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Papers by Constanza Contreras

Tiempo Historico, Aug 6, 2019

Constanza Rojas Contreras* David Har vey geógrafo británico publica originalmente esta obra en 20... more Constanza Rojas Contreras* David Har vey geógrafo británico publica originalmente esta obra en 2003 por Oxford University Press y luego es publicada en español por Ediciones Akal. En su trabajo presenta una reconstrucción del concepto Imperialismo, asociándolo netamente a lo que él llama Imperialismo Capitalista "que entiendo como una fusión contra-brought to you by CORE View metadata, citation and similar papers at core.ac.uk

Science Advances

The modulation of the host’s metabolism to protect tissue from damage induces tolerance to infect... more The modulation of the host’s metabolism to protect tissue from damage induces tolerance to infections increasing survival. Here, we examined the role of the thyroid hormones, key metabolic regulators, in the outcome of malaria. Hypothyroidism confers protection to experimental cerebral malaria by a disease tolerance mechanism. Hypothyroid mice display increased survival after infection with Plasmodium berghei ANKA, diminishing intracranial pressure and brain damage, without altering pathogen burden, blood-brain barrier disruption, or immune cell infiltration. This protection is reversed by treatment with a Sirtuin 1 inhibitor, while treatment of euthyroid mice with a Sirtuin 1 activator induces tolerance and reduces intracranial pressure and lethality. This indicates that thyroid hormones and Sirtuin 1 are previously unknown targets for cerebral malaria treatment, a major killer of children in endemic malaria areas.

Frontiers in Endocrinology

Reciprocal crosstalk between endocrine and immune systems has been well-documented both in physio... more Reciprocal crosstalk between endocrine and immune systems has been well-documented both in physiological and pathological conditions, although the connection between the immune system and thyroid hormones (THs) remains largely unclear. Inflammation and infection are two important processes modulated by the immune system, which have profound effects on both central and peripheral THs metabolism. Conversely, optimal levels of THs are necessary for the maintenance of immune function and response. Although some effects of THs are mediated by their binding to cell membrane integrin receptors, triggering a non-genomic response, most of the actions of these hormones involve their binding to specific nuclear thyroid receptors (TRs), which generate a genomic response by modulating the activity of a great variety of transcription factors. In this special review on THs role in health and disease, we highlight the relevance of these hormones in the molecular mechanisms linked to inflammation up...

Aging Cell

This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Journal of Endocrinology, 2019

Hypothyroidism is often associated with anemia and immunological disorders. Similar defects are f... more Hypothyroidism is often associated with anemia and immunological disorders. Similar defects are found in patients and in mice with a mutated dominant-negative thyroid hormone receptor α (TRα) and in knockout mice devoid of this receptor, suggesting that this isoform is responsible for the effects of the thyroid hormones in hematopoiesis. However, the hematological phenotype of mice lacking also TRβ has not yet been examined. We show here that TRα1/TRβ knockout female mice, lacking all known thyroid hormone receptors with capacity to bind thyroid hormones, do not have overt anemia and in contrast with hypothyroid mice do not present reduced Gata1 or Hif1 gene expression. Similar to that found in hypothyroidism or TRα deficiency during the juvenile period, the B-cell population is reduced in the spleen and bone marrow of ageing TRα1/TRβ knockout mice, suggesting that TRβ does not play a major role in B-cell development. However, splenic hypotrophy is more marked in hypothyroid mice th...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1998

Herein we report on the kinetic and protein expression of glucose-6-phosphate dehydrogenase (G6PD... more Herein we report on the kinetic and protein expression of glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase, and malic enzyme (ME) in the liver of the trout ( Oncorhynchus mykiss) during a long-term starvation-refeeding cycle. Starvation significantly depressed the activity of these enzymes by almost 60%, without changing the Michaelis constant. The time response to this nutritional stimulus increased with fish weight. The sharp decline in G6PDH and ME activities was due to a specific protein-repression phenomenon, as demonstrated by molecular and immunohistochemical analyses. Also, the dimeric banding pattern of liver G6PDH shifted from the fully reduced and partially oxidized forms, predominant in control, to a fully oxidized form, more sensitive to proteolytic inactivation. Refeeding caused opposite effects in both protein concentration and enzyme activities of about twice the control values in the first stages, later reaching the normal enzyme activity ...

Scientific reports, Jan 10, 2017

Map3k8 has been proposed as a useful target for the treatment of inflammatory diseases. We show h... more Map3k8 has been proposed as a useful target for the treatment of inflammatory diseases. We show here that during lipopolysaccharide-induced emergency granulopoiesis, Map3k8 deficiency strongly impairs the increase in circulating mature (Ly6G(high)CD11b(+)) and immature (Ly6G(low)CD11b(+)) neutrophils. After chimaeric bone marrow (BM) transplantation into recipient Map3k8(-/-) mice, lipopolysaccharide treatment did not increase circulating Ly6G(high)CD11b(+) cells and strongly decreased circulating Ly6G(low)CD11b(+) cells. Lipopolysaccharide-treated Map3k8(-/-) mice showed decreased production of granulocyte colony-stimulating factor (G-CSF), a key factor in neutrophil expansion, and a Map3k8 inhibitor blocked lipopolysaccharide-mediated G-CSF expression in endothelial cell lines. Ly6G(low)CD11b(+) BM cells from lipopolysaccharide-treated Map3k8(-/-) mice displayed impaired expression of CCAAT-enhancer-binding protein β, which depends on G-CSF for expression and is crucial for cell c...

Arteriosclerosis, Thrombosis, and Vascular Biology, 2016

Objective— Map3k8 (Cot/Tpl2) activates the MKK1/2-ERK1/2, MAPK pathway downstream from interleuki... more Objective— Map3k8 (Cot/Tpl2) activates the MKK1/2-ERK1/2, MAPK pathway downstream from interleukin-1R, tumor necrosis factor-αR, NOD-2R (nucleotide-binding oligomerization domain-like 2R), adiponectinR, and Toll-like receptors. Map3k8 plays a key role in innate and adaptive immunity and influences inflammatory processes by modulating the functions of different cell types. However, its role in atherogenesis remains unknown. In this study, we analyzed the role of this kinase in this pathology. Approach and Results— We show here that Map3k8 deficiency results in smaller numbers of Ly6C high CD11c low and Ly6C low CD11c high monocytes in ApoE − /− mice fed a high-fat diet (HFD). Map3k8 −/− ApoE −/− monocytes displayed high rates of apoptosis and reduced amounts of Nr4a1, a transcription factor known to modulate apoptosis in Ly6C low CD11c high monocytes. Map3k8 −/− ApoE −/− splenocytes and macrophages showed irregular patterns of cytokine and chemokine expression. Map3k8 deficiency alte...

Scientific Reports, 2016

Decreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic... more Decreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-κB and ERK, which play a key role in the response to inflammatory cytokines during sepsis. TR knockout mice showed down-regulation of hepatic inflammatory mediators, including interleukin 6 (IL-6) in response to LPS. Paradoxically, STAT3 and ERK activity were higher, suggesting that TRs could act as endogenous repressors of these pathways. Furthermore, hyperthyroidism increased cytokine production and mortality in response to LPS, despite decreasing hepatic STAT3 and ERK activity. This suggested that TRs could directly repress the response of the cells to inflammatory mediators. Indeed, we found that the thyroid hormone T3 suppresses IL-6 signalling in macrophages and hepatocarcinoma cells, inhibiting STAT3 activation. Consequently, the hormone strongly antagonizes IL-6-stimulated gene transcription, reducing STAT3 recruitment and histone acetylation at IL-6 target promoters. In conclusion, TRs are potent regulators of inflammatory responses and immune homeostasis during sepsis. Reduced responses to IL-6 should serve as a negative feedback mechanism for preventing deleterious effects of excessive hormone signaling during infections. Sepsis is characterized by an excessive inflammatory response to infection and is a major cause of mortality 1. Endotoxic shock, the most lethal form of sepsis, is caused by lipopolysaccharide (LPS), the main membrane component of Gram-negative bacteria. The liver plays a critical role in innate and adaptive immunity. In response to infection and inflammation, the liver synthetizes acute-phase proteins (APPs), which are key components of the immune response to infection 2,3. Innate immune responses triggered by LPS are mediated by Toll-like 4 receptors and involve the coordinated production of a large variety of inflammatory mediators, particularly Interleukin 6 (IL-6) and Tumor Necrosis α (TNFα) 4. Activation of Signal Transducer and Activator of Transcription 3 (STAT3) and Nuclear Factor kappa-Light-chain-enhancer of Activated B Cells (NF-κ B) by these cytokines plays a key role in the liver response to inflammation 3 , controlling the expression of a large number of genes 5. IL-6 leads to activation of STAT3 and/or Ras-mitogen-activated protein kinase (MAPK) signaling 6 , while TNFα induces the activation of NF-κ B 7. In response to IL-6, STAT3 is phosphorylated at tyrosine 705 8 , triggering dimerization and STAT translocation into the nucleus, where it binds to its consensus motifs in target genes, including APP genes 2,9. Activation of STAT3 also induces a negative feedback involving induction of phosphatases and Suppressor of Cytokine Signaling 3 (SOCS3) 10. In non-stimulated cells, cytoplasmic NF-κ B dimers are associated to inhibitory Iκ B proteins. In response to pro-inflammatory stimuli, such as TNFα , Iκ B is degraded, causing nuclear translocation and binding of NF-κ B to its cognate sequences 11. Some of the target genes are common for NF-κ B and STAT3 and both transcription factors are engaged in positive and negative cross-talk 2. The actions of the thyroid hormones (L-thyroxine, T4, and 3,3′ ,5-triiodo-L-thyronine, T3) are mediated by binding to nuclear receptors (TRα and TRβ). These receptors act as ligand-dependent transcription factors by binding, generally as heterodimers with the retinoid X receptor (RXR), to thyroid hormone response elements in target genes or by modulating the activity of other transcription factors or signalling pathways 12. There is

Proceedings of the National Academy of Sciences, 2016

Significance We show here that binding of the thyroid hormone triiodothyronine to the thyroid hor... more Significance We show here that binding of the thyroid hormone triiodothyronine to the thyroid hormone receptors (TRs) antagonizes TGF-β/SMAD (mothers against decapentaplegic)-dependent transcription. Transcriptionally inactive TR mutants that do not bind coactivators retained most of the capacity of suppressing transactivation by TGF-β/SMAD, whereas selective mutations in the DNA binding domain abolished this action. TGF-β is a major profibrogenic cytokine, and through this transcriptional mechanism, the hormone-bound TRs act as an endogenous barrier to moderate liver and skin fibrosis. These antagonistic actions on TGF-β/SMAD transcription suggest that TR ligands might be used to block the progression of fibrotic diseases. The natural hormone cannot be used clinically because of severe adverse effects, but novel synthetic ligands with fewer effects might be potentially developed and used.

Endocrine Abstracts, 2016

Molecular biology of the cell, Jan 5, 2015

Observations in thyroid patients and experimental animals show that the skin is an important targ... more Observations in thyroid patients and experimental animals show that the skin is an important target for the thyroid hormones. We have previously shown that deletion in mice of the thyroid hormone nuclear receptors TRα1 and TRβ (the main thyroid hormone binding isoforms), results in impaired epidermal proliferation, hair growth and wound healing. Stem cells located at the bulges of the hair follicles are responsible for hair cycling and contribute to the regeneration of the new epidermis after wounding. Therefore a reduction in the number or function of the bulge stem cells could be responsible for this phenotype. Bulge cells show increased levels of epigenetic repressive marks, can retain bromodeoxyuridine labeling for a long time and have colony formation efficiency (CFE) in vitro. Here, we demonstrate that mice lacking TRs do not have a decrease of the bulge stem cell population. Rather, they show an increase of label-retaining cells (LRCs) in the bulges and enhanced CFE in vitro....

Cellular Endocrinology in Health and Disease, 2014

The thyroid hormone receptors, TRα and TRβ, are ligand-dependent transcription factors that regul... more The thyroid hormone receptors, TRα and TRβ, are ligand-dependent transcription factors that regulate gene expression by recruitment of coactivators and corepressors. These receptors play an important role in normal and malignant cell proliferation. Particularly, we have shown that TRs antagonize ras-dependent proliferation, transformation and tumorigenesis in fibroblasts. Furthermore, expression of TRβ in human cancer cells retards tumor growth and inhibits invasiveness, extravasation and metastasis formation in euthyroid nude mice. When cells are inoculated into hypothyroid hosts, tumor growth is retarded, but tumors that do grow are more invasive and metastatic growth is enhanced. Increased malignancy of skin tumors is found in mice lacking TRs, further demonstrating the role of these receptors as inhibitors of tumor progression and suggesting that they represent a potential therapeutic target in cancer. TRs have a dual effect on proliferation, because they are required for proliferation of normal hepatocytes or keratinocytes, while acting as inhibitors of tumor progression.

PLoS ONE, 2014

Both clinical and experimental observations show that the skin is affected by the thyroidal statu... more Both clinical and experimental observations show that the skin is affected by the thyroidal status. In hypothyroid patients the epidermis is thin and alopecia is common, indicating that thyroidal status might influence not only skin proliferation but also hair growth. We demonstrate here that the thyroid hormone receptors (TRs) mediate these effects of the thyroid hormones on the skin. Mice lacking TRa1 and TRb (the main thyroid hormone binding isoforms) display impaired hair cycling associated to a decrease in follicular hair cell proliferation. This was also observed in hypothyroid mice, indicating the important role of the hormone-bound receptors in hair growth. In contrast, the individual deletion of either TRa1 or TRb did not impair hair cycling, revealing an overlapping or compensatory role of the receptors in follicular cell proliferation. In support of the role of the receptors in hair growth, TRa1/TRb-deficient mice developed alopecia after serial depilation. These mice also presented a wound-healing defect, with retarded re-epithelialization and wound gaping, associated to impaired keratinocyte proliferation. These results reinforce the idea that the thyroid hormone nuclear receptors play an important role on skin homeostasis and suggest that they could be targets for the treatment of cutaneous pathologies.

PLoS ONE, 2011

Background: Retinoids play an important role in skin homeostasis and when administered topically ... more Background: Retinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans also influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs) are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA) in mice. Methodology/Principal findings: We have compared the epidermal response of mice lacking the thyroid hormone receptor binding isoforms TRa1 and TRb to retinoids and TPA. Reduced hyperplasia and a decreased number of proliferating cells in the basal layer in response to 9-cis-RA and TPA were found in the epidermis of TR-deficient mice. Nuclear levels of proteins important for cell proliferation were altered, and expression of keratins 5 and 6 was also reduced, concomitantly with the decreased number of epidermal cell layers. In control mice the retinoid (but not TPA) induced parakeratosis and diminished expression of keratin 10 and loricrin, markers of early and terminal epidermal differentiation, respectively. This reduction was more accentuated in the TR deficient animals, whereas they did not present parakeratosis. Therefore, TRs modulate both the proliferative response to retinoids and their inhibitory effects on skin differentiation. Reduced proliferation, which was reversed upon thyroxine treatment, was also found in hypothyroid mice, demonstrating that thyroid hormone binding to TRs is required for the normal response to retinoids. In addition, the mRNA levels of the pro-inflammatory cytokines TNFa and IL-6 and the chemotactic proteins S1008A and S1008B were significantly elevated in the skin of TR knockout mice after TPA or 9-cis-RA treatment and immune cell infiltration was also enhanced. Conclusions/significance: Since retinoids are commonly used for the treatment of skin disorders, these results demonstrating that TRs regulate skin proliferation, differentiation and inflammation in response to these compounds could have not only physiological but also therapeutic implications.

Neurochemistry International, 2012

We have previously shown that the thyroid hormone triiodothyronine negatively regulates the trans... more We have previously shown that the thyroid hormone triiodothyronine negatively regulates the transcriptional activity of the b-amyloid precursor protein gene (APP) in cultured murine neuroblastoma cells, by a mechanism that involves binding of the nuclear thyroid hormone receptor (TR) to DNA sequences located within the first exon of the gene. In this report we present results showing that the thyroid hormones also repress the expression of APP in human neuroblastoma cells and in primary cultures of rat neurons. In addition, and in agreement with the results obtained in cultured cells, APP messenger RNA and protein levels are significantly higher in the brain of hypothyroid rats and mice, and also in Alzheimer-related brain regions dissected from KO mice lacking TRs. These results show that binding of the thyroid hormones to their nuclear receptors mediate their repressive effect on APP gene expression in vivo.

The Journal of Membrane Biology, 2005

Ion channels are being associated with a growing number of diseases including cancer. This overvi... more Ion channels are being associated with a growing number of diseases including cancer. This overview summarizes data on voltage-gated potassium channels (VGKCs) that exhibit oncogenic properties: ether-à-go-go type 1 (Eag1). Normally, Eag1 is expressed almost exclusively in tissue of neural origin, but its ectopic expression leads to uncontrolled proliferation, while inhibition of Eag1 expression produces a concomitant reduction in proliferation. Specific monoclonal antibodies against Eag1 recognize an epitope in over 80% of human tumors of diverse origins, endowing it with diagnostic and therapeutic potential. Eag1 also possesses unique electrophysiological properties that simplify its identification. This is particularly important, as specific blockers of Eag1 currents are not available. Molecular imaging of Eag1 in live tumor models has been accomplished with dye-tagged antibodies using 3-D imaging techniques in the near-infrared spectral range.

Journal of Biological Chemistry, 2011

We have analyzed the role of the thyroid hormone receptors (TRs) in epidermal homeostasis. Reduce... more We have analyzed the role of the thyroid hormone receptors (TRs) in epidermal homeostasis. Reduced keratinocyte proliferation is found in interfollicular epidermis of mice lacking the thyroid hormone binding isoforms TR␣1 and TR␤ (KO mice). Similar results were obtained in hypothyroid animals, showing the important role of the liganded TRs in epidermal proliferation. In addition, KO and hypothyroid animals display decreased hyperplasia in response to 12-O-tetradecanolyphorbol-13-acetate. Both receptor isoforms play overlapping functional roles in the skin because mice lacking individually TR␣1 or TR␤ also present a proliferative defect but not as marked as that found in double KO mice. Defective proliferation in KO mice is associated with reduction of cyclin D1 expression and up-regulation of the cyclin-dependent kinase inhibitors p19 and p27. Paradoxically, ERK and AKT activity and expression of downstream targets, such as AP-1 components, are increased in KO mice. Increased p65/NF-B and STAT3 phosphorylation and, as a consequence, augmented expression of chemokines and proinflammatory cytokines is also found in these animals. These results show that thyroid hormones and their receptors are important mediators of skin proliferation and demonstrate that TRs act as endogenous inhibitors of skin inflammation, most likely due to interference with AP-1, NF-B, and STAT3 activation.

Journal of Biological Chemistry, 2008

Ether-á-go-go-1 (Eag1) is a CNS-localized voltage-gated potassium channel that is found ectopical... more Ether-á-go-go-1 (Eag1) is a CNS-localized voltage-gated potassium channel that is found ectopically expressed in a majority of extracranial solid tumors. While circumstantial evidence linking Eag1 to tumor biology has been well established, the mechanisms by which the channel contributes to tumor progression remain elusive. In this study, we have used in vivo and in vitro techniques to identify a candidate mechanism. A mutation that eliminates ion permeation fails to completely abolish xenograft tumor formation by transfected cells, indicating that Eag1 contributes to tumor progression independently of its primary function as an ion channel. Our data suggest that Eag1 interferes with the cellular mechanism for maintaining oxygen homeostasis, increasing HIF-1 activity, and thereby VEGF secretion and tumor vascularization.