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A Nicole

Publications and source records attributed to A Nicole.

At least 37 records · Page 2Linked to original sources
PubMed1996

Peripheral antioxidant enzyme activities and selenium in elderly subjects and in dementia of Alzheimer's type--place of the extracellular glutathione peroxidase.

Defenses against free radical damage were determined in red blood cells and plasma from 40 patients with dementia of the Alzheimer-type (DAT) and 34 aged control subjects with normal cognitive function. No crude significant difference in erythrocyte copper-zinc superoxide dismutase (E-CuZnSOD), seleno-dependent glutathione peroxidase (E-GSH-Px), glutathione reductase (E-GSSG-RD) activities, and selenium (Se) concentration was found between DAT cases and control subjects. The peroxidation products evaluated in plasma by the thiobarbituric-reactive material (TBARS) were at the same level in the DAT group as compared to controls. In the DAT group, plasma GSH-Px (P-GSH-Px) activity and plasma Se (P-Se) were negatively correlated with age (r = -0.58; p < 0.001 and r = -0.63; p < 0.001 respectively). Moreover, erythrocyte GSH-Px activity and Se were also negatively correlated with age (r = -0.40; p < 0.01 and r = -0.46; p < 0.01, respectively). No significant correlation with age was observed in the controls. When controlling for age, a significant increase for P-GSH-Px activity and P-Se was observed in DAT patients as compared to controls. These significant differences mostly appeared in DAT subjects under 80 years. Some correlations were only observed in the DAT group such as P-GSH-Px and E-GSH-Px (r = +0.68; p < 0.001); P-GSH-Px and E-Se (r = +0.79; p < 0.001). Correlations between P-GSH-Px and P-Se, E-GSH-Px and P-Se, and P-Se with E-Se are greater in the DAT group (r = +0.84; p < 0.001; r = +0.76; p < 0.001 and r = 0.75; p < 0.001) than in the control group (r = 0.54, pI < 0.01; r = 0.43, p < 0.01 and r = +0.34, p < 0.05 respectively). The fact that first -- a significant increase in P-GSH-Px and P-Se, second -- some modifications in the relationships between antioxidant parameters, and third -- age-dependent decreases of glutathione-peroxidase activities and their cofactor, appeared only in the DAT group suggest that DAT is associated with an oxidative stress due to an imbalance between reactive oxygen species and the peripheral antioxidant opposing forces.

Aged↗
PubMed1996

Transgenic mice overexpressing the human Cu/Zn-SOD gene: ultrastructural studies of a premature thymic involution model of Down's syndrome (trisomy 21).

It has been suggested that the overexpression of copper-zinc superoxide dismutase (SOD-1) in Down's syndrome (DS) patients may be involved in expression of some of the phenotypic characteristics observed in these patients. To explore the possible role of SOD-1 overexpression in the premature thymic involution and immunologic disorders observed in DS patients, transgenic mice overexpressing the human SOD-1 gene have been generated and their thymuses have been studied at the ultrastructural level. Our observations show premature involution of the thymus in SOD-1 transgenic mice, with a strong modification of the thymic microenvironment starting at approximately 3-4 months of age. The thymic microenvironment in 7-month-old transgenic mice is similar to that observed in 20-month-old control mice. We suggest that these results are consistent with the role of SOD-1 overexpression in the early thymic involution observed in DS patients. These transgenic mice provide an interesting model to investigate the deleterious effect of increased dosage of some chromosome 21 genes such as SOD-1 in the pathogenesis of DS.

Animals↗
PubMed1995

Identification of new mutations in the Cu/Zn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons. Although most cases of ALS are sporadic, approximately 10% are inherited as an autosomal dominant trait. Mutations in the Cu/Zn superoxide dismutase gene (SOD 1) are responsible for a fraction of familial ALS (FALS). Screening our FALS kindreds by SSCP, we have identified mutations in 15 families, of which 9 have not been previously reported. Two of the new mutations alter amino acids that have never been implicated in FALS. One of them affects a highly conserved amino acid involved in dimer contact, and the other one affects the active-site loop of the enzyme. These two mutations reduce significantly SOD 1 enzyme activity in lymphoblasts. Our results suggest that SOD 1 mutations are responsible for > or = 13% of FALS cases.

Amino Acid Sequence↗
PubMed1993

Hippocampal mossy fiber changes in mice transgenic for the human copper-zinc superoxide dismutase gene.

The copper-zinc superoxide dismutase (SOD-1) gene, located on chromosome 21 and triplicated in Down's syndrome (DS), is suspected to be involved in the neuropathology observed in Alzheimer's disease (AD), DS and physiological aging. In order to explore the effect of an overproduction of SOD-1 in the mouse hippocampus, we investigated the Timm-stained mossy fiber (MF) innervation in the hippocampus of transgenic mice for the human SOD-1 gene (hSOD-1 mice). The results showed a decrease of the MF projection area in the hSOD-1 mice overexpressing the SOD-1 protein. These findings suggest that free radicals could play a role in this particular synaptic loss.

Animals↗
PubMed1993

Preferential expression of superoxide dismutase messenger RNA in melanized neurons in human mesencephalon.

The copper-zinc-dependent superoxide dismutase messenger RNA expression was studied at cellular level by in situ hybridization, using a 35S-labelled complementary DNA probe homologous to human copper-zinc-dependent superoxide dismutase messenger RNA, in the dopaminergic neuron-containing areas of the human mesencephalon (the substantia nigra pars compacta, ventral tegmental area, central gray substance and peri- and retrorubral region corresponding to catecholaminergic cell group A8). The autoradiographic labelling signal was localized in neurons. No detectable hybridization signal could be found in the glial cells. Copper-zinc-dependent superoxide dismutase messenger RNA was detected in melanin-containing neurons as well as in non-melanized neurons. Quantification at cellular level, taking the autoradiographic silver grain density as an index of the abundance of copper-zinc-dependent superoxide dismutase messenger RNA, indicated that hybridization level was higher in the melanized than in the non-melanized neurons within a region. Among melanized neurons, cellular copper-zinc-dependent superoxide dismutase messenger RNA content was lowest in the neurons of the substantia nigra. No significant difference in levels of transcripts was evidenced between the groups of non-melanized neurons. The data suggest that the abundance of copper-zinc-dependent superoxide dismutase messenger RNA is higher in the mesencephalic neurons containing neuromelanin compared to other neurons. Thus, the melanized neurons have a particular defence system against oxygen toxicity, which may represent a basis for their preferential vulnerability to Parkinson's disease.

Aged↗
PubMed1993

Selenium and oxygen-metabolizing enzymes in elderly community residents: a pilot epidemiological study.

OBJECTIVE: To investigate the relationship of selenium and oxygen-deactivating enzymes with age in the elderly. SAMPLE: The study sample consisted of volunteers recruited from the PAQUID study. This study is conducted in a representative sample of non-institutionalized individuals aged > or = 65 years living in Southwestern France; its main objective is to study longitudinally the incidence and risk factors of dementia. METHODS: Plasma and erythrocyte selenium and activities of oxygen metabolizing enzymes in erythrocytes (GSH-Px, CuZn-SOD, and GSSG-RD) were measured in 239 volunteers (108 males and 131 females; mean age 73.7 years). RESULTS: Plasma selenium (PSe) decreased significantly with age; a similar but non-significant trend was found for erythrocyte selenium (ESe). None of the enzyme activities showed a clear relationship with age. Women had significantly higher GSH-Px activities than men. For PSe levels lower than 77 ng/mL, there was a strong correlation between PSe and GSH-Px; above this value, the correlation decreased, suggesting that the selenium requirement for GSH-Px production had been satisfied. In this sample, CuZn-SOD was correlated negatively with GSH-Px (r = -0.18; P < or = 0.01) and positively with GSSG-RD (r = +0.20; P < or = 0.01). CONCLUSIONS: In individuals aged > or = 65 years, we found that blood selenium levels were negatively correlated with age. Our analysis of the relationship between selenium and GSH-Px activity suggests that low selenium values are associated with decreased GSH-Px activity.

Aged↗
PubMed1992

[Acute poisoning due to oral intake of an organic solvent].

We report a case of paint thinner intoxication by oral intake, with loss of consciousness, upper gastrointestinal injuries, renal failure, rhabdomyolysis and cervical plexus injury. The clinical picture was similar to other cases reported in the literature.

Acute Kidney Injury↗
PubMed1992

[Lesional pulmonary edema associated with tocolysis by hexoprenaline sulfate].

We report the case of a 24-year-old white female in need of tocolysis during the 25th week of pregnancy with i.v. hexoprenaline, while suffering from a discrete influenza-like syndrome with nasal discharge and sinusitis. A few hours later fulminant acute adult respiratory distress syndrome (ARDS) developed. ARDS is a rare (0.5-5%) but feared complication of tocolysis with beta-2 mimetic agents and magnesium sulfate. Its physiopathology is obscure, but iatrogenic hyperhydration and lesions of the alveolar-capillary membrane are suspected. In this case both factors were involved, but lesions of the alveolar-capillary membrane were predominant. A direct toxic effect of beta-2 mimetic agents on the alveolar-capillary membrane has not been demonstrated and other factors favoring pulmonary edema during tocolysis with beta-2 mimetic agents, especially infections, are discussed.

Adult↗
PubMed1992

Cellular clones and transgenic mice overexpressing copper-zinc superoxide dismutase: models for the study of free radical metabolism and aging.

Down's Syndrome (DS), the most frequent of congenital birth defects, results from the trisomy of the chromosome numbered 21 in all cells of affected patients. This disease is characterized by developmental anomalies, mental retardation and features of rapid aging, particularly in the brain where the occurrence of Alzheimer's disease (AD) is observed in all trisomy 21 patients over the age of 35. Elucidation of the biological mechanisms leading to brain aging in DS might provide new insight into the understanding of brain aging and AD in normal people. Copper-zinc superoxide dismutase (CuZnSOD) is one of the genes encoded by chromosome 21. As a consequence of gene dosage excess, CuZnSOD activity and protein are increased by 50% in all DS tissues. The level of CuZnSOD protein and mRNA is particularly high in hippocampal pyramidal neurons susceptible to degenerative processes in AD and in dopaminergic melanized-neurons vulnerable in Parkinson's disease. Increased CuZnSOD activity in these age-related neurodegenerative disorders might result in H2O2 overproduction and subsequently promote peroxidative damages within cells. Increase of seleno-dependent glutathione peroxidase (Se-GPx) in DS cells supports this concept. In order to test this hypothesis, cell and animal models of CuZnSOD overexpression have been designed. In cells transfected with the human CuZnSOD gene, and increased Se-GPx activity is observed, a situation which mimics DS. In mice transgenic for the human CuZnSOD, the expression pattern of the transgene in the brain is similar to that in humans, and we can observe an increased peroxidation in this tissue. These data, like others in the literature, support the hypothesis that excess CuZnSOD induces an imbalance in the regulation of oxygen-derived free radical production which might result in peroxidative brain damage and possibly contribute to accelerated aging and age-related neuropathology.

Aging↗
PubMed1992

Age-related changes in antioxidant enzymes and lipid peroxidation in brains of control and transgenic mice overexpressing copper-zinc superoxide dismutase.

The aim of our study was first to obtain a comprehensive profile of the brain antioxidant defense potential and peroxidative damage during aging. We investigated copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), seleno-dependent glutathione peroxidase (GSH-PX), glutathione reductase (GSSG-R) activities, endogenous and in vitro stimulated lipid peroxidation in 40 brains of control mice divided into 3 age groups: 2 months (young), 12 months (middle-aged) and 28 months (old). We found a positive correlation between age and activities of CuZnSOD (r = 0.47; P < 0.01) and GSH-PX (r = 0.72; P < 0.0001). CuZnSOD and GSH-PX activities are independently regulated during brain aging since temporal changes of these two enzymes do not correlate. No modification in MnSOD activity and basal lipid peroxidation was observed as a function of age. Nevertheless, stimulated lipid peroxidation was significantly higher at 12 months (6.53 +/- 0.71 mumole MDA/g tissue) than at 2 months (5.69 +/- 0.90) and significantly lower at 28 months (5.13 +/- 0.33) than at 12 months. Second, we used genetic manipulations to construct transgenic mice that specifically overexpress CuZnSOD to understand the role of CuZnSOD in neuronal aging. The human CuZnSOD transgene expression was stable during aging. The increased CuZnSOD activity in the brain (1.9-fold) of transgenic mice resulted in an enhanced rate of basal lipid peroxidation and in increased MnSOD activity in the 3 age groups. Other antioxidant enzymes did not exhibit modifications indicating the independence of the regulation between CuZnSOD and glutathione-related enzymes probably due to their different cellular localization in the brain.

Aging↗
PubMed1992

Age-correlated modifications of copper-zinc superoxide dismutase and glutathione-related enzyme activities in human erythrocytes.

To obtain a comprehensive profile of the erythrocyte antioxidant defense potential during aging, we investigated copper-zinc superoxide dismutase (CuZn-SOD), seleno-dependent glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-RD), and glutathione-S-transferase (GSH-S-T) activities in human erythrocytes from 167 apparently healthy subjects, ages one month to 63 years (102 females, 65 males). We found a negative correlation between age and activities of CuZn-SOD (r = 0.362, P less than 0.001), GSSG-RD (r = 0.549, P less than 0.001), and GSH-S-T (r = 0.575, P less than 0.001). In contrast, we found a positive correlation between age and GSH-Px activity (r = 0.401, P less than 0.001). To evaluate aging changes, we divided the subjects into five groups: Group 1 (newborn-age one year), Group 2 (1-11 years), Group 3 (11-25 years), Group 4 (25-40 years), and Group 5 (40-63 years). Significant age-related modifications in erythrocyte enzyme activities appeared in Group 3 for CuZn-SOD, GSSG-RD, and GSH-Px activity, whereas for GSH-S-T activity age-related modifications appeared in Group 2. We found no sex-related differences in erythrocyte CuZn-SOD, GSSG-RD, GSH-Px, and GSH-S-T activities.

Adult↗
PubMed1991

Neuronal-specific expression of human copper-zinc superoxide dismutase gene in transgenic mice: animal model of gene dosage effects in Down's syndrome.

It has been suggested that copper-zinc superoxide dismutase (CuZn SOD) increment, by accelerating hydrogen peroxide formation, might promote oxidative damage within trisomy 21 cells and might be involved in the various neurobiological abnormalities found in Down's syndrome such as premature aging and Alzheimer-type neurological lesions. In order to test this hypothesis, we have developed strains of transgenic mice carrying the human CuZn SOD gene. The human transgene expression resulted in increased CuZn SOD activity predominantly in the brain (1.93 fold). Immunohistochemical and in situ hybridization analysis of brain sections revealed that human CuZn SOD protein and mRNA was preferentially expressed in neurons, particularly in pyramidal cells of Ammon's horn and granule cells of gyrus dentate. The amount of thiobarbituric acid (TBA)-reactive material was significantly higher in transgenic brains compared to controls, strongly suggesting an increased level of peroxidation in vivo. These results support the notion that CuZn SOD gene dosage effect could play a role in the pathogenesis of rapid aging features in the brain of Down's syndrome patients.

Aging↗
PubMed1991

Increased SOD1 enzymatic activity and gene modifications in orangutans: evolutionary implications.

Superoxide dismutase CuZn (SOD1) enzymatic activity was measured in five orangutans (Pongo pygmaeus, PPY) and compared to that of man, chimpanzee, and gorilla. It was found to be increased by a factor of two in one orangutan (Ralfina) and by a factor of 1.5 in the four others. In situ hybridization of the SOD1 cDNA human probe showed a heterozygous intra-chromosomal rearrangement of pair PPY XXI, possibly an insertion, in Ralfina. Southern blotting showed that the SOD1 gene is modified in the three orangutans that were investigated and that a further modification of the 5'-end of the gene had occurred in Ralfina. The evolutionary implications of these observations are discussed.

Animals↗
PubMed1991

Neuronal localization of copper-zinc superoxide dismutase protein and mRNA within the human hippocampus from control and Alzheimer's disease brains.

The distribution of cells containing copper-zinc superoxide dismutase (CuZn SOD) protein and mRNA was studied in hippocampi from normal humans and patients with Alzheimer's disease (AD) by using immunohistochemistry and in situ hybridization. Using antisera against native and denatured CuZn SOD protein, we have determined that immunostaining was intense in pyramidal neurons of the cornu ammonis, in granule cells of the dentate gyrus and very weak in other cells. In the hippocampus of an Alzheimer's patient, successive immunostaining of the same tissue section by antiCuZn SOD and antipaired helical filaments antisera show that both normal and degenerating cells were labeled by the antiCuZn SOD antiserum. Thus, large pyramidal neurons which are susceptible to degenerative processes in AD have the property to contain high amount of CuZn SOD protein. In situ hybridization was performed on paraformaldehyde-fixed hippocampus sections of normal human brains and AD brains with a 35 S labeled DNA probe homologous to human CuZn SOD mRNA. Our results show that CuZn SOD transcripts are present at high abundance in pyramidal neurons of the CA1-CA4 fields, subiculum, and in granule cells of the dentate gyrus. This cellular distribution is similar to that obtained with the antiCuZn SOD antiserum. This might indicate that biochemical pathways leading to superoxide radicals generation are specially active in these neurons, requiring an active transcription of CuZn-SOD gene.

Aged↗
PubMed1991

Expression of human Cu-Zn superoxide dismutase gene in transgenic mice: model for gene dosage effect in Down syndrome.

It was suggested that increased Cu-Zn superoxide dismutase (SOD-1) might be involved in the various biological abnormalities found in Down's syndrome (DS) such as premature aging and Alzheimer-type neurological lesions. As a model system for testing this hypothesis we have developed two strains of transgenic mice carrying only one copy of the human SOD-1 gene. In the first strain (TG1), no expression has been found by northern blot analysis. The second strain (TG2) exhibited human SOD-1 mRNA and increased SOD-1 activity in the brain (1.93 fold), in the heart (1.69 fold), thymus (1.49 fold) and to a lesser extent in muscle (1.25 fold), liver (1.19 fold), kidney (1.18 fold), spleen (1.35 fold), lung (1.26 fold) and erythrocytes (1.09 fold). In this strain, increased SOD-1 activity in the brain did not induce modifications in the seleno-dependent glutathione peroxidase, glutathione reductase and glutathione S-transferase activities. In brain homogenates, we have focused our studies on Tau proteins which are known to be the major antigenic components of paired helical filaments (PHF), both in DS and Alzheimer's disease. Our results suggested that, in our experimental conditions, the overexpression of SOD-1 did not induce the modifications of Tau proteins similar to those seen during neurofibrillary degeneration.

Animals↗
PubMed1990

Down syndrome critical region around D21S55 on proximal 21q22.3.

We have analysed the DNA of 2 patients with many manifestations of Down syndrome and partial duplication of distinct regions of chromosome 21, respectively, q11.205----q22.300 and q22.300----qter (Rahmani et al.: Proceedings of the National Academy of Sciences of the United States of America 86:5958-5962, 1989). Assessment of the copy number of five chromosome 21 sequences (SOD1, D21S17, D21S55, ETS2, and D21S15) has shown that D21S55 was duplicated in both cases. The size of the common duplicated region can be estimated between 400 and 3,000 Kb, after the results of pulsed-field gel analysis and from the knowledge of regional mapping of the probes D21S17, D21S55, and ETS2. This region, located on the proximal part of 21q22.3, is postulated to contain genes the overexpression of which plays a major role in the pathogenesis of Down syndrome.

Child↗