Institute Biologia y Medicina Experimental

Gobernador Ingeniero Valentín Virasoro, Argentina

Institute Biologia y Medicina Experimental

Gobernador Ingeniero Valentín Virasoro, Argentina

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Amalfi S.,CONICET | Velez L.M.,CONICET | Heber M.F.,CONICET | Vighi S.,Hospital Of Clinicas | And 4 more authors.
PLoS ONE | Year: 2012

Prenatal hyperandrogenism is able to induce polycystic ovary syndrome (PCOS) in rats. The aim of the present study was to establish if the levels of prenatal testosterone may determine the extent of metabolic and endocrine alterations during the adult life. Pregnant Sprague Dawley rats were prenatally injected with either 2 or 5 mg free testosterone (groups T2 and T5 respectively) from day 16 to day 19 day of gestation. Female offspring from T2 and T5 displayed different phenotype of PCOS during adult life. Offspring from T2 showed hyperandrogenism, ovarian cysts and ovulatory cycles whereas those from T5 displayed hyperandrogenism, ovarian cysts and anovulatory cycles. Both group showed increased circulating glucose levels after the intraperitoneal glucose tolerance test (IPGTT; an evaluation of insulin resistance). IPGTT was higher in T5 rats and directly correlated with body weight at prepubertal age. However, the decrease in the body weight at prepubertal age was compensated during adult life. Although both groups showed enhanced ovarian steroidogenesis, it appears that the molecular mechanisms involved were different. The higher dose of testosterone enhanced the expression of both the protein that regulates cholesterol availability (the steroidogenic acute regulatory protein (StAR)) and the protein expression of the transcriptional factor: peroxisome proliferator-activated receptor gamma (PPAR gamma). Prenatal hyperandrogenization induced an anti-oxidant response that prevented a possible pro-oxidant status. The higher dose of testosterone induced a pro-inflammatory state in ovarian tissue mediated by increased levels of prostaglandin E (PG) and the protein expression of cyclooxygenase 2 (COX2, the limiting enzyme of PGs synthesis). In summary, our data show that the levels of testosterone prenatally injected modulate the uterine environment and that this, in turn, would be responsible for the endocrine and metabolic abnormalities and the phenotype of PCOS during the adult life. © 2012 Amalfi et al.


Maymo J.L.,University of Buenos Aires | Perez A.P.,University of Seville | Duenas J.L.,Hospital Universitario Virgen Macarena | Calvo J.C.,University of Buenos Aires | And 3 more authors.
Endocrinology | Year: 2010

Leptin, a 16-kDa protein mainly produced by adipose tissue, has been involved in the control of energy balance through its hypothalamic receptor. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in placenta, where it was found to be expressed. In the current study, we examined the effect of cAMP in the regulation of leptin expression in trophoblastic cells. We found that dibutyryl cAMP [(Bu) 2cAMP], a cAMP analog, showed an inducing effect on endogenous leptin expression in BeWo and JEG-3 cell lines when analyzed by Western blot analysis and quantitative RT-PCR. Maximal effect was achieved at 100 μM. Leptin promoter activity was also stimulated, evaluated by transient transfection with a reporter plasmid construction. Similar results were obtained with human term placental explants, thus indicating physiological relevance. Because cAMP usually exerts its actions through activation of protein kinase A (PKA) signaling, this pathway was analyzed. We found that cAMP response element-binding protein (CREB) phosphorylation was significantly increased with (Bu)2cAMP treatment. Furthermore, cotransfection with the catalytic subunit of PKA and/or the transcription factor CREB caused a significant stimulation on leptin promoter activity. On the other hand, the cotransfection with a dominant negative mutant of the regulatory subunit of PKA inhibited leptin promoter activity. We determined that cAMP effect could be blocked by pharmacologic inhibition of PKA or adenylyl ciclase in BeWo cells and in human placental explants. Thereafter, we decided to investigate the involvement of the MAPK/ERK signaling pathway in the cAMP effect on leptin induction. We found that 50 μM PD98059, a MAPK kinase inhibitor, partially blocked leptin induction by cAMP, measured both by Western blot analysis and reporter transient transfection assay. Moreover, ERK 1/2 phosphorylation was significantly increased with (Bu)2cAMP treatment, and this effect was dose dependent. Finally, we observed that 50 μM PD98059 inhibited cAMP-dependent phosphorylation of CREB in placental explants. In summary, we provide some evidence suggesting that cAMP induces leptin expression in placental cells and that this effect seems to be mediated by a cross talk between PKA and MAPK signaling pathways. Copyright © 2010 by The Endocrine Society.


Buffone M.G.,University of Pennsylvania | Ijiri T.W.,University of Pennsylvania | Cao W.,University of Pennsylvania | Merdiushev T.,University of Pennsylvania | And 3 more authors.
Molecular Reproduction and Development | Year: 2012

Sperm structure has evolved to be very compact and compartmentalized to enable the motor (the flagellum) to transport the nuclear cargo (the head) to the egg. Furthermore, sperm do not exhibit progressive motility and are not capable of undergoing acrosomal exocytosis immediately following their release into the lumen of the seminiferous tubules, the site of spermatogenesis in the testis. These cells require maturation in the epididymis and female reproductive tract before they become competent for fertilization. Here we review aspects of the structural and molecular mechanisms that promote forward motility, hyperactivated motility, and acrosomal exocytosis. As a result, we favor a model articulated by others that the flagellum senses external signals and communicates with the head by second messengers to affect sperm functions such as acrosomal exocytosis. We hope this conceptual framework will serve to stimulate thinking and experimental investigations concerning the various steps of activating a sperm from a quiescent state to a gamete that is fully competent and committed to fertilization. The three themes of compartmentalization, competence, and commitment are key to an understanding of the molecular mechanisms of sperm activation. Comprehending these processes will have a considerable impact on the management of fertility problems, the development of contraceptive methods, and, potentially, elucidation of analogous processes in other cell systems. © 2011 Wiley Periodicals, Inc.


Riggio M.,Institute Biologia y Medicina Experimental | Polo M.L.,Institute Biologia y Medicina Experimental | Blaustein M.,CONICET | Blaustein M.,University of Buenos Aires | And 5 more authors.
Carcinogenesis | Year: 2012

Using a model of medroxyprogesterone acetate (MPA)-induced mouse mammary tumors that transit through different stages of hormone dependence, we previously reported that the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT (protein kinase B) pathway is critical for the growth of hormone-independent (HI) mammary carcinomas but not for the growth of hormone-dependent (HD) mammary carcinomas. The objective of this work was to explore whether the activation of the PI3K/AKT pathway is responsible for the changes in tumor phenotype and for the transition to autonomous growth. We found that the inhibition of the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway suppresses HI tumor growth. In addition, we were able to induce mammary tumors in mice in the absence of MPA by inoculating HD tumor cells expressing a constitutively active form of AKT1, myristoylated AKT1 (myrAKT1). These tumors were highly differentiated and displayed a ductal phenotype with laminin-1 and cytokeratin 8 expression patterns typical of HI tumors. Furthermore, myrAKT1 increased the tumor growth of IBH-6 and IBH-7 human breast cancer cell lines. In the estrogen-dependent IBH-7 cell line, myrAKT1 induced estrogen-independent growth accompanied by the expression of the adhesion markers focal adhesion kinase and E-cadherin. Finally, we found that cells expressing myrAKT1 exhibited increased phosphorylation of the progesterone receptor at Ser190 and Ser294 and of the estrogen receptor α at Ser118 and Ser167, independently of exogenous MPA or estrogen supply. Our results indicate that the activation of the PI3K/AKT/mTOR pathway promotes tissue architecture remodeling and the activation of steroid receptors. © The Author 2011. Published by Oxford University Press. All rights reserved.


Ricci A.G.,CONICET | Ricci A.G.,Institute Biologia y Medicina Experimental | Olivares C.N.,CONICET | Bilotas M.A.,CONICET | And 2 more authors.
Reproductive Sciences | Year: 2011

The main factor involved in neovascularization of ectopic endometrial tissue in endometriosis is the vascular endothelial growth factor (VEGF), which is produced both by the endometrial implant and by peritoneal macrophages. On the other hand, bevacizumab is an antiangiogenic agent used in the treatment of different tumors, like colorectal, pulmonary, and recently mammary. We evaluated the effect of the inhibition of VEGF activity with bevacizumab (Avastin) on ectopic endometrial growth in a murine model of endometriosis. Two months old female BALB/c mice had surgery performed to induce endometriotic-like lesions. Treatment with bevacizumab started on post-surgery day 15 and continued during 2 weeks. Then, animals were sacrificed, peritoneal fluid was collected, and endometriotic-like lesions were counted, measured, and removed. Cell proliferation, vascular density, and apoptosis were assessed by immunohistochemistry for proliferating cell nuclear antigen (PCNA), immunohistochemistry for CD34, and Terminal Deoxynucleotidil Transferase-Mediated dUTP Nick End Labeling (TUNEL), respectively. Vascular endothelial growth factor levels were evaluated in the peritoneal fluid by enzyme-linked immunoassay (ELISA). Treatment with bevacizumab significantly inhibited endometriotic lesion development (P <.05). Consistently, bevacizumab significantly inhibited cell proliferation in lesions (P <.01), reduced vascular density (P <.001), as well as increased the apoptotic cell percentage (P <.001). In addition, bevacizumab reduced VEGF levels in peritoneal fluid of endometriosis-induced animals (P <.05). In conclusion, this study suggests a direct effect of bevacizumab on the reduction of endometrial implant growth and supports further research on VEGF inhibition as a novel therapeutic modality in endometriosis. © The Author(s) 2011.


Lopez-Bergami P.,Sanford Burnham Institute for Medical Research | Lau E.,Institute Biologia y Medicina Experimental | Ronai Z.,Sanford Burnham Institute for Medical Research
Nature Reviews Cancer | Year: 2010

Cooperation among transcription factors is central for their ability to execute specific transcriptional programmes. The AP1 complex exemplifies a network of transcription factors that function in unison under normal circumstances and during the course of tumour development and progression. This Perspective summarizes our current understanding of the changes in members of the AP1 complex and the role of ATF2 as part of this complex in tumorigenesis.


Di Lella S.,Institute Biologia y Medicina Experimental | Di Lella S.,University of Buenos Aires | Sundblad V.,Institute Biologia y Medicina Experimental | Cerliani J.P.,Institute Biologia y Medicina Experimental | And 5 more authors.
Biochemistry | Year: 2011

In the past decade, increasing efforts have been devoted to the study of galectins, a family of evolutionarily conserved glycan-binding proteins with multifunctional properties. Galectins function, either intracellularly or extracellularly, as key biological mediators capable of monitoring changes occurring on the cell surface during fundamental biological processes such as cellular communication, inflammation, development, and differentiation. Their highly conserved structures, exquisite carbohydrate specificity, and ability to modulate a broad spectrum of biological processes have captivated a wide range of scientists from a wide spectrum of disciplines, including biochemistry, biophysics, cell biology, and physiology. However, in spite of enormous efforts to dissect the functions and properties of these glycan-binding proteins, limited information about how structural and biochemical aspects of these proteins can influence biological functions is available. In this review, we aim to integrate structural, biochemical, and functional aspects of this bewildering and ancient family of glycan-binding proteins and discuss their implications in physiologic and pathologic settings. © 2011 American Chemical Society.


Fernandez M.,Institute Biologia y Medicina Experimental | Fernandez M.,University of Buenos Aires | Bourguignon N.,Institute Biologia y Medicina Experimental | Lux-Lantos V.,Institute Biologia y Medicina Experimental | And 2 more authors.
Environmental Health Perspectives | Year: 2010

Background: Bisphenol A (BPA), an endocrine disruptor, is a component of polycarbonate plastics, epoxy resins, and polystyrene. Several studies have reported potent in vivo effects, because BPA behaves as an estrogen agonist and/or antagonist and as an androgen and thyroid hormone antagonist. Ojectives: We investigated the effects of neonatal exposure to BPA on the reproductive axis in adult female Sprague-Dawley rats. Methods: Female rats were injected subcutaneously, daily from postnatal day 1 (PND1) to PND10 with BPA in castor oil at 500 μg/50 μL [BPA500; ~ 10 -4 M, a dose higher than the lowest observed adverse effect level (LOAEL) of 50 mg/kg], 50 μg/50 μL (BPA50), or 5 μg/50 μL (both BPA50 and BPA5 are doses lower than the LOAEL), or castor oil vehicle alone. In adults we studied a) the release of gonadotropin-releasing hormone (GnRH) from hypothalamic explants, b) serum sex hormone levels, and c) ovarian morphology, ovulation, and fertility. Results: Neonatal exposure to BPA was associated with increased serum testosterone and estradiol levels, reduced progesterone in adulthood, and altered in vitro GnRH secretion. Animals exposed to BPA500 had altered ovarian morphology, showing a large number of cysts. Animals exposed to BPA50 had reduced fertility without changes in the number of oocytes on the morning of estrus, whereas animals exposed to BPA500 showed infertility. Conclusions: Exposure to high doses of BPA during the period of brain sexual differentiation altered the hypothalamic-pituitary-gonadal axis in female Sprague-Dawley rats. These results have the potential to link neonatal exposure to high doses of BPA in rats with the development of polycystic ovarian syndrome. Studies of doses and routes of administration more consistent with human exposures are needed to determine the relevance of these findings to human health.


Houssay B.A.,Institute Biologia y Medicina Experimental
Revista Argentina de Endocrinologia y Metabolismo | Year: 2015

The production of diabetes after total pancreatectomy in the dog by von Mering and Minkowski was one of the greatest advances of the experimental medicine, that demostrated the internal secretion of the pancreas and led to the discovery of insulin. Diabetes was an unexpected finding in the course of experiments planned for the study of the intestinal absorption of fats. The hazard favored men well prepared, that were active in diabetic research. The real history of the events was unknown until recently and a lot of fantastic stories were widespread. The present publication of a personal letter of Minkowski, in German, accompanied by the Spanish translation (the English translation appeared in Diabetes, 1952, 1, 112-116, but not the german text), explains clearly the truth abouth these facts. Copyright ® 2015 por la Sociedad Argentina de Endocrinología y Metabolismo.


Braun-Menendez E.,Institute Biologia y Medicina Experimental
Revista Argentina de Endocrinologia y Metabolismo | Year: 2015

Different aspects of the relations between endocrine glands and the kidney are revised, among them the renotrophic action of these glands, their influence upon global kidney function, upon water and electrolite excretion and upon kidney metabolism and enzymes. In spite of the numerous papers written on that subject it has not yet been possible to conclude whether the endocrine glands exercise a direct influence on the kidney or whether the changes that can be detected in its morphology, excretion, and enzymatic activity are a direct consecuence of hormonal excess or defficiences, or secondary to more general metabolic changes. It has been fairly proved that the antidiuretic principle of posterior pitiuitary and the mineralcorticoid hormones act directly upon the kidney. The former increases the maximal capacity of renal tubules to reabsorb water and the latter increases the maximal ability of sodium reabsorption of the same. It is also probable that hormones act directly upon certain renal enzimes. The influence of endocrine glands upon the trophism and speciphic functions of the kidney are indirect owing to the profound influences of the pituitary, the thyroid and the sex male hormones in exerted through modifications in protein metabolism due to the either and excess or a defficiency of those hormones. The administration of protein rich diets has a great a renotrophic action as that of pituitary and thyroid hormones and the administration of protein poor diets produces hypotrophy and hypofunction of the kidney similar to those that follow hypophysectomy or thyroidectomy. These and other reasons have led the authors to the hypothesis that the renal mass and functions are controlled by a hypophetic substance-renotrophin-the blood level of which depends on the intensity of protein metabolism. The renotrophin (or renotrophins) might be a product of the intermediate metabolism of proteins. Copyright ® 2015 por la Sociedad Argentina de Endocrinología y Metabolismo.

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