Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy / Influência de polimorfismos nos genes PPARA, RXRA, NR1I2 e NR1I3 na eficácia hipolipemiante e na segurança da terapia com estatinas

OBJECTIVE: The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. SUBJECTS AND METHODS: The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. RESULTS: The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). CONCLUSION: The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.

OBJETIVO: O objetivo deste estudo foi investigar a associação de seis variantes genéticas nos genes de receptores nucleares PPARA, RXRA, NR1I2 e NR1I3 na eficácia hipolipemiante e na segurança da terapia com estatinas. SUJEITOS E MÉTODOS: O estudo foi realizado com 240 pacientes hipercolesterolêmicos em terapia com sinvastina e atorvastatina. Os polimorfismos foram analisados por meio de métodos baseados em PCR. RESULTADOS: A distribuição da frequência genotípica do polimorfismo NR1I3 rs2307424 foi diferente entre os pacientes com e sem efeito adverso à medicação; entre os sujeitos do grupo com efeitos adversos, nenhum homozigoto T/T foi observado, enquanto no grupo de indivíduos sem efeitos adversos a frequência desse genótipo foi 19,4% (P = 0,007, após correção para múltiplos testes P = 0,042). CONCLUSÃO: Os polimorfismos investigados nos genes PPARA (rs1800206), RXRA (rs11381416) e NR1I2 (rs1523130) não foram associados com eficácia hipolipemiante e segurança da terapia com estatinas. Nossos resultados mostram uma possível influência de variantes do gene NR1I3 (rs2307424) no desenvolvimento de efeitos adversos à terapia com estatinas.

Rapamycin pre-treatment abrogates Tumour Necrosis Factor-alpha down-regulatory effects on LXR-alpha and PXR mRNA expression via inhibition of c-Jun N-terminal kinase 1 activation in HepG2 cells

The Liver X Receptor (LXR) and Pregnane X Receptor (PXR) are members of the nuclear receptor superfamily. Previously, they have been classified as important regulators of lipid homeostasis. However, recent studies have shown that they may be implicated in anti-inflammatory responses as well. This study shows that Tumour Necrosis Factor-alpha (TNF-alpha) treatment reduces both LXR-alpha and PXR mRNA expression. However, pre-treatment with rapamycin, an mTOR inhibitor, followed by TNF-alpha stimulation, significantly induces LXR-alpha and PXR mRNA expression to ~17- and ~2-fold, respectively. This suggests that mTORC1, a multi-molecular complex of which mTOR is a member, may act as a negative regulator that inhibits the induction of LXR-alpha and PXR as anti-inflammatory genes. It is also shown here that inhibition of JNK1 via the mTOR/Akt pathway coincides with the up-regulation of LXR-alpha and PXR mRNA, after TNF-alpha treatment. Together, these observations suggest that JNK1 possibly act downstream of mTORC1 as an LXR-alpha and PXR inhibitor. From the results gleaned in this study, rapamycin (and its analogues) may be used to reduce acute inflammation by promoting the induction of LXR-alpha and PXR as anti-inflammatory genes.

Frequency of genetic polymorphisms of PXR gene in the Brazilian population

INTRODUCTION: PXR polymorphisms have been implicated in modulating CYP3A4 and PXR expression, potentially accounting for interindividual differences in drug metabolism. The prevalence of PXR polymorphisms varies among ethnic groups and data on the allelic distribution in the highly mixed Brazilian population is lacking. The aim of this study was to analyze genetic variations in the PXR gene in Brazilians and to compare the results to other ethnic groups. METHODS: DNA samples from 117 healthy Brazilians underwent PCR amplification and sequencing. RESULTS: Eleven polymorphisms were identified, 3 of which are highly associated with differences in CYP3A4 expression. We also identified 1 new synonymous variant in 1.3 percent of the alleles. Among the functional polymorphisms, -25913 C>T and -6994T>C occurred at a higher frequency comparedtothe Africanalleles (p < 0.05) but at a lower frequency compared to Caucasian alleles. The 8055 C>T allele was found at a similar frequency to those described in Caucasians and Africans (p > 0.05). CONCLUSION: We observed that functional variants of the PXR were frequent in our sample of the Brazilian population. Our results suggest that PXR gene variants may be of interest in pharmacogenetic studies involving Brazilians.

Expression of e-cadherin, n-cadherin and snail and their correlation with clinicopathological variants: an immunohistochemical study of 132 invasive ductal breast carcinomas in Egypt

OBJECTIVE: To evaluate the expression of the cell adhesion molecules E-cadherin and N-cadherin and the transcription factor Snail in invasive ductal breast carcinomas and to determine their relationships with clinicopathological features. METHODS: Immunohistochemistry was used to examine E-cadherin, N-cadherin, and Snail protein expression in 132 invasive breast carcinomas. RESULTS: The expression of E-cadherin was decreased (negative or weak) in 37.1 percent of invasive carcinomas, while N-cadherin and Snail overexpression were detected in 51.9 percent and 40.9 percent of carcinomas, respectively. Low E-cadherin expression was significantly correlated with poorly differentiated carcinoma (53.1 percent), positive node status (80.9 percent), poor Nottingham Prognostic Index (64.7 percent), and the presence of estrogen and progesterone receptors. Overexpression of N-cadherin and Snail were also significantly correlated with poorly differentiated carcinoma, positive node status, and poor Nottingham Prognostic Index but were correlated with the absence of hormone receptors. Loss of E-cadherin immunoexpression was strongly associated with the presence of membranous N-cadherin (87.8 percent) and nuclear Snail (69.4 percent). CONCLUSION: Loss of E-cadherin and overexpression of N-cadherin and Snail in breast carcinomas may play a central role in the development of invasive ductal breast carcinoma. These biomarkers may provide a valuable reference for the study of invasive ductal carcinoma progression and to characterize the biological behavior of the tumor. In the future, increased N-cadherin and decreased E-cadherin expression may be used as indicators of the progression and prognosis of invasive ductal carcinoma.

Localización extra nuclear de receptores esteroides y activación de mecanismos no genómicos / Extra nuclear localization of steroid receptors and non genomic activation mechanisms

Los receptores de hormonas esteroides han sido considerados históricamente como factores de transcripción nucleares. Sin embargo, en los últimos años surgieron evidencias que indican que su activación desencadena eventos rápidos, independientes de la transcripción y que involucran a diferentes segundos mensajeros; muchos de estos receptores han sido localizados en la membrana celular. Por otra parte, se han caracterizado varios receptores de hormonas esteroides noveles, de estructura molecular diferente al receptor clásico, localizados principalmente en la membrana celular. Esta revisión enfoca los diferentes efectos iniciados por los glucocorticoides, mineralocorticoides, andrógenos, estrógenos y progesterona, y los posibles receptores involucrados en los mismos.

Steroid hormone receptors have been historically considered as nuclear transcription factors. Nevertheless, in the last years, many of them have been detected in the cellular membrane. It has been postulated that their activation can induce transcription independent rapid events involving different second messengers. In addition, several novel steroid hormone receptors, showing a different molecular structure than the classical ones, have also been characterized and most of them are also located in the plasmatic membrane. This review focuses on the variety of effects initiated by glucocorticoids, mineralocorticoids, androgens, estrogens and progesterone, and the possible receptors involved mediating these effects.

Detección de receptores de estrógeno, progesterona y de proteína ligadora de corticosteroides en el tracto genital de hembras caninas (Cannis familiaris): estudio inmunohistoquímico / Detection of estrogen, progestorone receptors and corticosteroid binding globulin in the canine (Cannis familiaris) reproductive female tract: immunohistochemistry study

Los receptores esteroidales sexuales del tracto genital de la hembra tienen importancia dado que, a través de ellos, actúan las hormonas responsables de su desarrollo y de sus cambios morfofuncionales. En su mecanismo, uno de los factores a considerar son las posibles diferencias entre las distintas especies. El objetivo del presente estudio fue evaluar, en la especie canina (N=8), la presencia de receptores de estrógenos (RE), progesterona (RP) y la presencia de proteína ligadora de corticosteroides (CBG) en ovario, oviducto y útero de 3 hembras prepúberes (N=3) y 5 hembras adultas (N=5). La evaluación morfológica se realizó con tinción de hematoxilina-eosina (H-E) e inmunocitoquímica, según la técnica de Stemberger (1979). Los resultados revelaron en animales ciclando, inmunorreactividad (IR) positiva, RE en útero, oviducto y ovario siendo marcada en oviducto. La IR para RP fue leve y varió según el estadio del ciclo. En hembras prepúberes, los RE y RP no fueron evidenciados. La CBG mostró positividad en el tracto durante el ciclo y fue negativa en prepúberes. Se concluye que la presencia de RE y RP es detectable en útero, oviducto y ovario de la hembra canina adulta habiendo variaciones de concentración según el estadio del ciclo estral, siendo su presencia en las prepúberes no evidenciables, a diferencia de otras especies (oveja), donde son detectables en este estadio del desarrollo. La presencia de CBG constante durante el ciclo estral y variable en los otros estadios indica su posible participación en los procesos reproductivos.

The sexual steroid receptors of the genital tract of the female have significant importance since though them the hormones responsible acting. In their mechanism one of the factors to be kept in mind is the possible differences among the diverse species, the objective of this study was to evaluate in canine (N= 8) the presence of receptors of estrogens (ER), progesterone (PR) and the presence of corticosteroid binding globuline (CBG) in ovaries, oviduct and uterus of prepuberal female (N=.3) and matures: (N=5) It was used H-E and immunohistochemical study according to the technique of Stenberger (1979). The results during the oestrus showed: Immune reactivity (IR) positive, ER in uterus and ovary being much stronger in oviduct. The PR varied according the stage of oestrus cycle. In puberal female dog ER and PR were undetectable. The CBG revealed positive in reproductive tract of cycling females but negative in prepubertal. It was concluded that the presence of ER and PR are detectable in uterus, oviduct and ovary of mature female dogs varying their concentration according to the cycle. In prepuberal, its presences come undetectable differing from other species (ovine), in which they are detected at this stage of development. The constant of CBG presence during oeustrus cycle and such variation in other stages of the cycle, it might suggest its participation in the several reproductive activities.

Receptores de progesterona y grado histológico del cáncer ductal de glándula mamaria / Progesterone receptors and histological grade of ductal cancer of the mammary gland

El presente estudio buscó determinar la frecuencia porcentual que existe en la expresión para receptoreshormonales de progestágenos y estrógenos según el grado de diferenciación histológica del carcinomade glándula mamaria (GM). Se revisaron 56 pacientes con cáncer de GM en el Hospital de San José enel período comprendido entre enero 1 de 2004 a enero 31 de 2006, a quienes en la biopsia se les practicóanálisis de inmunohistoquímica para receptores de estrógenos y progestágenos. La información serecolectó en una base de datos y se analizó en el programa estadístico EPI INFO 6.0. De los 56 casosestudiados 16 fueron diagnosticados como grado 1 (28.6%), 26 grado 2 (46.4%) y 14 grado 3 (25%).De la totalidad de casos marcados para receptores de estrógenos 40 expresaron positividad y para progestágenos36. Este estudio demostró que la frecuencia del porcentaje de positividad para receptoresde estrógenos y progestágenos está relacionada con el grado de diferenciación histológica del tumor.

Uso antenatal de corticosteróide e evolução clínica de recém-nascidos pré-termo / Antenatal corticosteroid use and clinical evolution of preterm newborn infants

O objetivo é descrever a freqüência de utilização de corticosteróide antenatal e a evolução clínica dos recém-nascidos pré-termo. Estudo observacional prospectivo tipo coorte de todos os neonatos com idade gestacional entre 23 e 34 semanas nacidos na Rede Brasileira de Pesquisas Neonatais entre agosto e dezembro de 2001. Os prontuários médicos foram revistos, as mães entrevistadas e os pré-termos acompanhados. A análise dos dados foi realizada com o teste do qui-quadrado, t de Student, Mann-Whitney, ANOVA e regressão logística múltipla, com nível de significância de 5%.

Expressão dos fatores de proliferação celular PCNA e Ki-67 e receptores de estrogênio e progesterona em tecido mamário normal de mulheres na pós-menopausa submetidas a dois esquemas de terapia de reposição hormonal / Expression of cell proliferation factors PCNA and Ki-67 and estrogen and progesterone receptors in normal breast tissue of post-menopause women submitted to two types of hormonal replacement therapy

Foram colhidas amostras de tecido mamário de 32 mulheres saudáveis na pós-menopausa: 19 utilizaram esquema cíclico de estrogênio e pro-gestágeno (estrogênios conjugados 0,625mg, 21 dias por mês, associa-dos ao acetato de medroxiprogesterona, 5mg, nos últimos 12 dias) e 13 tomaram apenas estrogênios (estrogênios conjugados, 0,625mg, 21 dias por mês), todas durante 6 meses consecutivos. Foram realizadas biópsias mamárias antes e ao final dos 6 meses de tratamento. A análise imunohistoquímica foi feita com anticorpos anti-PCNA do tipo PC-10, anti-Ki-67 do tipo MIB-1, anti-receptor de estrogênio do tipo 1-D5 e anti-receptor de progesterona do tipo 1-A6. Não houve diferença significativa para os fatores de mediação (receptores) no grupo que utilizou o esquema cíclico (RE: P = 0,326; RP: P = 0,228). No grupo que utilizou apenas estrogênio, obteve-se um valor de P próximo ao limite de significância estatística para o RP (P = 0,053), mas não para o RE (P = 0,203). Com relação aos fatores de proliferação celular, não foi encontrada diferença estatisticamente significativa para o PCNA em ambos os grupos (esquema cíclico: P = 0,121; estrogênio isolado; P = 0,208). Houve tendência para elevação do Ki-67 no grupo que fez uso de estrogênio apenas (P = 0,084), o que não se observou no grupo que fez uso de esquema cíclico (P = 0,776). Estes resultados sugerem que a associação de progestágeno à terapia estrogênica nesse grupo de mulheres pós-menopausa, pode ter contribuído para uma possível redução na expressão do receptor de progesterona e a proliferação celular, estimada pelo marcador Ki-67, agindo como um fator moderador de proliferação celular. Novos estu-dos são necessários para comprovar esta hipótese.

Prevalence of steroid receptors and HER 2/neu in breast cancer biopsies of women living in Puerto Rico

OBJECTIVE: The purpose of this study is to determine the prevalence rate of estrogen and progesterone receptors and HER 2/neu in the breast cancer biopsies analyzed in the Laboratory of Immunohistochemistry of the University of Puerto Rico School of Medicine in the year 2000. This data may serve as a reference point for future studies of the epidemiological aspects of breast cancer among women living in Puerto Rico. BACKGROUND: Determination of estrogen receptor (ER) and progesterone receptor (PR) on biopsy specimens of breast carcinoma prior to treatment is standard practice in the management of breast carcinoma. ER and PR are used to identify patients who are likely to respond to endocrine therapy. The prevalence of ER, PR and Her2/neu among USA women is 77 per cent, 55 per cent and 10-34 per cent, respectively. One of the major clinical roles for testing HER 2/neu expression is to determine eligibility for treatment with Trastuzumab. METHODS: Retrospective analysis of 309 breast cancer biopsies was done. Paraffin embedded blocks of breast cancer tissue biopsies were received from different hospitals and Pathology Laboratories located throughout the island specifically for routine analysis of steroid receptor (ER/PR) and/or HER 2/neu expression. Immunostaining was performed in a Ventana Medical Systems automated instrument. RESULTS: Positive nuclear staining for ER and PR were seen in 65.9 per cent (203/308) and 51.8 per cent (159/307), respectively. In the HER2/neu test, 27.8 per cent (46/165) gave a strong and complete membranous staining (score 3+). CONCLUSIONS: There is a lower prevalence of estrogen receptor in the breast cancer biopsies of women living in Puerto Rico than their USA counterparts, but similar prevalence of progesterone receptorstatus and HER 2/neu protein over expression.

Receptores a estrógenos y progesterona / Estrogen and progesterone receptors

La estrogenoterapia está en aumento y ello obliga a un adecuado conocimiento del mecanismo de acción de los esteroides, siendo al momento conocidos su transporte y metabolismo. Por ello discutiremos los aspectos moleculares de la acción de los estrógenos a nivel de los receptores nucleares, precisando la estructura y funcionamiento de los mismos. Se revisa los factores de transcripción, describiendo sus dominios de unión al DNA y de activación. Se hace precisiones de la transcripción, el papel de la polimerasa II y los factores generales de transcripción, que forman el complejo de iniciación de transcripción. Se culmina exponiendo cómo es la regulación de la concentración del receptor a través del mecanismo de relleno y puntualizando algunas implicancias clínicas. La estrogenoterapia está en aumento y es conveniente que su uso sea consecuencia de un adecuado conocimiento del mecanismo de acción del estrógeno en su célula blanco; este conocimiento biomolecular permite comprender la respuesta individual o grupal a esa terapia. Los receptores hormonales a estrógenos y progesterona han sido encontrados y estudiados en todo el organismo y son parte de la regulación del medio interno; su comprensión explica la fisiología de hormonas esteroides.

Importância do fator de crescimento epidérmico (EGF) e seu receptor (EGF-R) no tecido endometrial / Epidermal growth factor (EGF) and its receptor (EGF-R) importance in the endometrial tissue

Os autores fazem uma revisäo sobre a influência que o EGF e seu receptor (EGF-R) exercem no tecido endometrial, enfocando sua possível regulaçäo pelos esteróides e seus receptores e sua importância nos processos de transformaçäo secretora e de decidualizaçäo.

Receptores esteróides no endométrio / Steroid receptors in the endometrium

Os autores fazem uma revisäo sobre o mecanismo de açäo, regulaçäo e concentraçäo dos receptores para estrogênio e progesterona no tecido endometrial humano.

Receptor localization of steroid hormones and drugs: discoveries through

The history of receptor autoradiography, its development and applications, testify to the utility of this histochemical tecnhique for localizing radiolabeled hormones and drugs at cellular and subcelullar sites of action in intact tissues. Loclization of duffusible compounds has been a challenge that was met through the introduction of the "thaw-mount" and "dry-mount" autoradiographic techniques thirty years ago. With this cellular receptor autoradiography, used alone or combined with other histochemical techniques, sites of specific binding and deposition in vivo and in vitro have been characterized. Numerous discoveries, some reviewed in this article, provided information that led to new concepts and opened new areas of research. As an example, in recent years more than fifty target tissues for vitamin D have been specified, challenging the conventional view about the main biological role of vitamin D. The functions of most of these vitamin D target tissues are unrelated to the regulation of systemic calcium homeostasis, but pertain to the (seasonal) regulation of endo- and exocrine secretion, cell proliferation, reproduction, neural, immune and cardiovascular responses, and adaptation to stress. Receptor autoradiography with cellula resolution has become an indispensable tool in drug research and development, since information can be obtained that is difficult or impossible to gain otherwise.

Mecanismo de la respuesta celular a las señales extracelulares mediada por canales iónicos y receptores intracelulares / Mechanism of the cellular response a the median extracellular signals for ionic channel and intracellular receptors

En este artículo, se revisa el mecanismo de respuesta celular para mensajeros que actúan por medio de receptores de membrana con canal iónico incorporado o de receptores intracelulares, también conocidos como esteroides. Los principales ligandos para los receptores con canal iónico son neurotransmisores que al cambiar la conductancia de la membrana celular a iones como el sodio, potasio, calcio y cloruro modifican la excitabilidad de las células blanco. Los receptores esteroides se localizan intracelularmente, en el citosol o en el núcleo. Las hormonas que actúan a través de este tipo de receptor después de penetrar la membrana celular forman un complejo con el receptor que regula la transcripción genética.

Tratamento endócrino dos meningiomas: uma revisäo / Endocrine treatment of meningiomas: a review

Os meningiomas säo tumores benignos do sistema central. Apresentam altas taxas de recidiva e muitas vezes säo considerados inoperáveis, como quando se localizam em local de difícil acesso cirúrgico ou quando englobam estruturas nobres do cérebro. Existem evidências clínicas, epidemiológicas, bioquímicas e de experimentos "in vitro" de que seu crescimento sofre influência do meio hormonal esteróideo. Vários ensaios terapêuticos têm explorado estas características do meningioma através do uso de substâncias que interferem na açäo destes esteróides: RU486 ( antiprogestínico e antiglicocorticóide), acetato de medroxiprogesterona (antiprogestínico), gestrinona (antiestrogênico e antiprogestínico), tamoxifen (antiestrogênico) e buserelin (superagonista do LHRH), além do octreotide (análogo da somatostatina) e a bromocriptina (agonista dopaminérgico). Outros medicamentos possuem potencial para o tratamento dos meningiomas: aminoglutetimina, suramin e trapidil. Nesta revisäo, analizamos a literatura sobre esses aspectos

Evidence against the involvement of ACTH/CRF release or corticosteroid receptors in the anxiolytic effect of corticosterone

The present study was designed to evaluate the role of ACTH and/or CRF release and corticosteroid receptors (glucocorticoid and mineralocorticoid) in the anxiolytic effect of corticosterone (CORT). Costicosteroid receptor mediation was evaluated using a dose-response analysis of the effect of CORT and by the action of dexamethasone (DEX), which binds to glucocorticoid receptors but not to mineralocorticoid receptors. DEX administration also permits indirect evaluation of the effect of ACTH/CRF release on the anxiolytic effect of CORT. Male Wistar rats (3 months old) weighing 250-350 g were treated sc with vehicle (N = 38), CORT 1.25 (N = 18), 2.5 (N = 13) and 5.0 (N = 24) mg/kg, or DEX 5.0 (N = 19) and 10.0 (N = 17) mg/kg and tested in the elevated plus-maze 2 h later. The group that received the highest dose of CORT (5.0 mg/kg) showed a significant increase in percent open arm entries (38 +/- 2.6, mean +/- SEM) as well as in percent time spent in open arms (27 +/- 4.0) when compared with the vehicle-treated rats (24.3 +/- 2.8 and 12.4 +/- 1.9, respectively; both P < 0.05). There were no other significant differences among groups in the two parameters tested or in total arm entries. These data corroborate previous findings of the anxiolytic effect of CORT and suggest that inhibition of ACTH/CRF release and corticosteroid receptors do not play a major role in the anxiolytic effect of CORT.