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1. A practical guide to request humoral autoimmunity markers and genetic tests in diabetes mellitus

Author

Silvina Valdez, Miguel Ángel Alonso Amorín, María Fernanda Álvarez Yuseff, Luz Andreone, Gloria Cerrone, Iris Mabel Ledesma, Alejandra Matejic, Laura Pelayo, Marcelo Javier Pelone, Aldana Trabucchi, and Gustavo Frechtel

Subjects
genética, autoanticuerpos, clasificación, diagnóstico clínico, Nutritional diseases. Deficiency diseases, RC620-627, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Diabetes mellitus (DM) is a heterogeneous disease, with diverse clinical phenotypes, all with hyperglycemia. Historically, four factors have been used to identify this diversity: the age at onset, the severity of the disease, that is, the degree of loss of beta cell function and insulin resistance, and the presence of circulating autoantibodies. Currently, the parameters used to classify the different types of DM make it difficult to diagnose and treat patients. The different clinical manifestations require an accurate diagnosis to achieve an effective therapeutic approach through the use of immunogenetics and clinical biochemistry. This practical guide aims to accurately classify the often uncertain clinical presentations within the two main types of diabetes.

Published
2022
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2. O16 Activation of Nrf2 pathway by Compound A (CpdA) protects b-cells against cytokine-mediated inflammatory injury

Author

Luz Andreone, Carolina Sétula, Juan Manuel Assad, and Marcelo Javier Perone

Subjects
hiperglucemia, célula-ß, cpda, Nutritional diseases. Deficiency diseases, RC620-627, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Introduction: The development of the autoimmune process during type 1 diabetes (DM1) contributes to insulitis; in this context, both β-cell stress and subsequent insulin secretory deficiency precede clinical signs of disease. Hyperglycemia triggers excess production of mitochondrial reactive oxygen species (ROS) that overwhelm the anti-oxidative capacity of β-cells, leading to oxidative stress. Islet inflammatory microenvironment during the autoimmune attack contributes to the activation of oxidative and endoplasmic reticulum (ER) stress resulting in β-cell dysfunction and death. The transcription factor Nrf2 regulates the expression of cytoprotective genes in response to oxidative stress, its induction is crucial for the normal β-cell physiology. We reported that Compound A (CpdA), a dissociative glucocorticoid receptor-ligand, is an effective modulator of key immune cells involved in insulitis, T and dendritic cells. In addition, we observed that CpdA ameliorates cytokine (IL-1b+IFN-g; CYT)-induced ER stress in β-cells and that in vivo CpdA administration leads to a significant delay of disease onset in an accelerated murine model of DM1. The development of new agents, with anti-inflammatory and immunomodulatory action and protective potential directed against dysfunctional signaling of β-cells is of clinical interest in diabetes. Objectives: The aim of this study was to explore the effect of CpdA on Nrf2 signaling pathway and CYT-induced oxidative stress in β-cells. Materials & Methods: A rat insulinoma cell line (INS-1E) was used as experimental model. CpdA chemical formula: 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride. A reporter plasmid (ARE-LUC) was used for the evaluation of Nrf2 transcriptional activity (luminometry); RTqPCR (Sybr Green) for analysis of mRNA expression; WB for protein expression analysis; a DCFDA based commercial kit to evaluate ROS (fluorometry); MTT assay for cell viability analysis and ELISA for insulin.

Published
2020
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3. Hormonal Regulation of Follicle-Stimulating Hormone Glycosylation in Males

Author

Stella Campo, Luz Andreone, Verónica Ambao, Mariela Urrutia, Ricardo S. Calandra, and Susana B. Rulli

Subjects
Follicle-stimulating hormone glycosylation, hormonal regulation, male gonad, Sertoli cell, inhibin, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

The Follicle-Stimulating Hormone plays an important role in the regulation of gametogenesis. It is synthesized and secreted as a family of glycoforms with differing oligosaccharide structure, biological action, and half-life. The presence of these oligosaccharides is absolutely necessary for the full expression of hormone bioactivity at the level of the target cell. The endocrine milieu modulates the glycosylation of this hormone. During male sexual development a progressive increase in FSH sialylation and in the proportion of glycoforms bearing complex oligosaccharides are the main features in this physiological condition. In late puberty, FSH oligosaccharides are largely processed in the medial- and trans-Golgi cisternae of the gonadotrope and remain without changes throughout adult life. In experimental models, the absence of gonads severely affects FSH sialylation; androgen administration is able to restore the characteristics observed under physiological conditions. The expression of ST6 beta-galactoside alpha-2,6-sialyltransferase 1 is hormonally regulated in the male rat; it decreases after short periods of castration but increases markedly at longer periods of androgen deprivation. Although ST3 beta-galactoside alpha-2,3-sialyltransferase 3 is expressed in the male rat pituitary it is not influenced by changes in the endocrine milieu. The oligosaccharide structure of FSH has an impact on the Sertoli cell endocrine activity. In more advanced stages of Sertoli cell maturation, both sialylation and complexity of the oligosaccharides are involved in the regulation of inhibin B production; moreover, FSH glycoforms bearing incomplete oligosaccharides may enhance the stimulatory effect exerted by gonadal growth factors. In this review, we discuss available information on variation of FSH glycosylation and its hormonal regulation under different physiological and experimental conditions, as well as the effect on Sertoli cell endocrine activity.

Published
2019
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4. The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis

Author

Marie Balslev Backe, Chunyu Jin, Luz Andreone, Aditya Sankar, Karl Agger, Kristian Helin, Andreas Nygaard Madsen, Steen Seier Poulsen, Madhusudhan Bysani, Karl Bacos, Charlotte Ling, Marcelo Javier Perone, Birgitte Holst, and Thomas Mandrup-Poulsen

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Aims. Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods. We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results. GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion. Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.

Published
2019
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5. Interactions Between the Neuroendocrine System and T Lymphocytes in Diabetes

Author

Luz Andreone, María Laura Gimeno, and Marcelo J. Perone

Subjects
T lymphocytes, inflammation, insulin resistance, adipose, muscle, liver, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

It is well established that there is a fine-tuned bidirectional communication between the immune and neuroendocrine tissues in maintaining homeostasis. Several types of immune cells, hormones, and neurotransmitters of different chemical nature are involved as communicators between organs. Apart of being key players of the adaptive arm of the immune system, it has been recently described that T lymphocytes are involved in the modulation of metabolism of several tissues in health and disease. Diabetes may result mainly from lack of insulin production (type 1 diabetes) or insufficient insulin and insulin resistance (type 2 diabetes), both influenced by genetic and environmental components. Herein, we discuss accumulating data regarding the role of the adaptive arm of the immune system in the pathogenesis of diabetes; including the action of several hormones and neurotransmitters influencing on central and peripheral T lymphocytes development and maturation, particularly under the metabolic burden triggered by diabetes. In addition, we comment on the role of T-effector lymphocytes in adipose and liver tissues during diabetes, which together enhances pancreatic β-cell stress aggravating the disease.

Published
2018
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6. Male Central Precocious Puberty: Serum Profile of Anti-Müllerian Hormone and Inhibin B before, during, and after Treatment with GnRH Analogue

Author

Romina P. Grinspon, Luz Andreone, Patricia Bedecarrás, María Gabriela Ropelato, Rodolfo A. Rey, Stella M. Campo, and Ignacio Bergadá

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

We aimed to describe the functional changes of Sertoli cells, based on the measurement of serum anti-Müllerian hormone (AMH) and inhibin B during treatment with GnRHa and after its withdrawal in boys with central precocious puberty. Six boys aged 0.8 to 5.5 yr were included. AMH was low at diagnosis in patients >1 yr but within the normal range in younger patients. AMH increased to normal prepubertal levels during treatment. After GnRHa withdrawal, AMH declined concomitantly with the rise in serum testosterone. At diagnosis, inhibin B was elevated and decreased throughout therapy, remaining in the upper normal prepubertal range. In patients with testicular volume above 4 mL AMH remained higher in spite of suppressed FSH. After treatment withdrawal, inhibin B rose towards normal pubertal levels. In conclusion, AMH did not decrease in patients

Published
2013
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7. Compound A attenuates proinflammatory cytokine-induced endoplasmic reticulum stress in beta cells and displays beneficial therapeutic effects in a mouse model of autoimmune diabetes

Author

Luz Andreone, Florencia Fuertes, Carolina Sétula, Andres E. Barcala Tabarrozzi, Miranda S. Orellano, Ricardo A. Dewey, Rita Bottino, Karolien De Bosscher, and Marcelo J. Perone

Subjects
Pharmacology, Cellular and Molecular Neuroscience, Molecular Medicine, Cell Biology, Molecular Biology
Published
2022
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8. Compound A attenuates proinflammatory cytokine-induced endoplasmic reticulum stress in ß-cells and displays beneficial therapeutic effects in a mouse model of autoimmune diabetes

Author

Luz Andreone, Florencia Fuertes, Carolina Sétula, Andres E. Barcala Tabarrozzi, Miranda S. Orellano, Ricardo A. Dewey, Rita Bottino, Karolien De Bosscher, and Marcelo J. Perone

Abstract

Type 1 diabetes (T1D) is characterized by an immune-mediated progressive destruction of the insulin-producing β-cells. Proinflammatory cytokines trigger endoplasmic reticulum (ER) stress and subsequent insulin secretory deficiency in cultured β-cells, mimicking the islet microenvironment in T1D. β-cells undergo physiologic ER stress due to the high rate of insulin production and secretion under stimulated conditions. Severe and uncompensated ER stress in β-cells is induced by several pathological mechanisms before onset and during T1D. We previously described that the small drug Compound A (CpdA), a selective glucocorticoid receptor (GR/NR3C1, nuclear receptor subfamily 3, group C, member 1) ligand with demonstrated inflammation-suppressive activity in vivo, is an effective modulator of effector T and dendritic cells and of macrophages, yet, in a GR-independent manner. Here, we focus on CpdA’s therapeutic potential in T1D cellular and animal models. We demonstrate that CpdA improves the unfolded protein response (UPR) by attenuating ER stress and favoring the survival and function of β-cells exposed to an environment of proinflammatory cytokines. CpdA administration to NODscid mice adoptively transferred with diabetogenic splenocytes (from diabetic NOD mice) led to a delay of disease onset and reduction of diabetes incidence. Histological analysis of the pancreas showed a reduction in islet leukocyte infiltration (insulitis) and preservation of insulin expression in CpdA-treated normoglycemic mice in comparison with control group. These new findings together with our previous reports justify further studies on the administration of this small molecule as a novel therapeutic strategy with dual targets (effector immune and β-cells) during autoimmune diabetes.

Published
2022
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9. Co-Transplantation of Marginal Mass Allogeneic Islets with 3D-Culture-Derived Adult Human Skin Cells Improves Glycemia in Diabetic Mice

Author

Janaina Macedo da Silva, Mari Cleide Sogayar, Talita C. Oliveira, Letícia Ferreira Terra, Leticia Labriola, Ancély Ferreira dos Santos, Giuseppe Palmisano, Luz Andreone, Rosangela A. M. Wailemann, Marcelo J. Perone, Vinícius M. Gomes, Maria Fernanda Forni, and Livia Rosa-Fernandes

Subjects
Co transplantation, medicine.medical_specialty, geography, Endocrinology, geography.geographical_feature_category, business.industry, Internal medicine, medicine, Diabetic mouse, Human skin, business, Islet
Abstract

Background. Pancreatic islets transplantation represents a promising therapeutic option for severe type 1 diabetes (T1D). Maintenance of long-term viability of transplanted islets still requires improvement. Stem cell use represents an option to repair and replace damaged islets or, alternatively, b cells in T1D. Mesenchymal stem cells (MSC) have been proposed as adjuvants for islet transplantation, facilitating grafting and improving their functionality. Aggregation of stem cells has gained interest in providing physiological interactions between cells and enhancing the in situ concentration of modulators of inflammation and immunity.Methods. We established a hanging-drop culture by the spontaneous aggregation of adult human skin fibroblast-like cells as spheroids. Adult skin spheroid-derived cells (SphCs) were characterized in vitro and in vivo. We assessed the potential benefit of SphCs as adjuvants to improve islet functionality by cotransplantation with a marginal mass of allogeneic islets in an experimental diabetic mouse model. We characterized the secretome of SphCs by mass spectrometry-based proteomics.Results. SphCs were characterized as multipotent progenitors by their surface expression of markers analyzed by flow cytometry and multilineage germ differentiation capacity. Coculture of SphCs with anti-CD3-stimulated mouse splenocytes diminished the proliferation of T-CD4+ lymphocytes and biased splenocyte cytokine secretion through an increase in the Th2/Th1 ratio. SphCs conditioned media attenuated apoptosis of islets induced by inflammatory cytokine challenge in vitro. Administration (i.t.) of SphCs showed the absence of tumorigenicity in immune-deficient mice.SphCs improved glycemic control when cotransplanted with a marginal mass of allogeneic islets in an experimental diabetic mouse model without pharmacological immunosuppression. SphCs’ protein secretome differed from its paired skin fibroblast-like counterpart in containing 70% of up- and downregulated proteins and biological processes that overall positively influence islets such as cytoprotection, cellular stress, metabolism, and survival.Conclusions. Hanging-drop cell culture methodology might contribute to the development of an efficient way to improve transplantation outcome by reducing undesirable consequences of pharmacological immunosuppression as well as the number of allogeneic islets required to achieve normoglycemia in T1D transplanted patients. Further studies might determine whether the identified proteins sustain immunomodulation and/or cytoprotective effects in transplanted allogeneic islets.

Published
2021
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10. The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis

Author

Karl Bacos, Luz Andreone, Kristian Helin, Aditya Sankar, Charlotte Ling, Madhusudhan Bysani, Thomas Mandrup-Poulsen, Marie Balslev Backe, Andreas N. Madsen, Birgitte Holst, Steen Seier Poulsen, Chunyu Jin, Marcelo Javier Perone, and Karl Agger

Subjects
0301 basic medicine, Jumonji Domain-Containing Histone Demethylases, medicine.medical_specialty, Article Subject, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Mice, SCID, Nod, Carbohydrate metabolism, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Streptozocin, Diabetes Mellitus, Experimental, Islets of Langerhans, Mice, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Mice, Inbred NOD, Insulin-Secreting Cells, Internal medicine, Diabetes mellitus, medicine, Animals, Homeostasis, Glucose homeostasis, Growth Disorders, Mice, Knockout, 2. Zero hunger, geography, lcsh:RC648-665, geography.geographical_feature_category, biology, Insulin, Streptozotocin, Islet, medicine.disease, 3. Good health, DNA-Binding Proteins, Mice, Inbred C57BL, Glucose, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Carbohydrate Metabolism, Demethylase, Insulin Resistance, Research Article, medicine.drug
Abstract

Aims. Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function.Materials and Methods. We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B.Results. GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice.Conclusion. Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.

Published
2019
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11. SPARC is required for the maintenance of glucose homeostasis and insulin secretion in mice

Author

Agostina Onorato, Mariana Malvicini, Marcelo J. Perone, María L. Gimeno, Catalina Atorrasagasti, Mariana Garcia, Luz Andreone, Esteban Fiore, Guillermo Mazzolini, and Juan Bayo

Subjects
Blood Glucose, Male, 0301 basic medicine, Aging, medicine.medical_specialty, GLUCOSE HOMEOSTASIS, medicine.medical_treatment, Type 2 diabetes, Carbohydrate metabolism, Diet, High-Fat, Diabetes Mellitus, Experimental, Islets of Langerhans, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Dietary Sucrose, Internal medicine, Diabetes mellitus, medicine, Animals, Homeostasis, Insulin, Glucose homeostasis, Osteonectin, Glucose Transporter Type 2, Mice, Knockout, Secretory Pathway, business.industry, SPARC, purl.org/becyt/ford/3.1 [https], General Medicine, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Adipogenesis, 030220 oncology & carcinogenesis, purl.org/becyt/ford/3 [https], Metabolic syndrome, business, Biomarkers, INSULIN SECRETION
Abstract

Obesity, metabolic syndrome, and type 2 diabetes, three strongly interrelated diseases, are associated to increased morbidity and mortality worldwide. The pathogenesis of obesity-associated disorders is still under study. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein expressed in many cell types including adipocytes, parenchymal, and non-parenchymal hepatic cells and pancreatic cells. Studies have demonstrated that SPARC inhibits adipogenesis and promotes insulin resistance; in addition, circulating SPARC levels were positively correlated with body mass index in obese individuals. Therefore, SPARC is being proposed as a key factor in the pathogenesis of obesity-associated disorders. The aim of this study is to elucidate the role of SPARC in glucose homeostasis. We show here that SPARC null (SPARC −/− ) mice displayed an abnormal insulin-regulated glucose metabolism. SPARC −/− mice presented an increased adipose tissue deposition and an impaired glucose homeostasis as animals aged. In addition, the absence of SPARC worsens high-fat diet-induced diabetes in mice. Interestingly, although SPARC −/− mice on high-fat diet were sensitive to insulin they showed an impaired insulin secretion capacity. Of note, the expression of glucose transporter 2 in islets of SPARC −/− mice was dramatically reduced. The present study provides the first evidence that deleted SPARC expression causes diabetes in mice. Thus, SPARC deficient mice constitute a valuable model for studies concerning obesity and its related metabolic complications, including diabetes. Fil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Onorato, Agostina Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Gimeno, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Andreone, Luz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: García, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Bayo Fina, Juan Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Perone, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina

Published
2019
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12. Role of FSH glycan structure in the regulation of Sertoli cell inhibin production

Author

Verónica Ambao, Luz Andreone, Selva B. Cigorraga, Eliana Herminia Pellizzari, Nazareth Loreti, and Stella Campo

Subjects
Male, 0301 basic medicine, Embryology, Glycosylation, Cellular differentiation, Oligosaccharides, law.invention, Rats, Sprague-Dawley, Follicle-stimulating hormone, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, law, Cyclic AMP, Inhibin-beta Subunits, chemistry.chemical_classification, Estradiol, Molecular Structure, biology, Chemistry, Obstetrics and Gynecology, Cell Differentiation, Activin A, Oligosaccharide, Sertoli cell, Recombinant Proteins, medicine.anatomical_structure, Recombinant DNA, Follicle Stimulating Hormone, Human, Inhibin B, CIENCIAS NATURALES Y EXACTAS, endocrine system, medicine.medical_specialty, Glycan, Otras Ciencias Biológicas, 030209 endocrinology & metabolism, In Vitro Techniques, Ciencias Biológicas, 03 medical and health sciences, Polysaccharides, Internal medicine, medicine, Animals, Inhibins, Protein Structure, Quaternary, FSH glycoforms, Sertoli Cells, Cell Biology, Rats, 030104 developmental biology, Reproductive Medicine, biology.protein, Follicle Stimulating Hormone, Hormone
Abstract

Variations in follicle-stimulating hormone (FSH) carbohydrate composition and structure are associated with important structural and functional changes in Sertoli cells (SCs) during sexual maturation. The aim of the present study was to investigate the impact of FSH oligosaccharide structure and its interaction with gonadal factors on the regulation of monomeric and dimeric inhibin production at different maturation stages of the SC. Recombinant human FSH (rhFSH) glycosylation variants were isolated according to their sialylation degree (AC and BA) and complexity of oligosaccharides (CO and HY). Native rhFSH stimulated inhibin α-subunit (Pro-αC) but did not show any effect on inhibin B (INHB) production in immature SCs isolated from 8-day-old rats. Activin A stimulated INHB and had a synergistic effect on FSH to stimulate Pro-αC. The less acidic/sialylated rhFSH charge analogues, BA, were the only charge analogue mix that stimulated INHB as well as the most potent stimulus for Pro-αC production. Native rhFSH stimulated both Pro-αC and INHB in SCs at a more advanced maturation stage, isolated from 20-day-old rats. In these cells, all rhFSH glycosylation variants increased INHB and Pro-αC production, even in the presence of growth factors. The BA preparation exerted a more marked stimulatory effect on INHB and Pro-αC than the AC. Glycoforms bearing high mannose and hybrid-type oligosaccharides, HY, stimulated INHB and Pro-αC more effectively than those bearing complex oligosaccharides, CO, even in the presence of gonadal growth factors. These findings demonstrate the modulatory effect of FSH oligosaccharide structure on the regulation of inhibin production in the male gonad. Fil: Andreone, Luz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Ambao, Veronica Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Pellizzari, Eliana Herminia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Loreti, Rosana Nazareth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Cigorraga, Selva Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Campo, Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina

Published
2017
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13. O16 La activación de NRF2 por el compuesto A (CPDA) protege a las células-ß de la injuria inflamatoria medida por citoquinas

Author

Marcelo Javier Perone, Carolina Sétula, Juan Manuel Assad, and Luz Andreone

Subjects
chemistry.chemical_classification, Reactive oxygen species, Chemistry, medicine.medical_treatment, Context (language use), medicine.disease, medicine.disease_cause, Molecular biology, Immune system, Cytokine, medicine, Unfolded protein response, General Earth and Planetary Sciences, Viability assay, Insulitis, Oxidative stress, General Environmental Science
Abstract

Introducción: el desarrollo del proceso autoinmune durante la diabetes tipo 1 (DM1) contribuye a la insulitis; en este contexto, el estrés de las células-ß y su posterior deficiencia en la secreción de insulina preceden a los signos clínicos de la enfermedad. La hiperglucemia desencadena la producción de especies reactivas de oxígeno (ROS) mitocondriales que superan la capacidad antioxidante de las células-ß conduciendo al estrés oxidativo. El microambiente inflamatorio del islote contribuye a la activación del estrés oxidativo y del retículo endoplásmico (RE) resultando en la disfunción y muerte de las células-ß. El factor de transcripción Nrf2 regula la expresión de genes citoprotectores en respuesta al estrés oxidativo, su inducción es necesaria para la fisiología normal de la célula-ß. Hemos reportado que el CpdA regula células inmunes clave en la respuesta inmune e inflamatoria y en la insulitis, linfocitos T y células dendríticas. También observamos que el CpdA disminuye el estrés de RE inducido por citoquinas inflamatorias (IL-1ß+IFN-g; CYT) en células-ß y que la administración in vivo del CpdA retarda la aparición de hiperglucemia en un modelo murino de diabetes autoinmune. El desarrollo de nuevos agentes con acción antiinflamatoria e inmunomoduladora y potencial protector dirigido a la señalización disfuncional de las células-ß posee interés clínico en la diabetes.Objetivos: explorar el efecto del CpdA sobre la vía de señalización de Nrf2 y el estrés oxidativo inducido por CYT en las células-ß.Materiales y métodos: como modelo experimental utilizamos la línea celular de insulinoma de rata (INS-1E). Fórmula química del CpdA: cloruro de 2-(4-acetoxifenil)-2- cloro-N-metil-etilamonio. Se utilizó un plásmido reportero (ARE-LUC) para la evaluación de la actividad transcripcional de Nrf2 (luminometría), RT-qPCR (Sybr Green) para el análisis de la expresión de ARNm, WB para el análisis de la expresión de proteínas, kit comercial basado en DCFDA para evaluar ROS (fluorometría), análisis de viabilidad celular por MTT y ELISA para insulina.

Published
2020
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14. Cooperative international neuromuscular research group duchenne natural history study demonstrates insufficient diagnosis and treatment of cardiomyopathy in duchenne muscular dystrophy

Author

Lisa Wahlgren, Cameron Kennedy, Betsy Malkus, Justin Malane, Casey Nguyen, Anjali Gupta, Erica Goude, Linda Johnson, Heather Gordish-Dressman, Victoria Rodriguez, Marcia Margolis, Susan Blair, Angela Gonzales, David D. Kilmer, Lori Walker, Paola Canelos, Julaine Florence, Amy Erickson, Jay Han, Angela Chiu, Laila Eliasoph, Nancy L. Kuntz, Gareth Parry, Eugenio Monasterio, Luz Andreone, Valentina Morettini, Zoë Sund, Avital Cnaan, Jason Weimer, Lucia Chen, Krista Coleman-Wood, Alina Nicorici, Ann Hoffman, Michelle Cregan, Hanna Kolski, Lauren P. Morgenroth, Richard Webster, Lorena Levi, C. Chidambaranathan, Paul Golumbak, Dani Villano, Reiko Shimizu, Stephanie Wicks, Caitlin Wright, Naomi Bartley, Alessandro Molteni, Anne Christine Alhander, Renee Renna, Hoda Abdel-Hamid, Christopher G. Bise, Duygu Selcen, Glenn Lopate, Debbie Yaffe, Suresh Kumar, K. Carroll, Rachel Young, Jennifer Thannhauser, Pura Fuste, David Walk, Ann Craig, Rachel A. Kennedy, T. Duong, Karen Jones, Elizabeth Hosaki, Elana Wisband, Robert S. McNeil, M. Al-Lozi, Wendy Korn-Petersen, Kristy Rose, Paula R. Clemens, Katy DeValle, Luca Capone, Jeanine Schierbacker, Catherine Seiner, Marissa Birkmeier, Robert Casper, Antonio Arrieta, Anna Karin Kroksmark, Sarah Kaminski, Mehrnaz Yousefi, Vivienne Harris, Maria Beneggi, Andrew J. Kornberg, Sheila Espada, Barbara Grillo, Cameron E. Naughton, Merete Glick, Christopher F. Spurney, Adina Bar Leve, Nanette C. Joyce, Jose Corderi, Ulrika Sterky, Carlos A. Luciano, Cassandra Feliciano, A. Zimmerman, Anne Berit Ekström, Judy Clift, Meegan Barrett-Adair, F. Hu, Brenda Deliz, Charlie Wulf, and Lilia Mesa

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Pediatrics, Physiology, business.industry, Duchenne muscular dystrophy, Cardiomyopathy, medicine.disease, nervous system diseases, Natural history, Cellular and Molecular Neuroscience, Physiology (medical), mental disorders, Physical therapy, medicine, In patient, Neurology (clinical), business, Natural history study
Abstract

Introduction Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD).

Published
2014
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15. The glycan structure in recombinant human FSH affects endocrine activity and global gene expression in human granulosa cells

Author

Nazareth Loreti, Elmer Andrés Fernández, Luz Andreone, Stella Campo, Saúl Lira Albarran, Fernando Larrea, Cristóbal Fresno, and David Barrera

Subjects
GENE EXPRESSION, endocrine system, medicine.medical_specialty, Glycan, Glycosylation, CIENCIAS MÉDICAS Y DE LA SALUD, Microarray, medicine.medical_treatment, Endocrine System, Medicina Clínica, HUMAN GRANULOSA CELL, Real-Time Polymerase Chain Reaction, Biochemistry, Structure-Activity Relationship, chemistry.chemical_compound, Endocrinology, Polysaccharides, Cell Line, Tumor, Endocrinología y Metabolismo, Internal medicine, FSH, Gene expression, medicine, Humans, Gene Regulatory Networks, Inhibins, Molecular Biology, Gene, Oligonucleotide Array Sequence Analysis, Granulosa Cells, biology, Gene Expression Profiling, Recombinant Proteins, Cell biology, Steroid hormone, STEROID, Gene Expression Regulation, INHIBIN, chemistry, biology.protein, Female, Follicle Stimulating Hormone, Human, Steroids, GLYCOSYLATION VARIANT, Function (biology), Hormone
Abstract

The aim of this study was to analyse the biological response to different recombinant human FSH (rhFSH)glycosylation variants on the endocrine activity and gene expression at whole-genome scale in human granulosa-like tumor cell line, KGN. The effects of differences in rhFSH sialylation and oligosaccharide complexity were determined on steroid hormone and inhibin production. A microarray approach was used to explore gene expression patterns induced by rhFSH glycosylation variants. Set enrichment analysis revealed that hormone sialylation and oligosaccharide complexity in rhFSH differentially affected the expression of genes involved in essential biological processes and molecular functions of KGN cells. The relevance of rhFSH oligosaccharide structure on teroidogenesis was confirmed assessing gene expression by real time-PCR. The results demonstrate that FSH oligosaccharide structure affects expression of genes encoding proteins, growth factors and hormones essential for granulosa cells function. Fil: Loreti, Nazareth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina Fil: Fresno, Cristobal. Universidad Católica de Córdoba. Facultad de Ingeniería. Biomedical Data Mining Group; Argentina Fil: Barrera, David. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Departamento de Biología de la Reproducción; México Fil: Andreone, Luz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina Fil: Lira Albarran, Saúl. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Departamento de Biología de la Reproducción; México Fil: Fernandez, Elmer Andres. Universidad Católica de Córdoba. Facultad de Ingeniería. Biomedical Data Mining Group; Argentina Fil: Larrea, Fernando. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Departamento de Biología de la Reproducción; México Fil: Campo, Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina

Published
2013
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16. Effect of sialylation and complexity of FSH oligosaccharides on inhibin production by granulosa cells

Author

Verónica Ambao, Ursula Bussmann, Nazareth Loreti, Luz Andreone, Stella Campo, and Romina Trigo

Subjects
endocrine system, Embryology, medicine.medical_specialty, Glycosylation, CIENCIAS MÉDICAS Y DE LA SALUD, Oligosaccharides, Ciencias de la Salud, Biology, Models, Biological, Rats, Sprague-Dawley, purl.org/becyt/ford/3.3 [https], chemistry.chemical_compound, Endocrinology, Internal medicine, FSH, medicine, Animals, Humans, Inhibins, Granulosa Cells, SIALYLATION, Obstetrics and Gynecology, Cell Biology, N-Acetylneuraminic Acid, Rats, Otras Ciencias de la Salud, Sprague dawley, Carbohydrate Sequence, INHIBIN, Reproductive Medicine, chemistry, Female, purl.org/becyt/ford/3 [https], Follicle Stimulating Hormone, hormones, hormone substitutes, and hormone antagonists
Abstract

Granulosa cell inhibin A and B production is regulated by FSH and gonadal factors. This gonadotrophin is released as a mixture of glycoforms, which induce different biological responses in vivo and in vitro. Our aim was to determine the effect of recombinant human FSH glycosylation variants on inhibin A and B production by rat granulosa cells. Preparative isoelectrofocusing was used to isolate more acidic/sialylated (pH5.00) rhFSH charge analogues. Concanavalin-A was used to isolate unbound and firmly bound rhFSH glycoforms on the basis of their oligosaccharide complexity. Granulosa cells, obtained from oestrogen-primed immature rats, were cultured with either native rhFSH or its glycosylation variants. Inhibin A and B were determined using specific ELISAs. Results were expressed as mean±SEM. Under basal conditions inhibin A was the predominant dimer produced (inhibin A: 673±55; inhibin B: 80±4 pg/mL). More acidic/sialylated charge analogues stimulated inhibin B production when compared to inhibin A at all doses studied; in contrast, less acidic/sialylated charge analogues stimulated inhibin A production and elicited no effect on inhibin B. Glycoforms bearing complex oligosaccharides showed a potent stimulatory effect on inhibin B when compared to inhibin A production (i.e. dose 1ng/mL: 4.9±0.5vs0.9±0.1 fold stimulation, P

Published
2013
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17. Male Central Precocious Puberty: Serum Profile of Anti-Müllerian Hormone and Inhibin B before, during, and after Treatment with GnRH Analogue

Author

Luz Andreone, María Gabriela Ropelato, Ignacio Bergadá, Patricia Bedecarrás, Stella Campo, Rodolfo Rey, and Romina P Grinspon

Subjects
endocrine system, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Article Subject, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Central precocious puberty, Ciencias de la Salud, Stimulation, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Andrology, purl.org/becyt/ford/3.3 [https], Endocrinology, INHIBIN B, Internal medicine, AMH, medicine, Inhibin b, lcsh:RC648-665, MALE, biology, urogenital system, Endocrine and Autonomic Systems, business.industry, Anti-Müllerian hormone, Sertoli cell, female genital diseases and pregnancy complications, Otras Ciencias de la Salud, Androgen receptor, medicine.anatomical_structure, PUBERTY, Clinical Study, biology.protein, purl.org/becyt/ford/3 [https], business, hormones, hormone substitutes, and hormone antagonists, After treatment, Hormone
Abstract

We aimed to describe the functional changes of Sertoli cells, based on the measurement of serum anti-Müllerian hormone (AMH) and inhibin B during treatment with GnRHa and after its withdrawal in boys with central precocious puberty. Six boys aged 0.8 to 5.5 yr were included. AMH was low at diagnosis in patients >1 yr but within the normal range in younger patients. AMH increased to normal prepubertal levels during treatment. After GnRHa withdrawal, AMH declined concomitantly with the rise in serum testosterone. At diagnosis, inhibin B was elevated and decreased throughout therapy, remaining in the upper normal prepubertal range. In patients with testicular volume above 4 mL AMH remained higher in spite of suppressed FSH. After treatment withdrawal, inhibin B rose towards normal pubertal levels. In conclusion, AMH did not decrease in patients

Published
2013
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18. GR-independent down-modulation on GM-CSF bone marrow-derived dendritic cells by the selective glucocorticoid receptor modulator Compound A

Author

Carla N. Castro, Luz Andreone, Sabine Vettorazzi, Laura Ariolfo, Julie Deckers, Marcelo J. Perone, Karolien De Bosscher, María L. Gimeno, María Antunica-Noguerol, Ana C. Liberman, Andrés Ezequiel Barcala Tabarrozzi, Jan Tuckermann, and Paula Mercedes Berguer

Subjects
Lipopolysaccharides, 0301 basic medicine, NF-KAPPA-B, Acetates, purl.org/becyt/ford/1 [https], Mice, 0302 clinical medicine, Glucocorticoid receptor, TLR4, Receptor, INDUCED APOPTOSIS, Multidisciplinary, INDUCED ARTHRITIS, MOUSE MODEL, Bioquímica y Biología Molecular, Acquired immune system, Endocytosis, Up-Regulation, Cell biology, TRANSCRIPTION FACTORS, DIFFERENTIATION, GLUCOCORTICOID RECEPTOR, B7-1 Antigen, Inflammation Mediators, CIENCIAS NATURALES Y EXACTAS, medicine.medical_specialty, Antigen presentation, Down-Regulation, Tyramine, Bone Marrow Cells, Biology, Article, MATURATION, Proinflammatory cytokine, Ciencias Biológicas, 03 medical and health sciences, Receptors, Glucocorticoid, Immune system, Downregulation and upregulation, Internal medicine, medicine, ANTIGEN PRESENTATION, Animals, REGULATORY T-CELLS, purl.org/becyt/ford/1.6 [https], Granulocyte-Macrophage Colony-Stimulating Factor, Biology and Life Sciences, Dendritic Cells, Toll-Like Receptor 4, 030104 developmental biology, Endocrinology, COMPOUND A, PLANT-ORIGIN, 030215 immunology
Abstract

Dendritic cells (DC) initiate the adaptive immune response. Glucocorticoids (GCs) down-modulate the function of DC. Compound A (CpdA, (2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride) is a plant-derived GR-ligand with marked dissociative properties. We investigated the effects of CpdA on in vitro generated GM-CSF-conditioned bone marrow-derived DC (BMDC). CpdA-exposed BMDC exhibited low expression of cell-surface molecules and diminution of the release of proinflammatory cytokines upon LPS stimulation; processes associated with BMDC maturation and activation. CpdA-treated BMDC were inefficient at Ag capture via mannose receptor-mediated endocytosis and displayed reduced T-cell priming. CpdA prevented the LPS-induced rise in pErk1/2 and pP38, kinases involved in TLR4 signaling. CpdA fully inhibited LPS-induced pAktSer473, a marker associated with the generation of tolerogenic DC. We used pharmacological blockade and selective genetic loss-of-function tools and demonstrated GR-independent inhibitory effects of CpdA in BMDC. Mechanistically, CpdA-mediated inactivation of the NF-κB intracellular signaling pathway was associated with a short-circuiting of pErk1/2 and pP38 upstream signaling. Assessment of the in vivo function of CpdA-treated BMDC pulsed with the hapten trinitrobenzenesulfonic acid showed impaired cell-mediated contact hypersensitivity. Collectively, we provide evidence that CpdA is an effective BMDC modulator that might have a benefit for immune disorders, even when GR is not directly targeted. Fil: Barcala Tabarrozzi, Andrés Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Investigación En Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Andreone, Luz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Investigación En Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Deckers, Julie. University of Ghent; Bélgica Fil: Castro, Carla Noemí. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Investigación En Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Gimeno, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Investigación En Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Ariolfo, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Investigación En Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Berguer, Paula Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Antunica Noguerol, María de Las Nieves. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Investigación En Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Liberman, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Investigación En Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Vettorazzi, Sabine. Universitat Ulm; Alemania Fil: Tuckermann, Jan P.. Universitat Ulm; Alemania Fil: De Bosscher, Karolien. University of Ghent; Bélgica Fil: Perone, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Investigación En Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina

Published
2016

19. Establishment of testicular endocrine function impairment during childhood and puberty in boys with Klinefelter syndrome

Author

Adriana Boywitt, Luz Andreone, Ignacio Bergadá, María Gabriela Ropelato, Andrea Arcari, Silvia Gottlieb, Patricia Bedecarrás, Stella Campo, Hamilton Cassinelli, Rodolfo Rey, María Gabriela Bastida, and Graciela Del Rey

Subjects
Anti-Mullerian Hormone, Male, endocrine system, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Karyotype, Aneuploidy, Enzyme-Linked Immunosorbent Assay, Biology, Testicle, Klinefelter Syndrome, Endocrinology, Internal medicine, Testis, medicine, Animals, Humans, Endocrine system, Inhibins, Testosterone, Protein Precursors, Child, Leydig cell, Puberty, Infant, Newborn, Infant, Leydig Cells, Luteinizing Hormone, medicine.disease, medicine.anatomical_structure, Child, Preschool, Klinefelter syndrome, Endocrine gland, Hormone
Abstract

Summary Objective To precisely characterize the chronology of testicular endocrine function impairment during childhood and adolescence in patients with Klinefelter syndrome. Design Retrospective chart review. Patients A total of 29 boys with Klinefelter syndrome with up to 12·3 years follow-up. Measurements Clinical features and serum hormone levels were analysed during follow-up. Results Of the 29 patients, 16 were prepubertal and 13 had already entered puberty at their first visit. Fifteen patients were followed up through late puberty. Before puberty, LH, FSH, testosterone, anti-Mullerian hormone (AMH) and inhibin B were within the expected range in almost all cases. However, levels of the inhibin α-subunit precursor Pro-αC were in the lowest levels of the normal range in most cases. During puberty, FSH levels increased earlier and more markedly than LH. Inhibin B and AMH declined to abnormally low or undetectable levels in advanced pubertal stages. Although testosterone and Pro-αC levels were within the reference ranges in most cases, they were abnormally low for the observed LH values. Conclusions In Klinefelter syndrome, a mild Leydig cell dysfunction is present from early childhood in most cases and persists throughout puberty. Sertoli cell function is normal until mid puberty, when a dramatic impairment is observed.

Published
2007
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20. Controversial role of inhibin α-subunit gene in the aetiology of premature ovarian failure

Author

Eduardo H. Charreau, Victoria Sundblad, Liliana Dain, Stella Campo, Luz Andreone, and Violeta A. Chiauzzi

Subjects
Candidate gene, endocrine system diseases, genotype, inhibin A, Primary Ovarian Insufficiency, inhibin B, Cohort Studies, Loss of heterozygosity, Gene Frequency, Polymorphism (computer science), Genotype, cytosine, adult, Rehabilitation, allele, article, risk assessment, Obstetrics and Gynecology, alpha chain, Inhibin α-subunit gene, female genital diseases and pregnancy complications, Premature ovarian failure, female, follicular phase, nucleic acid base substitution, Female, Amenorrhea, medicine.symptom, follitropin, Risk, Heterozygote, endocrine system, medicine.medical_specialty, Argentina, premature ovarian failure, Biology, amenorrhea, statistical analysis, Internal medicine, thymine, medicine, Humans, inhibin, heterozygosity, Inhibins, controlled study, human, Allele, Polymorphism, Genetic, Inhibin levels, negative feedback, Odds ratio, medicine.disease, major clinical study, Endocrinology, confidence interval, Reproductive Medicine, DNA polymorphism
Abstract

Background: Premature ovarian failure (POF) is characterized by hypergonadotropic amenorrhoea before the age of 40. Inhibin α-subunit (INHα) gene is proposed as a candidate gene due to its role in negative feedback control of FSH. Methods: Polymorphism -16 C>T of INHα gene was studied in 61 POF patients and 82 controls above 40 years old (C > 40). Substitution 769G>A was studied in 59 POF patients, 76 C > 40 and 73 controls below 40 years old (C < 40). Results: No significant difference in risk of POF development for -16T allele was found when comparing idiopathic POF (I-POF) with C > 40 (Odds ratio = 1.46; 95% confidence interval = 0.63-3.19). Implication of -16C>T polymorphism in serum inhibin levels was analysed in 46 controls, and no significant differences (P > 0.05) were found between CC and CT + TT genotype groups when comparing either mid-follicular phase Pro-αC and inhibin B values or mid-luteal phase Pro-αC and inhibin A values. Heterozygosity for substitution 769G>A was found in 1 of 59 POF woman, 2 of 76 C > 40 and 6 of 73 C < 40. Presence of this su bstitution in a relevant number of control subjects is herein described for the first time. Conclusion: Our results indicate that -16C>T and 769G>A variants in INHα gene may not be associated to POF disease. © 2006 Oxford University Press. Fil:Sundblad, V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Charreau, E.H. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.

Published
2006
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21. Involvement of the gonadal germinal epithelium during sex reversal and seasonal testicular cycling in the protogynous swamp eel,synbranchus marmoratus Bloch 1795 (teleostei, synbranchidae)

Author

Luz Andreone, F.L. Lo Nostro, Holcombe E. Grier, and G.A. Guerrero

Subjects
Male, Germinal epithelium, endocrine system, medicine.medical_specialty, Epithelium, Andrology, Internal medicine, Testis, medicine, Animals, Hermaphroditic Organisms, Spermatogenesis, Synbranchus marmoratus, biology, Ovary, Swamp eel, Synbranchus, Sex Determination Processes, Sex reversal, Sertoli cell, biology.organism_classification, Oocyte, Immunohistochemistry, Smegmamorpha, Endocrinology, medicine.anatomical_structure, Female, Animal Science and Zoology, Developmental Biology
Abstract

The swamp eel, Synbranchus marmoratus, is a protogynous, diandric species. During sex reversal, the ovarian germinal epithelium, which forms follicles containing an oocyte and encompassing follicle cells dur- ing the female portion of the life cycle, produces numerous invaginations, or acini, into the ovarian stroma. Within the acini, the gonia that formerly produced oocytes become spermatogonia, enter meiosis, and produce sperm. The acini are bounded by the basement membrane of the ger- minal epithelium. Epithelial cells of the female germinal epithelium, which formerly became follicle (granulosa) cells, now become Sertoli cells in the developing testis. Subsequently, lobules and testicular ducts form. The swamp eel testis has a lobular germinal compartment in both primary and secondary males, although the germinal compartment in testes of secondary males resides within the former ovarian lamellae. The germinal compartment, supported by a basement membrane, is composed of Ser- toli and germ cells that give rise to sperm. Histological and immunohistochemical techniques were used to de- scribe the five reproductive classes that were observed to occur during the annual reproductive cycle: regressed, early maturation, mid-maturation, late maturation, and regression. These classes are differentiated by the pres- ence of continuous or discontinuous germinal epithelia and by the types of germ cells present. Synbranchus mar- moratus has a permanent germinal epithelium. Differ- ences between the germinal compartment of the testes of primary and secondary males were not observed. J. Mor- phol. 257:107-126, 2003. © 2003 Wiley-Liss, Inc.

Published
2003
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22. Relation between the reproductive status and somatolactin cell activity in the pituitary of pejerrey,Odontesthes bonariensis(atheriniformes)

Author

Paula Gabriela Vissio, Dante A. Paz, Luz Andreone, Carlos Augusto Strüssmann, María Cristina Maggese, and Gustavo M. Somoza

Subjects
medicine.medical_specialty, Atheriniformes, media_common.quotation_subject, Immunocytochemistry, General Medicine, Biology, Fish Proteins, biology.organism_classification, Cell activity, Odontesthes bonariensis, Gonadosomatic Index, Endocrinology, Internal medicine, medicine, Animal Science and Zoology, Vitellogenesis, Reproduction, media_common
Abstract

The aim of this study was to analyze the relationship between somatolactin (SL) expressing cells and the reproductive status in a multiple spawning fish, the pejerrey Odontesthes bonariensis. Somatolactin cells were identified in adults of both sexes by immunocytochemistry using a heterologous piscine antiserum. The area of the cells that showed immunoreactivity to SL (ir-SL) was compared in specimens with different degrees of reproductive activity as inferred from histological examination of the gonads and calculation of the gonadosomatic index (GSI %). The results showed a significant difference between the area of ir-SL cells of resting/regressing (62.9 +/- 2.1 micron 2) and sexually active/vitellogenic (76.8 +/- 2.3 micron 2) females and a significant positive correlation between the ir-SL cellular area and the GSI % (P < 0.01 in both cases). In males, the correlation between the area of ir-SL cells and the GSI % was not statistically significant. However, in those animals with the highest GSI % values, the ir-SL cells appeared more numerous and showed an increase in the immunostained area when compared to individuals with lower GSI % values. The present in morphological observations are in accordance with biochemical data obtained from other species and support the assumption that SL might be involved in the regulation of reproduction in fish.

Published
2002
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23. A selective glucocorticoid receptor modulator (CpdA) attenuates cytokine-induced endoplasmic reticulum stress in ß-cells

Author

Ana C. Liberman, Laura Ariolfo, Maria Laura Gimeno, Marcelo J. Perone, Luz Andreone, Mariana J. Elías, Karolien De Bossher, and Sarah Gerlo

Subjects
Glucocorticoid receptor, Cytokine, Hepatology, business.industry, Endocrinology, Diabetes and Metabolism, Endoplasmic reticulum, medicine.medical_treatment, Gastroenterology, Medicine, business, Cell biology
Published
2017
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24. Vacuole Membrane Protein 1 expression in beta cells during naturally occurring diabetes in nod mice

Author

Luz Andreone, Laura Ariolfo, Alejandro Ropolo, Marcelo J. Perone, Maria I. Vaccaro, Mario Rossi, and M Laura Gimeno

Subjects
Hepatology, Biochemistry, business.industry, Endocrinology, Diabetes and Metabolism, Diabetes mellitus, Gastroenterology, medicine, VACUOLE MEMBRANE PROTEIN 1, medicine.disease, business, Beta (finance), NOD mice, Cell biology
Published
2017
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25. Regulation of inhibin/activin expression in rat early antral follicles

Author

Verónica Ambao, Dalhia Abramovich, Ethel V. Velasquez, Nazareth Loreti, Luz Andreone, Marta Tesone, Horacio B. Croxatto, Stella Campo, and Fernanda Parborell

Subjects
endocrine system, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, endocrine system diseases, ACTIVIN, Medicina Clínica, Biochemistry, Rats, Sprague-Dawley, chemistry.chemical_compound, Endocrinology, Ovarian Follicle, Internal medicine, Endocrinología y Metabolismo, Gene expression, Follicular phase, medicine, Endocrine system, Animals, Humans, Inhibins, Androstenedione, RNA, Messenger, Protein Precursors, Molecular Biology, Cells, Cultured, 25-HYDROXYCHOLESTEROL, Androsterone, Chemistry, INHA, Antral follicle, Aminoglutethimide, Hydroxycholesterols, Activins, Rats, INHBB, Protein Subunits, Gene Expression Regulation, INHIBIN, Female, Steroids, Follicle Stimulating Hormone, EARLY ANTRAL FOLLICLES, hormones, hormone substitutes, and hormone antagonists
Abstract

The aim of the present study was to determine the endocrine activity of cultured early antral follicles (EAF) isolated from prepubertal diethylstilbestrol-treated rats. The effect of steroidogenic substrates and FSH on steroid, inhibin A and B, Pro-αC and activin A production was evaluated. Androsterone was the predominant steroid produced by EAF. The addition of androstenedione, androstenedione + FSH and progesterone stimulated oestradiol production, whereas 25-hydroxycholesterol (25-OH-Chol) increased progesterone production. Inhibin A, B, Pro-αC, and activin A were produced under basal conditions. The predominance of inhibin B over inhibin A was not affected by the addition of androstenedione or progesterone. Inhibin A and activin A production was stimulated by FSH. 25-OH-Chol increased Inha, Inhba and Inhbb mRNA expression and the production of the three molecular forms of inhibins but decreased activin A production. These results show that FSH and the steroid follicular microenvironment differentially modulate the gene expression of inhibin/activin subunits, their assembly and secretion. Fil: Andreone, Luz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Velásquez, Ethel V.. Pontificia Universidad Católica de Chile; Chile Fil: Abramovich, Dalhia Nurit. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Ambao, Veronica Ana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Loreti, Rosana Nazareth. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Croxatto, Horacio B.. Instituto Chileno de Medicina Reproductiva; Chile. Universidad de Santiago de Chile; Chile Fil: Parborell, Maria Fernanda Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Tesone, Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Campo, Stella Maris. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina

Published
2009

27. Time course of the serum gonadotropin surge, inhibins, and anti-Müllerian hormone in normal newborn males during the first month of life

Author

Luz Andreone, Rodolfo Rey, Stella Campo, Patricia Bedecarrás, Carlos Milani, Silvia Gottlieb, Ignacio Bergadá, M. Gabriela Ropelato, and César Bergadá

Subjects
Anti-Mullerian Hormone, Male, endocrine system, medicine.medical_specialty, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Ontogeny, Clinical Biochemistry, Context (language use), Biochemistry, Endocrinology, Internal medicine, medicine, Humans, Inhibins, Testosterone, Longitudinal Studies, Protein Precursors, Glycoproteins, biology, Biochemistry (medical), Outcome measures, Infant, Newborn, Anti-Müllerian hormone, Liter, Luteinizing Hormone, Testicular Hormones, Cross-Sectional Studies, biology.protein, Female, Gonadotropin, Follicle Stimulating Hormone, hormones, hormone substitutes, and hormone antagonists, Hormone
Abstract

Newborns with ambiguous genitalia or males with nonpalpable gonads usually require an early assessment of the presence and functional state of testicular tissue.Our objective was to characterize the precise ontogeny of the serum patterns of gonadotropins, testosterone, anti-Müllerian hormone (AMH), and inhibins in normal newborn boys.We conducted a cross-sectional and longitudinal study.Serum samples were obtained in 57 boys and 13 girls on d 2 of life. A second sample was obtained on d 7, 10, 15, 20, and 30 (boys) and on d 30 (girls).Serum levels of gonadotropins, testosterone, AMH, and inhibins were measured.In males, LH and FSH were undetectable or very low on d 2. By d 7, LH increased to 3.94 +/- 3.19 IU/liter (mean +/- sd) and FSH to 2.04 +/- 1.67 IU/liter. LH/FSH ratios were 0.40 +/- 0.11 (d 2) and 2.02 +/- 0.20 (d 30). AMH rose from 371 +/- 168 pmol/liter (d 2) to 699 +/- 245 pmol/liter (d 30), and inhibin B rose from 214 +/- 86 ng/liter (d 2) to 361 +/- 93 ng/liter (d 30). The inhibin alpha-subunit precursor (pro-alphaC) remained stable during the first month of life. Testosterone levels were 66 +/- 42 ng/dl (d 2), 82 +/- 24 ng/dl (d 20), and 210 +/- 130 ng/dl (d 30). A sexual dimorphism was observed in AMH and inhibin B (lower in girls on d 2 and 30), in LH/FSH ratio (lower in girls on d 30) and in testosterone (lower in girls on d 30).Sertoli cell markers AMH and inhibin B are the earliest useful markers indicating the existence of normal testicular tissue.

Published
2006

28. Relation between the reproductive status and somatolactin cell activity in the pituitary of pejerrey, Odontesthes bonariensis (Atheriniformes)

Author

Paula G, Vissio, Luz, Andreone, Dante A, Paz, María C, Maggese, Gustavo M, Somoza, and Carlos A, Strüssmann

Subjects
Fish Proteins, Male, Aging, Pituitary Hormones, Pituitary Gland, Reproduction, Fishes, Animals, Gene Expression, Female, Immunohistochemistry, Glycoproteins
Abstract

The aim of this study was to analyze the relationship between somatolactin (SL) expressing cells and the reproductive status in a multiple spawning fish, the pejerrey Odontesthes bonariensis. Somatolactin cells were identified in adults of both sexes by immunocytochemistry using a heterologous piscine antiserum. The area of the cells that showed immunoreactivity to SL (ir-SL) was compared in specimens with different degrees of reproductive activity as inferred from histological examination of the gonads and calculation of the gonadosomatic index (GSI %). The results showed a significant difference between the area of ir-SL cells of resting/regressing (62.9 +/- 2.1 micron 2) and sexually active/vitellogenic (76.8 +/- 2.3 micron 2) females and a significant positive correlation between the ir-SL cellular area and the GSI % (P0.01 in both cases). In males, the correlation between the area of ir-SL cells and the GSI % was not statistically significant. However, in those animals with the highest GSI % values, the ir-SL cells appeared more numerous and showed an increase in the immunostained area when compared to individuals with lower GSI % values. The present in morphological observations are in accordance with biochemical data obtained from other species and support the assumption that SL might be involved in the regulation of reproduction in fish.

Published
2002

29. Effect of FSH and its Glycosylation Variants on Proliferation, Steroid and Inhibin Production in a Human Ovarian Granulosa-Like Tumor Cell Line (KGN)

Author

Stella Campo, Marta Tesone, Nazareth Loreti, Luz Andreone, Griselda Irusta, and Verónica Ambao

Subjects
medicine.medical_specialty, Glycosylation, medicine.medical_treatment, Tumor cells, Cell Biology, General Medicine, Biology, Steroid, chemistry.chemical_compound, Endocrinology, Reproductive Medicine, chemistry, Internal medicine, medicine, Cancer research, Line (text file)
Published
2010
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30. Seminiferous tubule function in delayed-onset X-linked adrenal hypoplasia congenita associated with incomplete hypogonadotrophic hypogonadism

Author

María Gabriela Ropelato, Luz Andreone, Stella Campo, Patricia Bedecarrás, Rodolfo Rey, Ignacio Bergadá, Paul Laissue, and Silvia Copelli

Subjects
Anti-Mullerian Hormone, Male, endocrine system, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Biology, Endocrinology, X-linked adrenal hypoplasia congenita, Internal medicine, Adrenal insufficiency, medicine, Humans, Inhibins, Child, X chromosome, Adrenal Hyperplasia, Congenital, DAX-1 Orphan Nuclear Receptor, Hypogonadism, Genetic Diseases, X-Linked, Seminiferous Tubules, medicine.disease, Sertoli cell, Hypoplasia, medicine.anatomical_structure, Seminiferous tubule, Hypoadrenocorticism, Familial, Child, Preschool, Mutation, Follicle Stimulating Hormone, Age of onset, Hypogonadotrophic hypogonadism, Adrenal Insufficiency
Abstract

Summary Objective X-linked adrenal hypoplasia congenita (AHC, OMIM 300200) due to mutations in the DAX-1 gene is frequently associated to hypogonadotrophic hypogonadism (HHG, OMIM 238320). Clinical variants with delayed-onset have been recognized. The objective of this study is to assess Sertoli cell function throughout pubertal development in patients with childhood-onset AHC due to stop mutations in the DAX-1 gene. Design Observational follow-up study of gonadotrophin pulsatility pattern, and serum levels of antimullerian hormone and inhibin B through pubertal development in these patients. Patients Three patients belonging to two families with AHC were included in this study. Measurements The gonadotrophic pattern, serum inhibin B and antimullerian hormone were determined in relation to clinical Tanner stage of pubertal development. Results One patient showed a marked elevation in serum FSH concomitantly with low inhibin B and antimullerian hormone levels, indicating a primary testicular dysfunction. The other two patients showed a gonadotrophic pattern of HHG, and their serum levels of inhibin B and antimullerian hormone also reflected a moderate primary testicular dysfunction. The three patients were azoospermic. Conclusions These cases give further insight into the clinical spectrum of phenotypes of the hypothalamic–pituitary–gonadal axis in patients with variants in hypogonadism associated with childhood-onset X-linked AHC due to DAX-1 mutations.

Published
2007
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31. Controversial role of inhibin α-subunit gene in the aetiology of premature ovarian failure.

Author

Victoria Sundblad, Violeta A. Chiauzzi, Luz Andreone, Stella Campo, Eduardo H. Charreau, and Liliana Dain

Subjects
AMENORRHEA, GENETIC polymorphisms, INHIBIN, SEX hormones
Abstract

BACKGROUND: Premature ovarian failure (POF) is characterized by hypergonadotropic amenorrhoea before the age of 40. Inhibin α-subunit (INHα) gene is proposed as a candidate gene due to its role in negative feedback control of FSH. METHODS: Polymorphism –16C>T of INHα gene was studied in 61 POF patients and 82 controls above 40 years old (C > 40). Substitution 769G>A was studied in 59 POF patients, 76 C > 40 and 73 controls below 40 years old (C < 40). RESULTS: No significant difference in risk of POF development for –16T allele was found when comparing idiopathic POF (I-POF) with C > 40 (Odds ratio = 1.46; 95% confidence interval = 0.63–3.19). Implication of –16C>T polymorphism in serum inhibin levels was analysed in 46 controls, and no significant differences (P > 0.05) were found between CC and CT + TT genotype groups when comparing either mid-follicular phase Pro-αC and inhibin B values or mid-luteal phase Pro-αC and inhibin A values. Heterozygosity for substitution 769G>A was found in 1 of 59 POF woman, 2 of 76 C > 40 and 6 of 73 C < 40. Presence of this substitution in a relevant number of control subjects is herein described for the first time. CONCLUSION: Our results indicate that –16C>T and 769G>A variants in INHα gene may not be associated to POF disease. [ABSTRACT FROM AUTHOR]

Published
2006
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