Biomedical subjects

F Bosch-Morell

Publications and source records attributed to F Bosch-Morell.

16 recordsLinked to original sources

PubMed2000

Beta-amyloid-induced activation of caspase-3 in primary cultures of rat neurons.

It is known that beta-amyloid peptide (Abeta) contributes to the neurodegeneration in Alzheimer's disease (AD) and operates through activation of an apoptotic pathway. Apoptotic signal is driven by a family of cysteine proteases called caspases. The beta-amyloid precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated beta-amyloid peptide formation. Cerebellar neurons from rat pups were treated with the aged Abeta(25-35) at 1 and 5 microM and fluorescence assays of caspase activity performed over 4 days. We observed an increase in caspase activity after 48 h treatment in both 1 and 5 microM treated cells, then (72-96 h) caspase activity decreased to control values. The data presented support the hypothesis that Abeta(25-35)-induced apoptosis is mediated by the activation of Caspase-3 and that this is a transient effect.

Amyloid beta-Peptides↗

PubMed2000

Reduction of brain antioxidant defense upon treatment with butylated hydroxyanisole (BHA) and Sudan III in Syrian golden hamster.

Treatment with the antioxidant butylated hydroxyanisole (BHA) or the azo dye Sudan III during two weeks led to changes in the brain enzymatic antioxidant defense of Syrian golden hamsters. BHA was able to induce liver superoxide dismutase (SOD) 2-fold but had no effect on the brain SOD activity, whereas SOD activity was reduced to 50% in brain and remained unchanged in liver with Sudan III. These two substances are known inducers of DT-diaphorase and in fact this enzymatic activity was induced 4- and 6-fold in liver with BHA and Sudan III, respectively. However, BHA promoted a significant 40% reduction, whereas no change was observed with Sudan III in brain DT-diaphorase activity. Glutathione(GSH)-related enzymatic activities were also assayed in brain and liver. No induction was observed with BHA or Sudan III for any of the activities tested in hamster brain: GSH S-transferase (GST), GSH peroxidase (GSH-Px) and glutathione disulfide (GSSG) reductase (GR). Only 1.3- and 1.4-fold increases of GST and GR activities were observed in liver and no change in any of these enzymatic activities in brain with BHA; a partial limitation of permeability to BHA of the blood-brain barrier may explain this results. Furthermore, Sudan III promoted reductions in all these GSH-related enzymatic activities in brain and liver. The possible explanations for these results are discussed.

Animals↗

PubMed1999

Serum vitamin E levels negatively correlate with severity of age-related macular degeneration.

Age-related macular degeneration (AMD) pathogenesis has been related to UV radiation and other factors that may promote increased oxidative damage to the retina. Patients with different AMD grading (n = 25) were compared with an age-matched group of AMD-free subjects (n = 15), both groups older than 60 years. A modification of the AMD grading system is proposed that allows patient grading and not single eye grading. AMD patients showed statistically significant lower serum levels of vitamin E and Zn than AMD-free subjects. Moreover, a negative correlation (Spearman's correlation coefficient r = -0.815, P < 0.001) could be established between AMD grading of both the patients' eyes and serum vitamin E levels. Sun exposure index (SEI) was also compared and found to be significantly higher in the AMD group. The results presented establish the importance of antioxidants in AMD, and set the basis for further studies on adjuvant therapies with antioxidants for AMD. Finally, the results also confirm the pathogenic role of UV radiation in AMD.

Aged↗

PubMed1999

4-Hydroxynonenal inhibits glutathione peroxidase: protection by glutathione.

4-Hydroxy-2,3-trans-nonenal, a lipid peroxidation product, inhibits glutathione peroxidase in a concentration-dependent manner. The concentration providing 50% inhibition is 0.12 mM. This inhibition can be almost completely (89%) prevented by 1 mM glutathione added to the incubation mixture 30 min before 4-hydroxy-2,3-trans-nonenal or 2,3-trans-nonenal, but not by other thiol-containing antioxidants such as 0.5 mM dithiothreitol or beta-mercaptoethanol. Again the addition of 1 mM glutathione, and not of 0.5 mM dithiothreitol or beta-mercaptoethanol, to the enzyme 30 min after incubation with 4-hydroxy-2,3-trans-nonenal restores activity to the same extent as does the preincubation with GSH. In view of the known reactivity of 4-hydroxy-2,3-trans-nonenal with lysine residues and the reversibility of the inhibition, the involvement of a lysine residue in GSH binding to glutathione peroxidase is proposed. The potential relevance of the inhibition of glutathione peroxidase by 4-hydroxy-nonenal to oxidative tissue damage is discussed with particular emphasis on neurological disorders.

Aldehydes↗

PubMed1999

Efficacy of the antioxidant ebselen in experimental uveitis.

Inflammation results in the production of free radicals. In a model of experimental uveitis upon subcutaneous injection of endotoxin to Lewis rats, i.e., endotoxin-induced experimental uveitis (EIU), we have evaluated the status of the antioxidant capacity of ocular tissues. EIU results in a decrease of glutathione (GSH) content and glutathione peroxidase (GPx) activity in whole eye homogenates 24-h after endotoxin administration. Furthermore, an increase in malondialdehyde (MDA) content was observed in these same samples, thus confirming the involvement of oxidative stress in the pathophysiology of the process. In view of the ability of the antioxidant ebselen as GPx enzyme mimic, we tested the effect of the oral treatment with two doses of 100 mg/kg body weight of ebselen (first dose administered at the same time of endotoxin, and the second after 12 h). Ebselen administration normalized the GSH and MDA contents and protected the GPx activity of the EIU rat eyes. The GPx activity in the eye homogenate of the treated rats could be completely acounted for by the ebselen-dependent GPx-like activity, i.e., GPx activity measured in the acidic supernatant of the homogenate after neutralization. Unmodified ebselen was detected in whole eye homogenates, thus it shows for the first time the penetration of ebselen through the blood-aqueous and blood-retina barrier. The results herein may allow the proposal of ebselen as a suitable antiinflammatory agent in ocular tissues.

Animals↗

PubMed1999

Glycemic control and not protein kinase C inhibition prevents the early decrease of glutathione peroxidase activity in peripheral nerve of diabetic mice.

Experimental diabetes promotes changes in biochemical activities of peripheral nervous tissue. Glutathione peroxidase activity decreases in sciatic nerve of diabetic mice very early after onset of experimental diabetes. Effective glycemic control with insulin restores the early lost glutathione peroxidase activity in peripheral nerve of diabetic mice to control values. Data are also presented demonstrating that glutathione peroxidase activity in diabetic mouse peripheral nerve is not modified by the constant delivery of calphostin C, a protein kinase C inhibitor, therefore this decrease seems to be independent on a protein kinase C mediated mechanism. Thus, the early glutathione peroxidase activity decrease in peripheral nerve of diabetic mice is closely related to hyperglycemia, and a tight glycemic control is rather effective in restoring the control levels of this enzymatic activity. The results herein do not rule out the benefits of antioxidant adjuvant therapies in diabetes to help recover the overall decrease in antioxidant defense in peripheral nerve elicited by the decrease of glutathione peroxidase activity.

Animals↗

PubMed1998

Experimental diabetic neuropathy: role of oxidative stress and mechanisms involved.

Oxidative stress has been related to the development of diabetic neuropathy. Experimental diabetes (alloxan injection of mice) promotes early biochemical changes in peripheral nervous tissue, e.g. decrease in Na,K-ATPase activity and glutathione (GSH) peroxidase (GSHPx) activity. The former decrease can be reverted by inhibiting protein kinase C (PKC), since it has been reported that PKC is activated in these experimental conditions. Here we present data demonstrating that the inhibition of PKC, as early as 4 days after alloxan administration, is not able to return to normal values GSHPx activity in sciatic nerve of diabetes mice. Thus, it would fit with our previous proposal of the possible glycation of this protein as an early event in experimental diabetes, and apparently rules out the control of GSHPx activity by PKC in this tissue.

Animals↗

PubMed1998

Serum malondialdehyde in HIV-seropositive children negatively correlates with CD4+ lymphocytes count.

Human immunodeficiency virus (HIV) infection is associated with oxidative stress as it has been demonstrated in adult-seropositive individuals. We show in this study that serum malondialdehyde (MDA) concentration of HIV-infected children was significantly higher than in control children. A negative correlation (r = -0.515) was found in HIV-infected children between their CD4+ lymphocyte count, and MDA concentration but not with serum antioxidant status. The increase of MDA concentration in HIV-seropositive children confirms the involvement of oxidative stress in the pathophysiology of this infection also in childhood. Because of the importance of oxidative stress and antioxidants for HIV viral replication, the adequacy of an adjuvant therapy with antioxidants should be considered; an adequate candidate for it could be N-acetylcysteine.

Biomarkers↗

PubMed1998

Serum malondialdehyde in HIV seropositive children.

Human immunodeficiency virus (HIV) infection is associated with oxidative stress as it has been demonstrated in adult seropositive individuals. We show in this study that serum malondialdehyde (MDA) concentration of HIV infected children was significantly higher than in control children. Moreover, a statistically significant decreased serum antioxidant status was detected in HIV infected children when compared with controls. No correlation was found in HIV infected children between their clinical or immunological categories, CD4+ lymphocyte count or CD4+/CD8+ ratio, and MDA concentration or serum antioxidant status. Newborn from HIV seropositive mothers had also a higher MDA concentration in cord blood serum than their corresponding controls from HIV seronegative mothers, whereas no difference could be established in the serum antioxidant status between both groups. No apparent correlation could be established between birth weight, gestational age or APGAR test values, and MDA in any of these groups. The results presented, (i.e., the increase of MDA concentration in HIV seropositive infants and children, and the decrease in serum total antioxidants in HIV seropositive children) confirm the involvement of oxidative stress in the pathophysiology of this infection also in childhood. Because of the importance of oxidative stress and antioxidants for HIV viral replication, the adequacy of an adjuvant therapy with antioxidants should be considered; an adequate candidate for it could be N-acetyl-cysteine.

Adolescent↗

PubMed1998

Chronic ethanol feeding induces cellular antioxidants decrease and oxidative stress in rat peripheral nerves. Effect of S-adenosyl-L-methionine and N-acetyl-L-cysteine.

Chronic ethanol feeding promotes oxidative stress in rat peripheral nerve. Malondialdehyde, a lipid peroxidation product, content increases in sciatic nerves of rats fed an ethanol-containing diet, when compared with pair-fed animals. Moreover, glutathione content and glutathione peroxidase activity in this same tissue decrease in ethanol-fed vs. pair-fed rats. S-Adenosyl-L-methionine and N-acetyl-L-cysteine, both with possible therapeutic action on alcoholism, were tested in this animal model. Only N-acetyl-L-cysteine was able to normalize malondialdehyde content and to restore glutathione content and glutathione peroxidase activity, to values not significantly different from those of sciatic nerves from pair-fed animals. The reasons for the different effect of both substances tested is also discussed.

Acetylcysteine↗

PubMed1998

Serum malondialdehyde: possible use for the clinical management of chronic hepatitis C patients.

Serum lipid peroxidation products are increased in inflammatory liver disease and, as we previously reported, also in chronic hepatitis C. We have performed a specific assay of malondialdehyde, the reported most abundant product of lipid peroxidation, in serum of twenty four chronic hepatitis C patients, before, during, and after interferon treatment. Liver biopsies were performed in each patient before and after interferon treatment. The results show higher serum malondialdehyde values in chronic hepatitis C patients than healthy subjects (n = 68) before interferon treatment (p < .001). Mean value of serum malondialdehyde levels after interferon treatment was significantly lower than before it (p < .002). Associating the histopathological findings in each of the 48 biopsies performed, with serum malondialdehyde and alanine aminotransferase activity levels, of the sample obtained the same day of biopsy, a much better correspondence with the histopathological severity was observed for malondialdehyde concentration than for alanine aminotransferase activity. These levels decreased significantly after interferon treatment. However, when the patients were grouped in responding (group I; n = 9) and non-responding (group II; n = 15) to interferon treatment, according to the histopathological findings before and after interferon, the values of group I before interferon treatment were significantly higher than group II (p < .03). Thus, a potential predictive value could be ascribed to the serum malondialdehyde levels before interferon treatment in these patients. We propose the utility of the specific assay of malondialdehyde for the clinical management of chronic hepatitis C patients.

Adult↗

PubMed1998

Lipid peroxidation products and antioxidants in human disease.

Lipid peroxidation (LPO) is a free radical-related process that in biologic systems may occur under enzymatic control, e.g., for the generation of lipid-derived inflammatory mediators, or nonenzymatically. This latter form is associated mostly with cellular damage as a result of oxidative stress, which also involves cellular antioxidants in this process. This article focuses on the relevance of two LPO products, malondialdehyde (MDA) and 4-hydroxynonenal (HNE), to the pathophysiology of human disease. The former has been studied in human serum samples of hepatitis C virus-infected adults and human immunodeficiency virus-infected children. In these two cases it is shown that the specific assay of serum MDA is useful for the clinical management of these patients. The presence of MDA in subretinal fluid of patients with retinal detachment suggests the involvement of oxidative stress in this process. Moreover, we were able to report the dependence of this involvement on the degree of myopia in these patients. The assay of MDA contents in the peripheral nerves of rats fed a chronic alcohol-containing diet or diabetic mice also confirms the pathophysiologic role of oxidative stress in these experimental models. In these two cases, associated with an increase in tissue LPO products content, we detected a decrease of glutathione peroxidase (GSHPx) activity in peripheral nerve, among other modifications. We have demonstrated that in vitro HNE is able to inhibit GSHPx activity in an apparent competitive manner, and that glutathione may partially protect and/or prevent this inactivation. The accumulation of LPO products in the brain of patients with Alzheimer's disease has also been described, and it is on the basis of this observation that we have tried to elucidate the role of oxidative stress and cellular antioxidants in beta-amyloid-induced apoptotic cell death of rat embryo neurons. Finally, we discuss the possible role of the observed vascular effects of HNE on human arteries.

Adult↗

PubMed1997

4-hydroxynonenal-induced relaxation of human mesenteric arteries.

The effect of 4-hydroxynonenal (4-HNE), a circulating lipid peroxidation product, on the vascular tone of human mesenteric arteries is studied. 4-HNE promotes relaxation of human mesenteric arterial rings in a concentration-dependent manner. Removal of the endothelium or treatment with N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME; 10(-4) M) partially prevented 4-HNE-induced relaxation, thus suggesting the intervention of nitric oxide from endothelial origin in the vascular effects of 4-HNE.

Adult↗

PubMed1996

Lipid peroxidation products in human subretinal fluid.

The concentrations of thiobarbituric acid reacting substances (TBARS) and proteins in the subretinal fluid (SF) of patients undergoing retinal detachment surgery have been determined. We have tried to establish the correlations between these biochemical and other clinical features of these patients: evolution time of the retinal detachment, age, degree of myopia, and macular affection. Caucasian patients, 19 men and 19 women (57.42 +/- 12.85 average age, interval 20-80) were randomly selected for this study. SF samples were obtained by puncture after scleral indentation. TBARS and protein concentrations were determined by the corresponding colorimetric assays. A linear correlation exists between TBARS and protein contents in these samples. No correlation could be established between evolution time of the retinal detachment and TBARS content in SF. TBARS in SF increases with increasing age in nonmyopic patients. In the samples of myopic patients the correlation was established between TBARS content and degree of myopia. The group of patients with more than 10 dioptres show a significant higher TBARS concentration in SF than any of the other groups studied. It can be concluded that lipid peroxidation products in SF originate, at least partially, from rod outer segments, and that lipid peroxidation is a process that might play a role in the pathogenesis of retinal detachment, specially in myopic patients.

Adult↗

PubMed1995

Phenytoin-induced glutathione depletion in rat peripheral nerve.

Administration of high doses (150-250 mg/kg body weight) of phenytoin (DPH) promote a 40% decrease in glutathione (GSH) content of rat sciatic nerve. This DPH-induced GSH depletion is accompanied with an electrophysiological impairment of peripheral neuromuscular function. H7 (20 mg/kg body weight IP, 30 min prior to DPH), a protein kinase C inhibitor, was able to prevent the DPH-induced GSH depletion only at the lower DPH dose used. This same inhibitor completely prevented the electrophysiological impairment at the lower DPH dose, and only partially at the higher DPH dose used. These results confirm the hypothesis of a DPH-dependent activation of PKC (that might be triggered by, or be the consequence of, the reduction of the intracellular antioxidant GSH), as one of the pathophysiological mechanisms involved in DPH-induced neurotoxicity.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1994

4-Hydroxynonenal, a lipid peroxidation product, induces relaxation of human cerebral arteries.

The relaxant effect of 4-hydroxynonenal (4-HNE), a lipid peroxidation product, on human cerebral arteries was studied. Addition of 4-HNE to artery rings promoted no contraction, and after stimulation with prostaglandin F2 alpha (PFG2 alpha; 10(-7)-3 x 10(-6) M), 100% relaxation was obtained with 3 x 10(-5) M 4-HNE. Inhibition of nitric oxide formation with NG-nitro-L-arginine methyl ester hydrochloride (L-NAME; (10(-4) M), as well as prostaglandin synthesis with indomethacin (3 x 10(-6) M), partially prevented 4-HNE-induced relaxation, but each of these substances separately failed to inhibit complete relaxation. Addition of both inhibitors together reduced 4-HNE-induced relaxation to approximately 50%, but relaxation could not be abolished. When the endothelium was removed, 4-HNE did not promote relaxation after PGF2 alpha stimulation. The possible roles of different intracellular signaling systems in the vascular effect of 4-HNE are discussed.

Aged↗