Lourdes Domínguez-Gerpe

University of Santiago de Compostela, Santiago de Compostela, Galicia, Spain

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Publications (17)43.62 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Application (1)H NMR spectroscopy techniques to the ex vivo study of thymus of 0.5-24 month-old C57BL/6 mice allowed the identification, the quantification and the estimation of some structural parameters (length and unsaturation) of various lipids in the thymus and their changes with age. An initial decrease of lipid metabolites in the thymus from 0.5 to 1 month of age was followed by large raises on further ageing, with 14, 8, and 4 fold increases for the total lipid content, fatty acids and glycerides, respectively, which correlated positively with age and negatively with thymus involution. The estimated average number of methylene groups per lipid chain essentially doubled its value from approximately 4-5 for the youngest mice to around 8 for the elderly, while the values obtained for the average number of double bonds per chain decreased with age from about 1-0.9 at 0.5/1 months of age to 0.6-0.7 for 18/24 months-old mice. The combination of NMR and histological data allowed studying the age-associated changes of the contribution of adipose- derived lipids to the total lipid content of the thymus and the amount of adipose tissue infiltrating the thymus. Both parameters initially showed a decrease from 0.5 months of age to (the adipose-free thymus at) 1 month of age. Afterwards, a continuous increase was observed on ageing: at 2 months about 55% of the lipids in the thymus were adipose-derived, while at 24 months they amounted to as much as about 95% of the total lipid content; for the same age-period, the estimated minimum adipose lipid content in the thymus changed from about 0.26% to 4.5%.
    Current Aging Science 02/2011; 4(1):57-69.
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    Lourdes Domínguez-Gerpe, David Araújo-Vilar
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    ABSTRACT: Ageing is thought to be a polygenic and stochastic process in which multiple mechanisms operate at the same time. At the level of the individual organism ageing is associated with a progressive deterioration of health and quality of life, sharing common features such as: alopecia and grey hair, loss of audition, macular degeneration, neurodegeneration, cardiovascular diseases, osteoporosis, cataract formation, type-2 diabetes, lipodystrophies; a generally increased susceptibility to infection, autoimmune disorders and diseases such as cancer; and an impaired ability to cope with stress. Recent studies of mechanisms involved in the ageing process are contributing to the identification of genes involved in longevity. Monogenic heritable disorders causing premature ageing, and animal models have contributed to the understanding of some of the characteristic organism-level features associated with human ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are the best characterized human disorders. Werner syndrome patients have a median life expectancy of 47 years with clinical conditions from the second decade of life. Hutchinson-Gilford progeria syndrome patients die at a median age of 11-13 years with clinical conditions appearing soon after birth. In both syndromes, alterations in specific genes have been identified, with mutations in the WRN and LMNA genes respectively being the most closely associated with each syndrome. Results from molecular studies strongly suggest an increase in DNA damage and cell senescence as the underlying mechanism of pathological premature ageing in these two human syndromes. The same general mechanism has also been observed in human cells undergoing the normal ageing process. In the present article the molecular mechanisms currently proposed for explaining these two syndromes, which may also partly explain the normal ageing process, are reviewed.
    Current Aging Science 12/2008; 1(3):202-12.
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    ABSTRACT: Type 2 familial partial lipodystrophy (FPLD2) is characterised by loss of fat in the limbs and buttocks and results from mutations in the LMNA gene. To evaluate the role of several genes involved in adipogenesis in order to better understand the underlying mechanisms of regional loss of subcutaneous adipose tissue (scAT) in patients with FPLD2. In total, 7 patients with FPLD2 and 10 healthy control participants were studied. A minimal model was used to calculate the insulin sensitivity (IS). scAT was obtained from abdomen and thigh by biopsy. Relative gene expression was quantified by real-time reverse transcription PCR in a thermal cycler. Prelamin A western blot analysis was carried out on scAT and prelamin A nuclear localisation was determined using immunofluorescence. Adipocyte nuclei were examined by electron microscopy. Patients with FPLD2 were found to have significantly lower IS. The expression of LMNA was similar in both groups. The expression of PPARG2, RB1, CCND3 and LPL in thigh but not in abdomen scAT was significantly reduced (67%, 25%, 38% and 66% respectively) in patients with FPLD2. Significantly higher levels of prelamin A were found in peripheral scAT of patients with FPLD2. Defects in the peripheral heterochromatin and a nuclear fibrous dense lamina were present in the adipocytes of patients with FPLD2. In FPLD2 participants, prelamin A accumulation in peripheral scAT is associated with a reduced expression of several genes involved in adipogenesis, which could perturb the balance between proliferation and differentiation in adipocytes, leading to less efficient tissue regeneration.
    Journal of Medical Genetics 10/2008; 46(1):40-8. · 5.70 Impact Factor
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    ABSTRACT: Mutations in SLC16A2, the gene encoding the thyroid hormone (TH)-specific transporter monocarboxylate transporter 8 (MCT8), result in a thyroid phenotype and severe mental retardation caused by neuronal TH deficiency. These mutational effects raise the question of whether polymorphic variation in SLC16A2 may also be associated with differences in serum levels of TH and/or TSH. This is the first major study of the frequency of the SLC16A2 rs6647476 single nucleotide polymorphism (SNP) (amino acid change Ser107Pro). We also studied the relationships of SLC16A2 genetic variants with serum levels of TSH, T4 and T3, with their mRNA expression and with expression of the TH-responsive genes ZAKI-4 and BTEB in white blood cells. Experiments in cultured fibroblasts were carried out to ascertain the dynamics of the T3 response. A total of 276 men were studied. Genotyping of the S107P SNP was carried out using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP); serum hormone levels were determined by chemiluminescence; expression of mRNA was quantified by real-time PCR. The SLC16A2 S107P SNP was found in 36% of Galician males. With the present sample size we did not find any association of this polymorphism with variability in serum levels of TSH, free T4 (fT4) or fT3, or with basal expression of mRNA for SLC16A2 or the two TH-responsive genes ZAKI-4 and BTEB, either in white blood cells or in cultured human fibroblasts from either Ser107 or Pro107 genotypes under T3 stimulation. The S107P change in MCT8 is frequent in the male population in Galicia. In the population studied in this report an association with a thyroid phenotype was not demonstrated, even though the S107P SNP causes an important amino acid change.
    Clinical Endocrinology 09/2008; 70(4):636-43. · 3.40 Impact Factor
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    ABSTRACT: Lipodystrophies are a heterogeneous group of diseases characterized by abnormal fat distribution. Familial partial lipodystrophy 2 (FPLD2) is due to mutations in the LMNA gene. Previous studies have suggested that LMNA mutations 5' to the nuclear localization signal (NLS) are more likely to underlie laminopathies with cardiac or skeletal muscle involvement, while mutations 3' to the NLS are more likely to underlie lipodystrophy and progeroid syndromes. To study the clinical and molecular features of a subject with FPLD. We carried out mutational analysis of LMNA gene in a woman with FPLD phenotype and in her relatives. Insulin resistance was evaluated by minimal model. Body composition was evaluated by dual-energy X-ray absorptiometry (DEXA). Echocardiography was done in affected subjects. 3T3-L1 preadipocytes were transfected with wild-type or mutant prelamin A constructs. In transfected cells, lamin A was detected using a Cy3-conjugated monoclonal anti-FLAG antibody. The patient showed atypical fat distribution, insulin resistance, severe aortic stenosis and hypertrophic cardiomyopathy. She has an affected 11-year-old son, not yet lipodystrophic but with an incipient aortic disease. LMNA sequencing showed that mother and son were both heterozygous for a novel c.1772G > T missense mutation in exon 11, which causes the substitution of the cysteine at residue 591 by a phenylalanine (C591F). In mouse preadipocytes transfected with the mutant human LMNA gene, the mutant lamin A isoform was mislocated in the nucleus. This patient shows a novel clinical form of FPLD2, due to a mutation affecting lamin A only, with cardiac involvement.
    Clinical Endocrinology 07/2008; 69(1):61-8. · 3.40 Impact Factor
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    ABSTRACT: Septic shock is one of various causes of nonthyroidal illness syndrome (NTIS). In humans, the molecular mechanisms involved in NTIS are mostly unknown. The aim of this study was to investigate, in patients with NTIS secondary to septic shock, changes in the expression of genes involved in the actions of thyroid hormones and in the activity of deiodinase enzymes, in two tissues important for protein and energy metabolism, skeletal muscle (SM) and subcutaneous adipose tissue (SAT). Hospitalized patients were divided into a control and a septic shock NTIS group. Serum collection for biochemical measurements, and SM and SAT biopsies for mRNA expression analysis of thyroid hormone receptors (THRB1, THRA1), retinoid X receptors (RXRA, RXRB, RXRG), nuclear receptor corepressor (NCOR1), silencing mediator of retinoid and thyroid hormone receptor (SMRT), steroid receptor coactivator (SRC1), type 1 and 2 deiodinases (D1, D2), monocarboxylate transporter 8 (MCT8), SECIS binding protein 2 (SBP2) and uncoupling protein 3 (UCP3) as well as D1, D2 and D3 enzyme activity measurements. The NTIS group had lower serum TSH, and free T3 and higher rT3 than controls. D1 and D3 were detected in SAT, with no differences found between the two groups; SM had very low D2 activity and again no differences were found between groups; D3 activity in SM was higher in NTIS than controls. SM expression of THRB1, RXRG and D2 was lower and RXRA higher in NTIS than controls. SAT from NTIS patients had lower MCT8, THRB1, THRA1, RXRG and SMRT, and higher UCP3 expression than controls. In patients with septic shock NTIS tissue responses are orientated to decrease production and increase degradation (muscle) or decrease uptake (adipose tissue) of T3, as well as to decrease thyroid hormone actions.
    Clinical Endocrinology 06/2008; 68(5):821-7. · 3.40 Impact Factor
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    ABSTRACT: We studied two families from Galicia (northwest Spain) with Pendred syndrome (PS) and unusual thyroid phenotypes. In family A, the proposita had a large goiter and hypothyroxinemia but normal TSH and free T3 (FT3). In family B, some affected members showed deafness but not goiter. Our objective was to identify the mutations causing PS and molecular mechanisms underlying the thyroid phenotypes. Interventions included extraction of DNA and of thyroid tissue. Propositi and 10 members of the two families participated in the study. Main outcome measures included SLC26A4 gene analysis, deiodinase activities in thyroid tissue, and c.416-1G-->A effects on SLC26A4 splicing. In addition, a primary PS thyrocyte culture, T-PS2, was obtained from propositus B and compared with another culture of normal human thyrocytes, NT, by Western blotting, confocal microscopy, and iodine uptake kinetics. Proposita A was heterozygous for c.578C-->T and c.279delT, presented with goiter, and had normal TSH and FT3 but low FT4 attributable to high type 1 and type 2 iodothyronine deiodinase activities in the goiter. Propositus B bore c.279delT and a novel mutation c.416-1G-->A; some deaf relatives were homozygous for c.416-1G-->A but did not present goiter. The c.279delT mutation was associated with identical haplotype in the two families. T-PS2 showed truncated pendrin retained intracellularly and high iodine uptake with low efflux leading to iodine retention. c.279delT is a founder mutation in Galicia. Proposita A adapted to poor organification by increasing deiodinase activities in the goiter, avoiding hypothyroidism. Lack of goiter in subjects homozygous for c.416-1G-->A was due to incomplete penetrance allowing synthesis of some wild-type pendrin. Intracellular iodine retention, as seen in T-PS2, could play a role in thyroid alterations in PS.
    Journal of Clinical Endocrinology &amp Metabolism 02/2008; 93(1):267-77. · 6.43 Impact Factor
  • Lourdes Domínguez-Gerpe
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    ABSTRACT: This study investigated some effects of weaning and immobilization stress in C57BL/6 mice aged 22-68 days, i.e., over a period including activation of the hypothalamus-pituitary-adrenal (HPA) axis and puberty. Specifically, the study evaluated the evolution, over the referred age interval, of a set of variables (body, thymus, spleen and axillary lymph nodes weights, the proportion of lymphoid cells in the bone marrow, the relative chemoattraction capacity of thymic supernatants for lymphoid cells and the migratory capacity of bone marrow lymphoid cells) in either weaned mice or weaned mice subjected to immobilization stress, compared to "non-stressed" unweaned mice. Cyclic patterns, observed for most variables in unweaned mice, were especially pronounced in two cases: the relative migratory capacity of bone marrow lymphoid cells collected at different ages towards neonatal thymic supernatant, and the relative chemoattraction capacity of thymic supernatants of different ages as tested against a sample of bone marrow lymphoid cells from mice aged 35 days. Weaning stress tended to intensify the involution stages of the cycles in thymus, spleen and lymph node weight, but increased the relative proportion of lymphoid cells in the bone marrow cell population. Both types of exogenous stress tended to affect cycle phase, i.e., cycle peaks and troughs were shifted in time. Correlations were observed between patterns seen in the thymus and bone marrow, suggesting the existence of an autoregulatory feedback loop governing pre-T cell migration and bone marrow/thymus homeostasis. These results also suggest that exogenous stress acts as a non-programmed regulator, modulating the naturally programmed cyclic patterns.
    Immunobiology 02/2007; 212(8):613-27. · 2.81 Impact Factor
  • Lourdes Domínguez-Gerpe, Manuel Rey-Méndez
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    ABSTRACT: During embryogenesis and in the early stages of life, the thymus is a crucial organ for the generation of the T cell repertoire. T cells are generated from hematopoietic stem cells already differentiated to precursor T cells in the bone marrow. These cells enter the thymus guided by chemotactic factors secreted by this organ. The complex maturation process takes place that ensures self-tolerance and homeostasis. Thymocytes that show autoreactivity do not leave the thymus, but rather die by apoptosis. The final percentage of mature T cells that survive to migrate from the thymus to the periphery is very low: at most 5%, under optimal conditions. The highest migration occurs in childhood and adulthood, at least in mice and humans; however, it declines throughout life and is minimal in the elderly. Under normal circumstances, the thymus commences involution soon after birth, and this involution correlates with the capacity to export mature T cells to the periphery. Hormones, cytokines, and neurotransmitters all play a role in this age-associated process, but the reasons for and mechanisms of this involution remain unknown. Apart from physiological conditions that change throughout life and govern age-related thymus evolution, random states and events provoked by intrinsic or extrinsic factors can induce either thymus involution, as in reversible transient thymic hypoplasias, or thymic hyperplasias. The age-associated involution, unlike transient involutions, follows a regular pattern for all individuals, though there are clear differences between the sexes. Nevertheless, even the age-associated involution seems to be reversible, raising the possibility of therapeutic strategies aimed at enhancing thymus function in the elderly.
    Microscopy Research and Technique 01/2004; 62(6):464-76. · 1.59 Impact Factor
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    L Domínguez-Gerpe, M Rey-Méndez
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    ABSTRACT: The immune system is particularly sensitive to stress. Although acute stress generally has positive effects, chronic stress typically provokes immunosuppression. The elucidation of the mechanisms involved in immunosuppression are of interest for the design of therapeutic approaches to avoid the appearance of stress disorders. This study aimed to investigate chronic stress-induced alterations on lymphocyte subset distribution and percentages. The experiments were performed with C57BL/6 mice subjected to chronic immobilization stress. Stress caused a marked increase in apoptosis inside the thymus, and a reduction in the total number of thymocytes. Furthermore, the proportion of immature thymocytes declined significantly suggesting that the increased apoptosis mainly affected cells of immature phenotype. In blood, the total number of lymphocytes diminished but not all lymphocyte populations showed the same tendency: while the relative proportion of B cells declined slightly, the relative proportion of circulating CD3+ cells, and particularly some T cell subsets showing an immature phenotype (CD3+PNA+), increased under stress. The spleen and lymph nodes show a marked reduction in cellularity, but the relative proportion of T cells increased, while no change or only a slight reduction was observed in the relative proportion of B cells. Similarly, the relative proportion of T cells increased in bone marrow. Detailed data on the alterations of lymphoid cell subsets occurring under immobilization stress, both in the bloodstream and in different lymphoid tissues, are obtained. In general, T cells are more affected than B cells and, in particular, a marked increase in the percentage of a subset of circulating PNA+CD3+ T cells is observed.
    BMC Immunology 02/2001; 2:7. · 2.61 Impact Factor
  • L Domínguez-Gerpe, M Rey-Méndez
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    ABSTRACT: Male C57BL/6 mice were stressed by immobilization for 1, 2, 3, or 5 h per day for 14 days, with subsequent assessment of (a) thymic involution, (b) in vitro migration of stressed mice bone marrow cells toward thymocyte culture supernatants from neonates and from control or stressed mice, (c) composition of the bone marrow cell population, and (d) in vitro migration of normal bone marrow cells toward stressed mice thymocyte culture supernatants. The results obtained support the view that the reduced repopulation of thymus by precursor T cells contributes to thymus involution associated with stress. It is further shown that this effect could be owing to a reduction in the number of precursor T cells in the bone marrow, and/or to a diminished production of precursor T-cell chemoattractants.
    Scandinavian Journal of Immunology 12/2000; 52(5):470-6. · 2.20 Impact Factor
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    L. Dominguez-Gerpe, M. Rey-Mendez
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    ABSTRACT: Male C57BL/6 mice were stressed by immobilization for 1, 2, 3, or 5 h per day for 14 days, with subsequent assessment of (a) thymic involution, (b) in vitro migration of stressed mice bone marrow cells toward thymocyte culture supernatants from neonates and from control or stressed mice, (c) composition of the bone marrow cell population, and (d) in vitro migration of normal bone marrow cells toward stressed mice thymocyte culture supernatants. The results obtained support the view that the reduced repopulation of thymus by precursor T cells contributes to thymus involution associated with stress. It is further shown that this effect could be owing to a reduction in the number of precursor T cells in the bone marrow, and/or to a diminished production of precursor T-cell chemoattractants.
    Scandinavian Journal of Immunology 11/2000; 52(5):470-476. · 2.20 Impact Factor
  • L Domínguez-Gerpe, M Rey-Méndez
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    ABSTRACT: C57BL/6 and Balb C male and female mice of various ages were stressed by immobilization for 1 h/day (1, 2, 3, 5, 8, 11 or 14 consecutive days). The animals were then killed for determination of total body weight and the weights of the thymus, spleen and axillary lymph nodes. In addition, the total number of cells in the thymus and the proportion of lymphoid cells in the bone marrow cell population was defined. The effects of stress were modulated by age, sex and strain. Stress-induced involution of the thymus was generally more pronounced in older animals, while for the spleen was the opposite. Involution of the thymus was higher in males than in females, but there were no marked differences between the sexes in the response of the spleen. In general C57BL/6 mice were more sensitive to stress than Balb C mice. However, for the involution induced by stress on lymph nodes there were not a clear trend with age, sex or strain. In male and female mice of all ages and both strains, stress led to statistically significant reductions in the absolute number of cells inside the thymus and spleen and in the proportion of lymphoid cells in the bone marrow.
    Mechanisms of Ageing and Development 09/1998; 104(2):195-205. · 3.26 Impact Factor
  • L Domínguez-Gerpe, M Rey-Méndez
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    ABSTRACT: The present work describes the murine immune tissue evolution with age with special emphasis on the bone marrow. To that effect we monitored the weights of the thymus, spleen and axillary lymph nodes over the first year of life in C57BL/6 male and female mice. In addition, we monitored the relative proportions of erythroid, lymphoid and myeloid cells in the bone marrow, and performed in vitro migration assays of bone marrow cells to thymic supernatants, with the aim of determining whether the migration of such cells or the thymic attractive capacity are affected by age. Before puberty, a remarkable decline in the relative weight of the thymus, spleen and lymph nodes was observed; after that stage, however, only the thymus showed an involution. The proportion of myeloid cells in the bone marrow showed an increase with age. Furthermore, the migration of myeloid cells to thymic supernatants increased with age and paralleled the time-course of the myeloid cell increase found in the bone marrow. More interestingly, the proportion of lymphoid cells to total bone marrow cells showed a clear decline with age. The time-course of this decline closely paralleled that of thymus weight, suggesting that the involution of the thymus may be related to changes in the cell composition of the bone marrow.
    Immunological investigations 06/1998; 27(3):153-65. · 1.73 Impact Factor
  • Lourdes Domínguez-Gerpe, Manuel Rey-Méndez
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    ABSTRACT: Groups of 35-day-old male C57BL/6 mice were stressed 1 hour per day by immobilization for 1, 2, 3, 5, 8, 11 or 14 consecutive days. Control groups were left undisturbed. The animals were then killed and body weight and the weights of the thymus, spleen and axillary lymph nodes determined. Chronic immobilization stress caused involution of the thymus, spleen and lymph nodes to an extent depending on the number of days of stress. The thymus showed the fastest response: thymus weight was significantly lower in stressed animals than in controls by the third day of stress while significant effects on spleen and lymph node weight were not observed until day 5. Fast recovery of lymphoid organ weight was observed after the stress period. The thymus recovered most quickly: control values were re-attained approximately 8 days after cessation of stress, and indeed by day 20 thymus weight was about 12% higher than in normal animals. The spleen and lymph nodes recuperated weight more slowly, re-attaining control values after about 20 days.
    Life Sciences 02/1997; 61(10):1019-27. · 2.56 Impact Factor
  • L Domínguez-Gerpe, I Lefkovits
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    ABSTRACT: B and T cells present in the spleen and other sites of the immune system play a crucial role in the protection of individuals by mounting a specific primary and secondary immune response. Disturbances in their signaling and functioning could lead to a deterioration of the defense mechanisms and thereby lead to infections, pathologies or diseases. In this work, we studied the effects of stress on the protein synthesis and metabolism of mouse splenocytes. The study was done by radiolabeling the entire mouse with 35S-methionine (in vivo procedure) or by culturing spleen cells under various conditions of stimulation in the presence of 35S-methionine (in vitro labeling). The stimulus was lipopolysaccharide (LPS), LPS + interleukin-4 (IL-4) and concanavalin A (on A). Samples from immobilization stressed and control animals were studied in parallel. The results showed minimum alterations due to stress on B cells, though a small decrease in proliferative capacity was observed. In contrast, T cells are profoundly affected by stress. More than 100 new proteins are expressed on 2D-gel patterns of T cells from stressed animals as compared with controls, some of which could be implicated in different signaling, or could have appeared because of an alteration in a pathway of synthesis, or even as a consequence of a change in the composition of T cell populations induced by stress.
    Immunology Letters 10/1996; 52(2-3):109-23. · 2.34 Impact Factor
  • Inmunología. 01/1991; 10:18.