Olga Pernía - Academia.edu (original) (raw)

Papers by Olga Pernía

Neuroendocrinology, 2016

Obesity is associated with increased fever and sickness behavior in response to infection. The hy... more Obesity is associated with increased fever and sickness behavior in response to infection. The hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the reaction to immune stimuli. Bacterial infection, or bacterial lipopolysaccharide (LPS), induces the expression of peripheral cytokines that stimulate the hypothalamus and the hippocampus and activate the HPA axis. In this study, we explored whether the hypothalamic and hippocampal responses to infection are altered during the development of diet-induced obesity. Male mice were exposed to a high-fat diet (HFD) or a low-fat diet (LFD) for 15 days. They were then administered a single intraperitoneal injection of bacterial LPS or vehicle and sacrificed 24 h later. LPS increased circulating levels of insulin and leptin, but only in LFD animals. LPS induced a significant decrease in hypothalamic corticotrophin-releasing hormone and glucocorticoid receptor mRNA levels in LFD animals but exerted the opposite effect in HFD-fed mice....

Cancer Research, 2015

Introduction: The radioresistance of non-small cell lung cancer cells is a less explored and poor... more Introduction: The radioresistance of non-small cell lung cancer cells is a less explored and poorly defined field compared with drug resistance. Our group has previously reported that the loss of IGFBP-3 expression by promoter hypermethylation results in reduced tumor cell sensitivity to cisplatin in NSCLC, however the role of the IGF-I/IGBP-3 axe on radiosensitivity in cancer is controversial because of the differing results when various tumor types are evaluated. The purpose of the present study is to investigate the role of radiotherapy on the biology of IGFBP-3 promoter methylation and its clinical value as a potential tool for deciding on a concomitant radiotherapy after NSCLC surgery. Experimental procedure: In the present study we have worked with 5 human cancer cell lines, 40 NSCLC surgical sample patients with known response to CDDP and radiotherapy treatments and 10 control samples with non neoplastic pathology. We have study the relationship between a dose-response radiot...

Journal of Endocrinology, 2008

It has been previously reported that the neuroprotective hormone oestradiol reduces microglia inf... more It has been previously reported that the neuroprotective hormone oestradiol reduces microglia inflammatory activity. The objective of this study was to test whether two selective oestrogen receptor modulators, tamoxifen and raloxifene, modulate in vivo the activation of microglia induced by the peripheral administration of lipopolysaccharide (LPS). Activation of microglia was assessed in the white matter of the cerebellum using immunoreactivity for major histocompatability complex-II. Oestradiol, tamoxifen and raloxifene decreased microglia activation induced by LPS in male and ovariectomized female rats, although the doses of oestradiol that were effective in decreasing microglia reactivity were not the same in both sexes. Tamoxifen reduced microglia activation in all experimental groups at all doses tested (0 . 5-2 mg/kg b.w.) while raloxifene lost its anti-inflammatory activity at the higher dose tested (2 mg/kg b.w). In addition, raloxifene had per se a moderate pro-inflammatory activity in the brain of control female rats and its antiinflammatory activity was partially impaired in female animals after 1 month of deprivation of ovarian hormones. Spots of oestrogen receptor (ER)-a immunoreactivity were detected in the soma and cell processes of microglia. Treatment with LPS, oestradiol or tamoxifen induced an increase of ER-a immunoreactive spots in the perikaryon of microglia, while oestradiol antagonized the effect of LPS. The results indicate that some oestrogenic compounds decrease brain inflammation by a mechanism that may involve ERs expressed by microglia. The findings support the potential therapeutic role of oestrogenic compounds as protective anti-inflammatory agents for the central nervous system.

International journal of clinical and experimental pathology, 2015

Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancers, which are th... more Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancers, which are the leading cause of cancer-related deaths in the world. Tyrosine kinase inhibitors such as erlotinib represent one therapeutic options presently recommended for tumors produced by activating mutations in the gene coding of epidermal growth factor receptor (EGFR). The aim of this study is the identification of possible biomarkers for tumor sensitivity to erlotinib in the absence of the main EGFR mutations. The erlotinib sensitivity of cells isolated from 41 untreated NSCLC patients was determined and compared with the presence of the more frequent EGFR mutations. Several patients had tumor cells highly sensitive to erlitinib in the absence of the EGFR mutations analyzed. The gene expression profile of 3 erlotinib-sensitive tumors was compared with that of 4 resistant tumors by DNA microarray hybridization. Sixteen genes were expressed at significantly higher levels in the resistant tumors ...

Background: Conflicting epidemiologic studies have suggested insulin and their analogues currentl... more Background: Conflicting epidemiologic studies have suggested insulin and their analogues currently used in the management of type 2 diabetes to be involved in tumor progression and development. Surprisingly, time of exposure to insulin analogs reported in those retrospective studies is too short for be a carcinogen. We hypothesized that differential affinity that insulin analogs display for insulin receptor and IGF-1R at CICs may account for this possibility. [AspB10]insulin (X10) is a long-acting insulin analog that displays greater affinity for IGF1R than either the long-acting insulin analog GLA or human insulin (HI) in vitro. X10 is tumorigenic in animal models whereas GLA is not. GLA is rapidly metabolized to the metabolites, M1 and M2 that exhibit metabolic and mitogenic profiles similar to that of HI in vitro. CICs are cancer cells with self-renewing, stem cell-like properties with the ability to proliferate and differentiate into specific cells found in tumor types and thus ...

Orphanet Journal of Rare Diseases, 2014

SERPING1 mutations causing Hereditary Angioedema type I (HAE-I) due to C1-Inhibitor (C1-INH) defi... more SERPING1 mutations causing Hereditary Angioedema type I (HAE-I) due to C1-Inhibitor (C1-INH) deficiency display a dominant-negative effect usually resulting in protein levels far below the expected 50%. To further investigate mechanisms for its reduced expression, we analyzed the promoter DNA methylation status of SERPING1 and its influence on C1-INH expression. Global epigenetic reactivation correlated with C1-INH mRNA synthesis and protein secretion in Huh7 hepatoma cells. However, PBMCs extracted from controls, HAE-I and HAE-II patients presented identical methylation status of the SERPING1 promoter when analyzed by bisulphite sequencing; the proximal CpG island (exon 2) is constitutively unmethylated, while the most distant one (5.7 Kb upstream the transcriptional start site) is fully methylated. These results correlate with the methylation profile observed in Huh7 cells and indicate that there is not a direct epigenetic regulation of C1-INH expression in PBMCs specific for each HAE type. Other indirect modes of epigenetic regulation cannot be excluded.

Revista del Laboratorio Clínico, 2014

ABSTRACT In the context of personalised medicine, epigenetics has an important role as regards th... more ABSTRACT In the context of personalised medicine, epigenetics has an important role as regards the prevention, diagnosis, prognosis, and treatment of diseases such as cancer. Of the different epigenetic control processes, gene silencing by DNA methylation is most frequent in this disease, and contributes to a wide variety of clinical applications such as, prediction of the therapeutic response, the prognosis associated with the molecular characteristics of the tumour, and the follow-up pf patients after treatment by surgery or chemotherapy. One of the main advantages of these epigenetic alterations is that they can be reversed with pharmacological treatments, although they are associated with multiple side effects. It for this reason, it is of great importance to continue studying epigenetic regulation in cancer, complementing with biological systems, as well as the identification of specific drugs that may decrease these adverse effects, and which should help to determine the real biological implications of these biomarkers and may lead to achieving personalised medicine.

Epigenetics, 2014

The methylation status of the IGFBP-3 gene is strongly associated with cisplatin sensitivity in p... more The methylation status of the IGFBP-3 gene is strongly associated with cisplatin sensitivity in patients with non-small cell lung cancer (NSCLC). In this study, we found in vitro evidence that linked the presence of an unmethylated promoter with poor response to radiation. Our data also indicate that radiation might sensitize chemotherapy-resistant cells by reactivating IGFBP-3-expression through promoter demethylation, inactivating the PI3K/AKT pathway. We also explored the IGFBP-3 methylation effect on overall survival (OS) in a population of 40 NSCLC patients who received adjuvant therapy after R0 surgery. Our results indicate that patients harboring an unmethylated promoter could benefit more from a chemotherapy schedule alone than from a multimodality therapy involving radiotherapy and platinum-based treatments, increasing their OS by 2.5 y (p = .03). Our findings discard this epi-marker as a prognostic factor in a patient population without adjuvant therapy, indicating that radiotherapy does not improve survival for patients harboring an unmethylated IGFBP-3 promoter.

Oncogene, 2013

Although many cancers initially respond to cisplatin (CDDP)-based chemotherapy, resistance freque... more Although many cancers initially respond to cisplatin (CDDP)-based chemotherapy, resistance frequently develops. Insulin-like growth factor-binding protein-3 (IGFBP-3) silencing by promoter methylation is involved in the CDDP-acquired resistance process in non-small cell lung cancer (NSCLC) patients. Our purpose is to design a translational-based profile to predict resistance in NSCLC by studying the role of IGFBP-3 in the phosphatidyl inositol 3-kinase (PI3K) signaling pathway. We have first examined the relationship between IGFBP-3 expression regulated by promoter methylation and activation of the epidermal growth factor receptor (EGFR), insulin-like growth factor-I receptor (IGFIR) and PI3K/AKT pathways in 10 human cancer cell lines and 25 NSCLC patients with known IGFBP-3 methylation status and response to CDDP. Then, to provide a helpful tool that enables clinicians to identify patients with a potential response to CDDP, we have calculated the association between our diagnostic test and the true outcome of analyzed samples in terms of cisplatin IC 50 ; the inhibitory concentration that kills 50% of the cell population. Our results suggest that loss of IGFBP-3 expression by promoter methylation in tumor cells treated with CDDP may activate the PI3K/AKT pathway through the specific derepression of IGFIR signaling, inducing resistance to CDDP. This study also provides a predictive test for clinical practice with an accuracy and precision of 0.84 and 0.9, respectively, (P ¼ 0.0062). We present a biomarker test that could provide clinicians with a robust tool with which to decide on the use of CDDP, improving patient clinical outcomes.

Journal of Neuroscience Research, 2010

Previous studies have shown that progesterone modulates the activity of different kinases and the... more Previous studies have shown that progesterone modulates the activity of different kinases and the phosphorylation of Tau in the brain. These actions of progesterone may be involved in the hormonal regulation of neuronal differentiation, neuronal function, and neuroprotection. However, the action of progesterone on protein phosphatases in the nervous system has not been explored previously. In this study we have assessed the effect of the administration of progesterone to adult ovariectomized rats on protein phosphatase 2A (PP2A) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in the hypothalamus, the hippocampus, and the cerebellum. Total levels of PP2A, the state of methylation of PP2A, and total levels of PTEN were unaffected by the hormone in the three brain regions studied. In contrast, progesterone significantly increased the levels of PP2A phosphorylated in tyrosine 307 in the hippocampus and the cerebellum and significantly decreased the levels of PTEN phosphorylated in serine 380 in the hypothalamus and in the hippocampus compared with control values. Estradiol priming blocked the effect of progesterone on PP2A phosphorylation in the hippocampus and on PTEN phosphorylation in the hypothalamus and the hippocampus. In contrast, the action of progesterone on PP2A phosphorylation in the cerebellum was not modified by estradiol priming. These findings suggest that the regulation of the phosphorylation of PP2A and PTEN may be involved in the effects of progesterone on the phosphorylation of Tau and on the activity of phophoinositide-3 kinase and mitogen-activated protein kinase in the brain.

Journal of Neuroinflammation, 2012

Background: Stress during fetal life increases the risk of affective and immune disorders later i... more Background: Stress during fetal life increases the risk of affective and immune disorders later in life. The altered peripheral immune response caused by prenatal stress may impact on brain function by the modification of local inflammation. In this study we have explored whether prenatal stress results in alterations in the immune response in the hippocampus of female mice during adult life. Methods: Pregnant C57BL/6 mice were subjected three times/day during 45 minutes to restraint stress from gestational Day 12 to delivery. Control non-stressed pregnant mice remained undisturbed. At four months of age, non-stressed and prenatally stressed females were ovariectomized. Fifteen days after surgery, mice received an i.p. injection of vehicle or of 5 mg/kg of lipopolysaccharide (LPS). Mice were sacrificed 20 hours later by decapitation and the brains were removed. Levels of interleukin-1β (IL1β), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), interferon γ-inducible protein 10 (IP10), and toll-like receptor 4 mRNA were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 immunoreactivity was assessed by immunocytochemistry. Statistical significance was determined by one-way or two-way analysis of variance.

Glia, 2007

Translocator protein (18 kDa) (TSPO), previously known as peripheral-type benzodiazepine receptor... more Translocator protein (18 kDa) (TSPO), previously known as peripheral-type benzodiazepine receptor, is a critical component of the mitochondrial permeability transition pore. Brain inflammation results in the induction of the expression of TSPO in glial cells and some TSPO ligands decrease reactive gliosis after brain injury. However, since some TSPO ligands are neuroprotective, their effects on reactive gliosis may be the consequence of a reduced neurodegeneration. To assess whether TSPO ligands can modulate reactive gliosis in absence of neuronal death, we have tested their effects on the inflammatory response induced in the hippocampus of male rats by the intracerebroventricular infusion of lipopolysaccharide (LPS). LPS treatment did not induce neuronal death, assessed by Fluoro jade-B staining, but increased the number of cells immunoreactive for vimentin and MHC-II, used as markers of reactive astrocytes and reactive microglia, respectively. Furthermore, LPS produced an increase in the number of proliferating microglia. The TSPO ligand PK11195 reduced the number of MHC-II immunoreactive cells and the proliferation of microglia in LPS treated rats. In contrast, another TSPO ligand, Ro5-4864, did not significantly affect the response of microglia to LPS. Neither PK11195 nor Ro5-4864 affected the LPS-mediated increase in the number of vimentin-immunoreactive astrocytes at the time point studied, although PK11195 reduced vimentin immunoreactivity. These findings identify TSPO as a potential target for controlling neural inflammation, showing that the TSPO ligand PK11195 may reduce microglia activation by a mechanism that is independent of the regulation of neuronal survival.

Experimental Gerontology, 2012

Clinical studies suggest that aging may affect the neural outcome of estrogen therapy in postmeno... more Clinical studies suggest that aging may affect the neural outcome of estrogen therapy in postmenopausal women. In this study we have assessed whether age influences the behavioral outcome of estradiol therapy in rats. Animals were ovariectomized at 2 or 20 months of age. Immediately after ovariectomy animals were treated for 10 weeks with estradiol valerate or vehicle. Estradiol therapy decreased body weight in both young and older rats compared to animals injected with vehicle. In contrast, estradiol treatment improved object recognition memory and decreased anxiety-like behavior in the circular open field of older but not young rats and decreased depressive-like behavior of young but not older animals. Thus, our findings indicate that age affects the outcome of estradiol therapy in the brain.

Endocrinology, 2009

After brain injury, astrocytes acquire a reactive phenotype characterized by a series of morpholo... more After brain injury, astrocytes acquire a reactive phenotype characterized by a series of morphological and molecular modifications, including the expression of the cytoskeletal protein vimentin. Previous studies have shown that estradiol down-regulates reactive astrogliosis. In this study we assessed whether raloxifene and tamoxifen, two selective estrogen receptor modulators, have effects similar to estradiol in astrocytes. We also assessed whether aging and the timing of estrogenic therapy after ovariectomy influence the action of the estrogenic compounds. Four groups of animals were studied: 1) young rats, ovariectomized at 2 months of age; 2) middle-aged rats, ovariectomized at 8 months of age; 3) aged rats, ovariectomized at 18 months of age; and 4) aged rats, ovariectomized at 2 months and sham operated at 18 months of age. Fifteen days after ovariectomy or sham surgery, animals received a stab wound brain injury and the treatment with the estrogenic compounds. The number of vimentin-immunoreactive astrocytes after injury was significantly higher in the hippocampus of aged rats after a long-term ovariectomy compared with aged animals after a short-term ovariectomy and middle-aged rats. In addition, reactive astrocytes were more numerous in the two groups of aged animals than in young animals. Despite these differences, the estrogenic compounds reduced reactive astrogliosis in all animal groups. These findings indicate that estradiol, raloxifene, and tamoxifen are potential candidates for the control of astrogliosis in young and older individuals and after a prolonged depletion of ovarian hormones.

Developmental Neurobiology, 2008

The transition from adolescence to adulthood is accompanied by substantial plastic modifications ... more The transition from adolescence to adulthood is accompanied by substantial plastic modifications in the cerebral cortex, including changes in the growth and retraction of neuronal processes and in the rate of synaptic formation and neuronal loss. Some of these plastic changes are prevented in female rats by prepubertal ovariectomy. The ovarian hormone estradiol modulates neuronal differentiation and survival and these effects are in part mediated by the interaction with insulin-like growth factor-I (IGF-I). In this study, we have explored whether the activation by estradiol of some components of IGF-I receptor signaling is altered in the prefrontal cortex during puberty. Estradiol administration to rats ovariectomized after puberty resulted, 24 h after the hormonal administration, in a sustained phosphorylation of Akt and glycogen synthase kinase 3b in the prefrontal cortex. However, this hormonal effect was not observed in animals ovariectomized before puberty. These findings suggest that during pubertal maturation there is a programming by ovarian hormones of the future regulatory actions of estradiol on IGF-I receptor signaling in the prefrontal cortex. The modification in the regulation of IGF-I receptor signaling by estradiol during pubertal maturation may have implications for the developmental changes occurring in the prefrontal cortex in the transition from adolescence to adulthood. '

Clinical and Translational Oncology, 2011

Metformin is a biguanine, the most widely used antidiabetic drug for the treatment of type 2 diab... more Metformin is a biguanine, the most widely used antidiabetic drug for the treatment of type 2 diabetes. Some studies suggest that metformin decreases the incidence of cancer and cancer-related mortality in diabetic patients. Metformin activates the AMP-activated protein kinase (AMPK) pathway, a major sensor of the energy status of the cell and an inhibitor of mammalian target of rapamycin (mTOR) catalytic activity, inducing a decrease in blood glucose by decreasing hepatic gluconeogenesis and stimulating glucose uptake in the muscle. Some preclinical data supports the inhibition of tumour cancer cell growth associated with mTOR inhibition and a decrease in phosphorylation of S6K, rpS6 and 4E-BP1. Here we have summarised some of the preclinical data and data of many clinical trials that are exploring the true value of metformin for cancer patients, mainly breast and prostate cancer.