.
Aging↗
Differences in the glutathione system of cultured aortic smooth muscle cells from young and aged rats.
We studied the relation between the glutathione (GSH) system and cell proliferation in a model of smooth muscle cells (SMC) derived from the thoracic aorta of 4-6-week-old (young) and 15-month-old (aged) rats. SMC from aged rats showed greater levels of total non-protein thiol compounds (T-SH), increased glutathione transferase (GST) and increased glutathione reductase (GSSG-Red) activities compared with cells from young rats. These changes were associated with an increased proliferation rate of SMC from aged rats. To evaluate the role of GSH on cell proliferation better, a specific inhibitor of gamma-glutamyl-cystein synthetase, DL-buthionine-SR-sulphoximine (BSO) was used. BSO showed a dose-dependent inhibition of cell growth, with an IC50 of 10(-4) M, after 48-72 h of incubation. Removal of BSO restored cell growth, further suggesting a link between GSH levels and vascular cell proliferation. The inhibitory effect of BSO was about two times greater on SMC from young than on SMC from aged rats. BSO showed 56% inhibition on the proliferation of SMC from young rats and 32% inhibition on SMC from aged rats (10(-4) M, 72 h of incubation). A parallel reduction of GSH levels of 38% and 19% for SMC from young and aged rats, respectively, was observed, suggesting that age-related factors may influence the involvement of GSH system in cell proliferation.
Aging↗
Hypoxia-induced coronary flow changes in the perfused rat heart: effects of high L-carnitine concentrations.
1. Hemodynamic effects of physiological (0.04 and 0.07 mM) and high (8, 15 and 25 mM) L-carnitine (LC) concentrations were tested on the normally oxygenated and hypoxic perfused rat heart. 2. No effect was detected on aerobic hearts, whereas a dose-dependent rise in coronary flow (CF) during both the hyperemic and constrictive phases was observed in hypoxic hearts with 8, 15 and 25 mM LC. This action was apparently unrelated to a resting tension (RT) improvement, which was observed only with 25 mM LC. 3. When 11 mM glucose was replaced by 11 mM mannitol in the perfusion buffer, LC effects on the hyperemic phase were abolished; however, 25 mM LC resulted in CF-values still significantly higher than those detected without the drug, though RT was similar in these glucose-free groups. 4. It may be concluded that LC is ineffective on the perfused rat heart in aerobic conditions, whereas high LC concentrations can enhance CF only during hypoxia, these effects being independent of heart function improvements and partly unrelated to glucose presence.
Aerobiosis↗
Myocardial antioxidant defenses during cardiopulmonary bypass.
In 31 male patients undergoing coronary bypass surgery who underwent different periods of cardioplegic hypothermic arrest, the activities of glutathione peroxidase, glutathione reductase, glutathione transferase, copper/zinc-containing and manganese-containing superoxide dismutases, and catalase were studied in the right atrial myocardium, before and 5 minutes after aortic cross-clamping. The levels of thiobarbituric acid reactive substances (TBARS) and nonproteic thiol compounds (NP-SH) were also assessed. Prolonged ischemia followed by reperfusion induced activation of the major myocardial antioxidant enzymes with marked NP-SH depression and TBARS increase, despite cold crystalloid cardioplegic protection. These changes were significantly related to the duration of the ischemic arrest, suggesting: (1) that reperfusion free radical generation is dependent on the severity of the previous ischemic period; and (2) the occurrence of myocardial oxidative stress during cardiopulmonary bypass.
Adult↗
TBA test and "free" MDA assay in evaluation of lipid peroxidation and oxidative stress in tissue systems.
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Animals↗
Heparin: does it act as an antioxidant in vivo?
Previous studies have shown that heparin antagonizes oxygen radical-mediated injury to endothelial cells, suggesting an antioxidant role of the drug. In the present investigation, the hypothesis that heparin exerts direct antioxidant effects was tested in several experimental models. We have found that 1, 3, 5, 10, 20, 40 and 80 U/mL of heparin do not scavenge superoxide anion, hydrogen peroxide, hydroxyl radical or the stable free radical 1,1-diphenyl-2-pycrylhydrazyl. Moreover, the drug is ineffective towards iron-driven linolenic acid peroxidation, autooxidation of brain homogenate and linolenic acid peroxidation mediated by human internal mammary artery homogenate. Specific studies on the potential iron-binding-inactivating capacity of heparin prove the drug to be totally ineffective. Finally, the loss of protein sulphydryls from human plasma induced by hypoxanthine-xanthine oxidase-generated oxygen radicals is not prevented by heparin. In conclusion, heparin, even at concentrations far higher than those usually used therapeutically, has no direct antioxidant properties. Thus, other mechanisms not strictly antioxidant-type must be involved in heparin-mediated cell protection against toxic oxygen metabolites.
Animals↗
Gallbladder hypokinesia and normal gastric emptying of liquids in patients with dyspeptic symptoms. A double-blind placebo-controlled clinical trial with cisapride.
Gastric and gallbladder emptying after a standard liquid meal were studied in 65 patients with early satiety, bloating, pain at the right hypochondrium or the epigastrium, nausea, and occasionally vomiting. Fifty normal subjects were studied as a control group. Gastric and gallbladder emptying were evaluated by means of real-time ultrasonography (RUS). Serial RUS scans were made after a 12-hr fast and every 15 min after a standard meal for 2 hr. Patients were considered to have delayed gastric emptying or hypokinetic gallbladder when gastric diameters and gallbladder volume evaluated 45 min after meal were 2 SD above the corresponding mean values of the normal subject group. Fifteen patients (23%) were found with delayed gastric emptying and 20 (30.7%) a reduced gallbladder emptying. None of our patients showed delayed gastric emptying and hypokinetic gallbladder simultaneously. The 20 patients with reduced gallbladder emptying were included in a double-blind randomized, placebo controlled, change-over study with cisapride (10 mg three times a day) for 30 days. Cisapride treatment reversed the gallbladder hypomotility within the normal range while placebo did not change the response to meal. Symptom score improved significantly after cisapride and placebo. It is concluded that in dyspeptic patients with reduced gallbladder response to a meal cisapride may be of help in improving the kinetic abnormality. Dyspeptic symptoms, however, do not seem to be corrected with the described gallbladder motor abnormality.
Adult↗
Glutathione-related enzyme activities and lipoperoxide levels in human internal mammary artery and ascending aorta. Relations with serum lipids.
The relation among glutathione-related enzyme activities, thiobarbituric acid-reactive substances of the human aorta and internal mammary artery, and serum lipids was studied in 40 male patients undergoing coronary revascularization. Glutathione peroxidase and glutathione reductase activities were significantly higher in the internal mammary artery, whereas glutathione transferase activity was elevated in the aortic wall. Moreover, non-selenium-dependent glutathione peroxidase activity was detectable only in the aorta. The levels of thiobarbituric acid-reactive substances were significantly higher in the aorta. A positive correlation was found among the activity of glutathione peroxidase, glutathione reductase, and thiobarbituric acid-reactive substances in the internal mammary artery and total cholesterol, low density lipoprotein cholesterol, and triglycerides. In the aortic wall, a positive correlation among the activity of glutathione peroxidase, glutathione transferase, thiobarbituric acid-reactive substances, and the previously mentioned serum lipids was evident. In contrast, high density lipoprotein cholesterol was inversely related to enzymatic activities and thiobarbituric acid-reactive substances in both the internal mammary artery and aorta. In conclusion, significant differences in the levels of glutathione-related enzyme activities and thiobarbituric acid-reactive substances in the internal mammary artery and aorta were found, suggesting a different ability of the two tissues to counteract oxidative stress: the glutathione-related antioxidant properties and the level of lipid peroxidation in the arterial tissue seem to be specifically influenced by serum lipids.
Adult↗
Circadian variations in antioxidant defences and lipid peroxidation in the rat heart.
Circadian variations in antioxidant defences and lipid peroxidation were investigated in 12 rat hearts perfused during light (i.e., at 08.00, n = 6) and dark cycle (i.e., at 19.00, n = 6). Higher levels of non proteic thiol compounds (P < 0.01), glutathione transferase activity (P < 0.05) and lipid peroxidation (P < 0.01) were detected in evening-excised hearts, associated with a lower (P < 0.05) selenium-dependent glutathione peroxidase activity; superoxide dismutase and glutathione reductase activities, as well as vitamin E content, were similar in the two groups. Moreover, a greater release of thiobarbituric acid reactive substances (P < 0.01) and proteins (P < 0.05) was detected in the myocardial effluent of another group of 5 evening-excised hearts perfused with Krebs-Henseleit buffer containing 30 microM cumene hydroperoxide, as compared to 5 light-cycle hearts. In conclusion, a higher oxidative stress seems to be operative in the rat heart during early stages of the dark phase, in spite of the increase level of non proteic thiol compounds (namely, glutathione). An imbalance of antioxidant defences, and/or higher radical generation and unsaturation degree of biomembranes lipids, may be hypothesized to favour myocardial oxidative stress at the beginning of the motor activity phase in rats.
Animals↗