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2. Histidine decarboxylase inhibitors: a novel therapeutic option for the treatment of leydigioma

Author

Abiuso, Adriana María Belén, primary, Varela, María Luisa, additional, Raices, Trinidad, additional, Irusta, Griselda, additional, Lazzati, Juan Manuel, additional, Besio Moreno, Marcos, additional, Cavallotti, Alina, additional, Belgorosky, Alicia, additional, Pignataro, Omar Pedro, additional, Berensztein, Esperanza, additional, and Mondillo, Carolina, additional

Published
2022
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4. Histidine decarboxylase inhibitors: a novel therapeutic option for the treatment of leydigioma.

Author

Belén Abiuso, Adriana María, Luisa Varela, María, Raices, Trinidad, Irusta, Griselda, Manuel Lazzati, Juan, Besio Moreno, Marcos, Cavallotti, Alina, Belgorosky, Alicia, Pedro Pignataro, Omar, Berensztein, Esperanza, and Mondillo, Carolina

Subjects
HISTIDINE, LEYDIG cells, EPIGALLOCATECHIN gallate, CHILD patients, PSYCHOSOCIAL factors, ENDOCRINE diseases, METABOLIC disorders
Abstract

Recent reports indicate an increase in Leydig cell tumor (LCT) incidence. Radical orchiectomy is the standard therapy in children and adults, although it entails physical and psychosocial side effects. Testis-sparing surgery can be a consideration for benign LCT of 2.5 cm or less in size. Malignant LCTs respond poorly to conventional chemotherapy, so new treatment modalities are needed. In this study, we observed increased histidine decarboxylase expression and pro-angiogenic potential in LCT surgically resected from pediatric patients (fetal to pubertal) vs control samples from patients without endocrine or metabolic disorders which were collected at necropsy. We, therefore, evaluated for the first time the antitumor efficacy of two histidine decarboxylase inhibitors (a-methyl-dl-histidine dihydrochloride (a-MHD) and epigallocatechin gallate (EGCG)), alone and combined with carboplatin, in two preclinical models of LCT. MA-10 and R2C Leydig tumor cells, re presenting two different LCT subtypes, were used to generate syngeneic and xenograft mouse LCT models, respectively. In the syngeneic model, monotherapy with a-MHD effectively reduced tumor growth and angiogenesis. In the xenografts, which showed co-expression of histidine decarboxylase and CYP19, the combination of EGCG plus carboplatin was the most effective therapy, leading to LCT growth arrest and undetectable levels of plasmatic estradiol. Testicular and body weights remained unaltered. On the basis of this study, histidine decarboxylase may emerge as a novel pharmacological target for LCT treatment. [ABSTRACT FROM AUTHOR]

Published
2022
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7. Inhibition of cytochrome P-450 C17 enzyme by a GnRH agonist in ovarian follicles from gonadotropin-stimulated rats

Author

Irusta, Griselda, Parborell, Fernanda, and Tesone, Marta

Subjects
Hormone antagonists -- Research, Cytochrome P-450 -- Research, Gonadotropin releasing hormone -- Research, Metabolic regulation -- Research, Physiological research, Biological sciences
Abstract

Our objective was to study the direct action of a GnRH-I agonist, leuprolide acetate (LA), on ovarian steroidogenesis in preovulatory follicles obtained from equine chorionic gonadotropin (eCG)-treated rats. Previously, we have demonstrated an inhibitory effect of LA on steroidogenesis and follicular development. In this study, we tested the hypothesis that gonadotropin-releasing hormone (GnRH) exerts its negative effect on follicular development by inhibiting thecal cytochrome P-450 C17 (P450C17) [alpha]-hydroxylase expression and, consequently, androgen synthesis. Studies were carried out in prepubertal female rats injected with either eCG (control) or eCG plus LA (LA) and killed at different time points. Immunohistochemical studies indicated that LA induced steroidogenic acute regulatory protein (STAR) expression mainly in theca cells of preantral and antral follicles. In addition, serum progesterone levels increased significantly (P < 0.05), whereas those of androsterone decreased (P < 0.05) after 8 h of LA treatment. This inhibition caused by LA seemed to be a consequence of the decreased expression of follicular P450C17 [alpha]-hydroxylase, as demonstrated by Western blot and RT-PCR techniques. In vitro studies using follicles isolated from 48-h-eCG-treated rats and cultured with LA showed a significant (P < 0.05) inhibition of FSH-induced androsterone follicular content as well as P450C17 [alpha]-hydroxylase protein levels, as determined by Western analysis. However, LA increased StAR protein expression in these follicles without significant changes in P450scc enzyme levels. Taking all these findings into account, we suggest that GnRH-I exerts a direct inhibitory action on gonadotropin-induced follicular development by decreasing the temporal expression of the P450C17 enzyme and, consequently, androgen production, thus reducing the supply of estrogens available to developing follicles. ovary; follicle; gonadotropin-releasing hormone agonist; steroidogenesis doi:10.1152/ajpendo.00226.2006

Published
2007

10. Metformin has a direct effect on ovarian cells that is dependent on organic cation transporters

Author

Di Pietro, Mariana, primary, Velazquez, Candela, additional, Matzkin, María Eugenia, additional, Frungieri, Mónica Beatriz, additional, Peña, Mariana Gómez, additional, de Zúñiga, Ignacio, additional, Pascuali, Natalia, additional, Irusta, Griselda, additional, Bianchi, María Silvia, additional, Parborell, Fernanda, additional, and Abramovich, Dalhia, additional

Published
2020
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15. Platelet-derived growth factor BB and DD and angiopoietin1 are altered in follicular fluid from polycystic ovary syndrome patients

Author

Scotti, Leopoldina, Parborell, Maria Fernanda Agustina, Irusta, Griselda, de Zuñiga, Ignacio, Bisioli, Claudio, Pettorossi, Hernan, Tesone, Marta, and Abramovich, Dalhia Nurit

Subjects
PLATELET-DERIVED GROWTH FACTORS, Medicina Básica, CIENCIAS MÉDICAS Y DE LA SALUD, PCOS, FOLLICULAR FLUID, ANGIOPOIETIN1, Obstetricia y Ginecología, Medicina Clínica, Bioquímica y Biología Molecular
Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age, and is characterized by abnormalities in ovarian angiogenesis, among other features. Consistent with this association, follicular fluid (FF) concentration and ovarian expression of vascular endothelial growth factor (VEGF) are increased in PCOS patients. In this study, we examined the protein levels of platelet-derived growth factor (PDGF) BB and DD (PDGFBB and PDGFDD), angiopoietin 1 and 2 (ANGPT1 and ANGPT2), and their soluble receptor sTIE2 in FF from PCOS and control patients undergoing assisted reproductive techniques. We also analyzed the effect of FF from PCOS and control patients on tight and adherens junction protein expression[0] in an endothelial cell line. PDGFBB and PDGFDD were significantly whereas ANGPT1 concentration was significantly higher in FF from PCOS patients than from control patients. No changes were found in the concentration of ANGPT2 or sTIE2. Expression of claudin-5 was significantly increased in endothelial cells incubated for 24 h in the presence of FF from PCOS versus from control patients, while vascular-endothelial cadherin, β-catenin, and zonula occludens 1 expression were unchanged. The changes observed in the levels of PDGF isoforms and ANGPT1 may prevent VEGF-induced vascular permeability in the PCOS ovary by regulating endothelial-cell-junction protein levels. Restoring the levels of angiogenic factors may provide new insights into PCOS treatment and the prevention of ovarian hyperstimulation syndrome in affected women. Fil: Scotti, Leopoldina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Parborell, Maria Fernanda Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Irusta, Griselda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: de Zuñiga, Ignacio. Centro Médico PREGNA Medicina Reproductiva; Argentina Fil: Bisioli, Claudio. Centro Médico PREGNA Medicina Reproductiva, ; Argentina Fil: Pettorossi, Hernan. Centro Médico PREGNA Medicina Reproductiva; Argentina Fil: Tesone, Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Abramovich, Dalhia Nurit. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina

Published
2014

16. Independent anti-angiogenic capacities of coagulationfactors x and xa

Author

Lange, Soledad, Gonzalez, Ibeth, Pinto, Mauricio P., Arce, Maximiliano, Valenzuela, Rodrigo, Aranda, Evelyn, Elliot, Matias, Alvarez, Marjorie, Henriquez, Soledad, Velasquez, Ethel V., Orge, Felipe, Oliva, Barbara, Gonzalez, Pamela, Villalon, Manuel, Cautivo, Kelly M., Kalergis, Alexis M., Pereira, Karla, Mendoza, Camila, Saez, Claudia, Kato, Sumie, Cuello, Mauricio A., Parborell, Fernanda, Irusta, Griselda, Palma, Veronica, Allende, Miguel L., and Owen, Gareth I.

Published
2014

17. Independent anti-angiogenic capacities of coagulation factors x and xa

Author

Lange, Soledad, Gonzalez, Ibeth, Pinto, Mauricio P., Arce, Maximiliano, Valenzuela, Rodrigo, Aranda, Evelyn, Elliot, Matias, Alvarez, Marjorie, Henriquez, Soledad, Velasquez, Ethel V., Orge, Felipe, Oliva, Barbara, Gonzalez, Pamela, Villalon, Manuel, Cautivo, Kelly M., Kalergis, Alexis M., Pereira, Karla, Mendoza, Camila, Saez, Claudia, Kato, Sumie, Cuello, Mauricio A., Parborell, Fernanda, Irusta, Griselda, Palma, Veronica, Allende, Miguel L., and Owen, Gareth I.

Published
2014

18. Independent anti-angiogenic capacities of coagulation factors X and Xa

Author

Lange, Soledad, Gonzalez, Ibeth, Pinto, Mauricio P., Arce, Maximiliano, Valenzuela, Rodrigo, Aranda, Evelyn, Elliot, Matias, Alvarez, Marjorie, Henriquez, Soledad, Velazquez, Ethel, Orge, Felipe, Oliva, Bárbara, Gonzalez, Pamela, Villalon, Manuel, Cautivo, Kelly M., Kalergis, Alexis M., Pereira, Karla, Mendoza, Camila, Saez, Claudia, Kato, Sumie, Cuello, Mauricio, Parborell, Maria Fernanda Agustina, Irusta, Griselda, Palma, Verónica, Allende, Miguel L., and Owen, Gareth I.

Subjects
FXa, CIENCIAS MÉDICAS Y DE LA SALUD, Neovascularization, Pathologic, ANGIOGENESIS INHIBITORS, Cell Cycle, COAGULATION, Neovascularization, Physiologic, Patología, Angiogenesis Inhibitors, Chick Embryo, Helminth Proteins, Ciencias Biológicas, Medicina Básica, Biología Celular, Microbiología, Cell Movement, Cell Line, Tumor, Factor X, Factor Xa, Human Umbilical Vein Endothelial Cells, Animals, Humans, Receptor, PAR-1, FX, CIENCIAS NATURALES Y EXACTAS, Zebrafish
Abstract

Knockout models have shown that the coagulation system has a role in vascular development and angiogenesis. Herein, we report for the first time that zymogen FX and its active form (FXa) possess anti-angiogenic properties. Both the recombinant FX and FXa inhibit angiogenesis in vitro using endothelial EA.hy926 and human umbilical cord vascular endothelial cells (HUVEC). This effect is dependent on the Gla domain of FX. We demonstrate that FX and FXa use different mechanisms: the use of Rivaroxaban (RX) a specific inhibitor of FXa attenuated its anti-angiogenic properties but did not modify the anti-angiogenic effect of FX. Furthermore, only the anti-angiogenic activity of FXa is PAR-1dependent. Using in vivo models, we show that FX and FXa are anti-angiogenic in the zebrafish intersegmental vasculature (ISV) formation and in the chick embryo chorioallantoic membrane (CAM) assays. Our results provide further evidence for the non-hemostatic functions of FX and FXa and demonstrate for the first time a biological role for the zymogen FX. Fil: Lange, Soledad. Pontificia Universidad Católica de Chile; Chile Fil: Gonzalez, Ibeth. Pontificia Universidad Católica de Chile; Chile Fil: Pinto, Mauricio P.. Pontificia Universidad Católica de Chile; Chile Fil: Arce, Maximiliano. Pontificia Universidad Católica de Chile; Chile Fil: Valenzuela, Rodrigo. Pontificia Universidad Católica de Chile; Chile Fil: Aranda, Evelyn. Pontificia Universidad Católica de Chile; Chile Fil: Elliot, Matias. Universidad de Chile. Facultad de Ciencias; Chile Fil: Alvarez, Marjorie. Universidad de Chile. Facultad de Ciencias; Chile Fil: Henriquez, Soledad. Pontificia Universidad Católica de Chile; Chile Fil: Velazquez, Ethel. Pontificia Universidad Católica de Chile; Chile Fil: Orge, Felipe. Pontificia Universidad Católica de Chile; Chile Fil: Oliva, Bárbara. Pontificia Universidad Católica de Chile; Chile Fil: Gonzalez, Pamela. Pontificia Universidad Católica de Chile; Chile Fil: Villalon, Manuel. Pontificia Universidad Católica de Chile; Chile Fil: Cautivo, Kelly M.. Pontificia Universidad Católica de Chile; Chile Fil: Kalergis, Alexis M.. Pontificia Universidad Católica de Chile; Chile Fil: Pereira, Karla. Pontificia Universidad Católica de Chile; Chile Fil: Mendoza, Camila. Pontificia Universidad Católica de Chile; Chile Fil: Saez, Claudia. Pontificia Universidad Católica de Chile; Chile Fil: Kato, Sumie. Pontificia Universidad Católica de Chile; Chile Fil: Cuello, Mauricio. Pontificia Universidad Católica de Chile; Chile Fil: Parborell, Maria Fernanda Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Irusta, Griselda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Palma, Verónica. Universidad de Chile. Facultad de Ciencias; Chile Fil: Allende, Miguel L.. Universidad de Chile. Facultad de Ciencias; Chile Fil: Owen, Gareth I.. Pontificia Universidad Católica de Chile; Chile. Biomedical Research Consortium Chile; Chile

Published
2013

21. Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN)

Author

Irusta, Griselda, Pazos Maidana, María Camila, Abramovich, Dalhia Nurit, de Zúñiga, Ignacio Javier, Parborell, Maria Fernanda Agustina, and Tesone, Marta

Subjects
CIENCIAS MÉDICAS Y DE LA SALUD, NOTCH SYSTEM, PI3K/AKT SIGNALING, purl.org/becyt/ford/3.2 [https], purl.org/becyt/ford/3 [https], Obstetricia y Ginecología, Medicina Clínica, KGN CELLS, APOPTOSIS
Abstract

Ovarian granulosa cell tumors (GCTs) represent 3%-5% of all ovarian malignancies. Treatments have limited proven efficacy and biologically targeted treatment is lacking. The aim of this study was to investigate the role of Notch signaling in the proliferation, steroidogenesis, apoptosis, and phosphatidylinositol 3-kinase (PI3K)/AKT pathway in a FOXL2-mutated granulosa tumor cell line (KGN) representative of the adult form of GCTs. When Notch signaling is initiated, the receptors expose a cleavage site in the extracellular domain to the metalloproteinase TACE and, following this cleavage, Notch undergoes another cleavage mediated by the presenilin-gamma-secretase complex. To achieve our goal, DAPT, an inhibitor of the gamma-secretase complex, was used to investigate the role of the Notch system in parameters associated with cell growth and death, using a human granulosa cell tumor line (KGN) as an experimental model. We observed that JAGGED1, DLL4, NOTCH1, and NOTCH4 were highly expressed in KGN cells as compared to granulosa-lutein cells obtained from assisted reproductive techniques patients. The proliferation and viability of KGN cells, as well as progesterone and estradiol production, decreased in the presence of 20 μM DAPT. Apoptotic parameters like PARP and caspase 8 cleavages, BAX, and BCLXs increased in KGN cells cultured with DAPT, whereas others such as BCL2, BCLXl, FAS, and FAS ligand did not change. AKT phosphorylation decreased and PTEN protein increased when Notch signaling was inhibited in KGN cells. We conclude that the Notch system acts as a survival pathway in KGN cells, and might be interacting with the PI3K/AKT pathway. Fil: Irusta, Griselda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Pazos Maidana, María Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Abramovich, Dalhia Nurit. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: de Zúñiga, Ignacio Javier. Centro Médico PREGNA Medicina Reproductiva; Argentina Fil: Parborell, Maria Fernanda Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Tesone, Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina

Published
2013

23. Mecanismos involucrados en la atresia del folículo ovárico : relación entre esteroidogénesis, angiogénesis y apoptosis

Author

Irusta, Griselda and Tesone, Marta

Subjects
endocrine system, ESTEROIDOGENESIS, GNRH-I, OVARIO, OVARY, STEROIDOGENESIS, ANGIOGENESIS, APOPTOSIS
Abstract

En este trabajo se han realizado experimentos para dilucidar la función local en el ovario de la Hormona Liberadora de Gonadotrofinas (GnRH-I). Se han estudiado procesos fundamentales del desarrollo folicular como la síntesis de esteroides sexuales y la angiogénesis ovárica en su relación con la apoptosis folicular. En nuestro laboratorio se postuló que el GnRH-I ejerce una acción inhibitoria durante el desarrollo folicular actuando como modulador intraovárico. En ratas estimuladas con gonadotrofinas analizamos los niveles de esteroides sexuales y la expresión y contenido de enzimas ováricas responsables de la síntesis de esteroides luego del tratamiento con un agonista de GnRH-I, Acetato de Leuprolide (LA). Los efectos observados se han corroborado con experimentos realizados in vitro utilizando este mismo agonista. Además, estudiamos factores angiogénicos esenciales para el desarrollo y establecimiento de la vasculatura en el folículo ovárico, como también parámetros de la atresia folicular. El tratamiento con el agonista afectó la síntesis de esteroides ováricos al igual que el contenido folicular de las enzimas esteroidogénicas, produciendo una disminución en la síntesis de andrógenos y como consecuencia, en la producción de estradiol. Estos resultados se observaron en los experimentos realizados in vivo e in vitro. También se observó una disminución en el contenido de factores angiogénicos y de sus receptores, acompañado de un aumento de la actividad de caspasa-3, enzima efectora clave en el proceso de apoptosis folicular. Se concluyó que el factor GnRH-I actuaría en el ovario localmente afectando factores esenciales para el desarrollo folicular. Este factor interfiere en la foliculogénesis inducida por gonadotrofinas, alterando la síntesis de esteroides gonadales e inhibiendo la angiogénesis folicular. Esto alteraría el balance de los factores de supervivencia de las células foliculares, causando la activación de proteínas reguladoras de la apoptosis, llevando a los folículos en desarrollo al proceso de atresia. In the present work, we have performed experiments to elucidate the local ovarian role of Gonadotropin Releasing Hormone-I (GnRH-I). Main processes of the follicular development were studied as sexual steroids synthesis, angiogenesis and its relationship with the follicular apoptosis. In our laboratory, it was proposed that GnRH-I exerts an inhibitory action of follicular development acting as a local ovarian modulator. In gonadotropin-stimulated rats treated with a GnRH-I agonist, Leuprolide Acetate (LA), we analyzed the sexual steroids levels and the expression and content of steroidogenic enzymes. The in vivo results were compared and corroborated by performing in vitro experiments using the agonist. Moreover, we analyzed essential angiogenic factors for the development and stabilization of the vascular vessels in the ovarian follicle as well as, follicular atresia parameters. The agonist treatment altered the ovarian steroids synthesis and the follicular content of the steroidogenic enzymes, diminishing the androgen synthesis and as a consequence, the estradiol production. These results were observed in in vivo and in vitro experiments. We also observed a decrease in follicular angiogenic factors and their receptors content, and this was parallel to an increase in the activity of caspase-3 enzyme, key effector of the follicular apoptosis process. We concluded that GnRH-I would act locally in the ovary affecting essential factors for follicular development. In addition it interferes in the gonadotropin-induced folliculogenesis, altering gonadal steroids synthesis and inhibiting follicular angiogenesis. This will lead to an imbalance of the survival factors of the follicular cells, causing the activation of apoptotic regulatory proteins and inducing atresia in the developing follicles. Fil: Irusta, Griselda. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.

Published
2008

24. Regulation of ovarian angiogenesis and apoptosis by GnRH-I analogs

Author

Parborell, Maria Fernanda Agustina, Irusta, Griselda, Rodriguez Celin, Alejandra Jimena, and Tesone, Marta

Subjects
Vascular Endothelial Growth Factor A, CIENCIAS MÉDICAS Y DE LA SALUD, Injections, Subcutaneous, Neovascularization, Physiologic, Apoptosis, ANGIOGENESIS, Gonadotropin-Releasing Hormone, Rats, Sprague-Dawley, Structure-Activity Relationship, Ovarian Follicle, GNRH, Angiopoietin-1, Animals, Caspase 3, Ovary, Bioquímica y Biología Molecular, Receptor, TIE-2, Vascular Endothelial Growth Factor Receptor-2, APOPTOSIS, Rats, Enzyme Activation, Medicina Básica, OVARY, Female, Leuprolide, Oligopeptides
Abstract

An adequate vascular supply is important to provide endocrine and paracrine signals during follicular development. We evaluated the direct in vivo effects of both the GnRH-agonist Leuprolide acetate (LA) and the GnRH-antagonist Antide (Ant) on the expression of VEGF-A and ANPT-1 and their receptors in ovarian follicles from prepubertal eCG-treated rats. We also examined whether the changes observed in apoptosis by GnRH-I analogs have an effect on the caspase cascade. LA significantly decreased the levels of VEGF-A, its receptor Flk-1, and ANPT-1 when compared to controls, while the co-injection of Ant interfered with this effect. No changes were observed in the levels of Tie-2 after treatment with these analogs. When we measured the follicular content of caspase-3 protein, we observed that LA significantly increased the level of the active form. The co-injection of Ant interfered with this effect and Ant alone significantly decreased caspase-3 cleavage. IHC analyses corroborated these data. Notably, while LA increased caspase-3 activity levels, Ant decreased them when compared to controls. In follicles obtained from LA-treated rats, cleavage of PARP (a substrate of caspase-3) from the intact 113-kDa protein showed a significant enhancement in an 85-kDa fragment. The co-injection of Ant interfered with this effect. Ant alone significantly decreased PARP cleavage as compared to controls. We conclude that the decrease in VEGF-A, its receptor Flk-1/KDR, and ANPT-1 produced by the administration of GnRH-I agonist is one of the mechanisms involved in ovarian cell apoptosis. This suggests an intraovarian role of an endogenous GnRH-like peptide in gonadotropin-induced follicular development. 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. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Irusta, Griselda. 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. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Rodriguez Celin, Alejandra Jimena. 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. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Tesone, Marta. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina. 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

Published
2007

25. The GnRH antagonist Antide inhibits apoptosis of preovulatory follicle cells in rat ovary

Author

Parborell, Maria Fernanda Agustina, Irusta, Griselda, Vitale, Alejandra Mariel, Gonzalez, Olga, Pecci, Adali, and Tesone, Marta

Subjects
CIENCIAS MÉDICAS Y DE LA SALUD, purl.org/becyt/ford/3.2 [https], purl.org/becyt/ford/3 [https], Medicina Critica y de Emergencia, Medicina Clínica
Abstract

Analogs of GnRH, including agonists (GnRH-a) and antagonists (GnRH-ant), have been widely used to inhibit gonadotropin pituitary release. Aside from the effect of GnRH analogs on the pituitary-gonadal axis, studies have shown that GnRH has extrapituitary effects, particularly on rat and human ovaries. In the present study, we evaluated the direct in vivo effects of the GnRH-a, leuprolide acetate (LA), or the GnRH-ant, Antide (Ant), either singly or together, on ovarian follicular development in prepubertal eCG-treated rats. LA significantly decreased ovarian weight, whereas Ant increased ovarian weight compared with controls; however, coinjection of both compounds had no effect. In addition, LA increased the number of preantral follicles (PFs) and atretic follicles, and decreased the number of early antral follicles (EAFs) and preovulatory follicles (POFs). Coinjection of Ant interfered with this LA effect. Ant alone increased the number of POFs compared with that of controls. Analysis of apoptosis has shown that LA increases the percentage of apoptotic cells in PFs, EAFs, and POFs; however, Ant prevented this effect. In addition, Ant alone decreased the percentage of apoptotic cells in EAFs and POFs. Data have shown that Ant per se inhibited BAX translocation from cytosol to mitochondria and retained cytochrome C in the mitochondria, whereas LA induced cytochrome C release. We conclude that Ant inhibits apoptosis in preovulatory follicles through a decrease of BAX translocation to mitochondria, suggesting that GnRH may act as a physiological intraovarian modulator factor that is able to interfere with follicular development through an increase in apoptotic events mediated by an imbalance among the BCL-2 family members. 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. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina Fil: Irusta, Griselda. 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. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina Fil: Vitale, Alejandra Mariel. 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. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina Fil: Gonzalez, Olga. 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. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina Fil: Pecci, Adali. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; 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. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina

Published
2005

27. Independent Anti-Angiogenic Capacities of Coagulation Factors X and Xa

Author

Lange, Soledad, primary, Gonzalez, Ibeth, additional, Pinto, Mauricio P., additional, Arce, Maximiliano, additional, Valenzuela, Rodrigo, additional, Aranda, Evelyn, additional, Elliot, Matias, additional, Alvarez, Marjorie, additional, Henriquez, Soledad, additional, Velasquez, Ethel V., additional, Orge, Felipe, additional, Oliva, Barbara, additional, Gonzalez, Pamela, additional, Villalon, Manuel, additional, Cautivo, Kelly M., additional, Kalergis, Alexis M., additional, Pereira, Karla, additional, Mendoza, Camila, additional, Saez, Claudia, additional, Kato, Sumie, additional, Cuello, Mauricio A., additional, Parborell, Fernanda, additional, Irusta, Griselda, additional, Palma, Veronica, additional, Allende, Miguel L., additional, and Owen, Gareth I., additional

Published
2014
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43. In vivo intrabursal administration of bioactive lipid sphingosine-1-phosphate enhances vascular integrity in a rat model of ovarian hyperstimulation syndrome.

Author

Di Pietro M, Pascuali N, Scotti L, Irusta G, Bas D, May M, Tesone M, Abramovich D, and Parborell F

Subjects
3-Hydroxysteroid Dehydrogenases genetics, 3-Hydroxysteroid Dehydrogenases metabolism, Animals, Antigens, CD genetics, Antigens, CD metabolism, Cadherins genetics, Cadherins metabolism, Claudin-5 genetics, Claudin-5 metabolism, Corpus Luteum metabolism, Corpus Luteum pathology, Cytochrome P-450 Enzyme System genetics, Cytochrome P-450 Enzyme System metabolism, Disease Models, Animal, Female, Gene Expression Regulation drug effects, Gonadotropins, Equine pharmacology, Humans, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Occludin genetics, Occludin metabolism, Organ Size, Ovarian Follicle metabolism, Ovarian Follicle pathology, Ovarian Hyperstimulation Syndrome genetics, Ovarian Hyperstimulation Syndrome metabolism, Ovarian Hyperstimulation Syndrome pathology, Phosphoproteins genetics, Phosphoproteins metabolism, Pregnancy, Progesterone blood, Rats, Rats, Sprague-Dawley, Receptors, Lysosphingolipid genetics, Receptors, Lysosphingolipid metabolism, Sphingosine pharmacology, Sphingosine-1-Phosphate Receptors, Capillary Permeability drug effects, Corpus Luteum drug effects, Lysophospholipids pharmacology, Ovarian Follicle drug effects, Ovarian Hyperstimulation Syndrome drug therapy, Sphingosine analogs & derivatives
Abstract

Study Question: Can the bioactive lipid sphingosine-1 phosphate (S1P) act as an endothelial barrier-enhancing molecule and, in turn, restore the vascular integrity and homoeostasis in a rat model of ovarian hyperstimulation syndrome (OHSS)., Study Answer: In vivo administration of S1P may prevent the early onset of OHSS and decrease its severity., What Is Known Already: Although advances in the prediction and treatment of OHSS have been made, complete prevention has not been possible yet. S1P in follicular fluid from women at risk of developing OHSS are lower in comparison from women who are not at such risk and administration of S1P in an OHSS rat model decreases ovarian capillary permeability., Study Design, Size, Duration: We used an animal model that develops OHSS in immature Sprague-Dawley rats. The rats were randomly divided into three groups: the control group, which was injected with 10 IU of pregnant mare's serum gonadotropin (PMSG), and 10 IU of hCG 48 h later; the OHSS group, which was injected with excessive doses of PMSG (50 IU/day) for four consecutive days, followed by hCG; and the OHSS + S1P group, which was injected with the same doses of PMSG and hCG as the OHSS group and then treated with 5 μl S1P (1 mM) under the bursa of both ovaries, whereas the other groups of animals received the S1P vehicle., Participants /materials, Setting, Methods: Rats were killed by decapitation 48 h after the hCG injection for ovary, endometrium and blood collection. The ovaries were weighed and then used for subsequent assays, while the serum was used for hormone assays. One of the ovaries from each rat (n = 6) was used for Western immunoblot and the other for immunohistochemical analysis. Statistical comparisons between groups were carried out., Main Results and the Role of Chance: S1P administration reduced the ovarian weight (P < 0.05), and decreased the concentration of serum progesterone in the OHSS group compared to the OHSS group without treatment (P < 0.001). The percentage of antral follicles in the OHSS group was lower than that in the control group. S1P increased the percentage of antral follicles (P < 0.05) and decreased the percentage of corpora lutea (P < 0.01) and cystic structures in the OHSS group (P < 0.05). S1P had no effect on the expression levels of the enzymes 3β-hydroxysteroid dehydrogenase (3βHSD) or cholesterol side-chain cleavage enzyme (P450scc), but reduced the levels of steroidogenic acute regulatory protein (StAR) in OHSS rat ovaries (P < 0.05). S1P decreased the endothelial (P < 0.05) and periendothelial (P < 0.01) cell area in OHSS rat ovaries. S1P restored the levels of N-cadherin and VE-cadherin proteins to control values. Furthermore, S1P enhanced the levels of claudin-5, occludin (P < 0.05) and sphingosine-1-phosphate receptor 1 (S1PR1) in OHSS (P < 0.01). In addition, no histological differences were found in endometrium between OHSS and S1P-treated OHSS animals., Limitations Reasons for Caution: The results of this study were generated from an in vivo OHSS experimental model, which has been used by several authors and our group due to the similarity between the rat and human angiogenic systems. Further studies in patients will be needed to evaluate the effects of S1P in the pathogenesis of OHSS., Wider Implications of the Findings: These findings concern the pathophysiological importance of S1P in OHSS. More studies on the regulation of endothelial cell barrier function by S1P in reproductive pathological processes and its therapeutic application are required., Large Scale Data: N/A., Study Funding and Competing Interest(s): This work was supported by grants from ANPCyT (PICT 2012-897), CONICET (PIP 5471), Roemmers and Baron Foundations, Argentina. The authors declare no conflicts of interest., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2017
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44. Effects of an inhibitor of the γ-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).

Author

Irusta G, Pazos MC, Abramovich D, De Zúñiga I, Parborell F, and Tesone M

Subjects
Adaptor Proteins, Signal Transducing, Amyloid Precursor Protein Secretases metabolism, Calcium-Binding Proteins metabolism, Cell Line, Tumor, Dipeptides, Female, Forkhead Box Protein L2, Gonadal Steroid Hormones biosynthesis, Granulosa Cell Tumor genetics, Humans, Intercellular Signaling Peptides and Proteins metabolism, Jagged-1 Protein, Membrane Proteins metabolism, Mutation, Ovarian Neoplasms genetics, Receptors, Notch antagonists & inhibitors, Serrate-Jagged Proteins, Amyloid Precursor Protein Secretases antagonists & inhibitors, Apoptosis drug effects, Cell Proliferation drug effects, Forkhead Transcription Factors genetics, Granulosa Cell Tumor metabolism, Ovarian Neoplasms metabolism, Receptors, Notch metabolism
Abstract

Ovarian granulosa cell tumors (GCTs) represent 3%-5% of all ovarian malignancies. Treatments have limited proven efficacy and biologically targeted treatment is lacking. The aim of this study was to investigate the role of Notch signaling in the proliferation, steroidogenesis, apoptosis, and phosphatidylinositol 3-kinase (PI3K)/AKT pathway in a FOXL2-mutated granulosa tumor cell line (KGN) representative of the adult form of GCTs. When Notch signaling is initiated, the receptors expose a cleavage site in the extracellular domain to the metalloproteinase TACE and, following this cleavage, Notch undergoes another cleavage mediated by the presenilin-gamma-secretase complex. To achieve our goal, DAPT, an inhibitor of the gamma-secretase complex, was used to investigate the role of the Notch system in parameters associated with cell growth and death, using a human granulosa cell tumor line (KGN) as an experimental model. We observed that JAGGED1, DLL4, NOTCH1, and NOTCH4 were highly expressed in KGN cells as compared to granulosa-lutein cells obtained from assisted reproductive techniques patients. The proliferation and viability of KGN cells, as well as progesterone and estradiol production, decreased in the presence of 20 μM DAPT. Apoptotic parameters like PARP and caspase 8 cleavages, BAX, and BCLXs increased in KGN cells cultured with DAPT, whereas others such as BCL2, BCLXl, FAS, and FAS ligand did not change. AKT phosphorylation decreased and PTEN protein increased when Notch signaling was inhibited in KGN cells. We conclude that the Notch system acts as a survival pathway in KGN cells, and might be interacting with the PI3K/AKT pathway.

Published
2013
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45. Regulation of ovarian angiogenesis and apoptosis by GnRH-I analogs.

Author

Parborell F, Irusta G, Rodríguez Celín A, and Tesone M

Subjects
Angiopoietin-1 antagonists & inhibitors, Angiopoietin-1 biosynthesis, Animals, Apoptosis physiology, Caspase 3 drug effects, Caspase 3 metabolism, Enzyme Activation drug effects, Female, Injections, Subcutaneous, Leuprolide administration & dosage, Neovascularization, Physiologic physiology, Oligopeptides administration & dosage, Ovarian Follicle cytology, Ovarian Follicle drug effects, Ovarian Follicle metabolism, Ovary blood supply, Ovary cytology, Rats, Rats, Sprague-Dawley, Receptor, TIE-2 biosynthesis, Receptor, TIE-2 drug effects, Structure-Activity Relationship, Vascular Endothelial Growth Factor A biosynthesis, Vascular Endothelial Growth Factor A drug effects, Vascular Endothelial Growth Factor Receptor-2 biosynthesis, Vascular Endothelial Growth Factor Receptor-2 drug effects, Apoptosis drug effects, Gonadotropin-Releasing Hormone analogs & derivatives, Gonadotropin-Releasing Hormone pharmacology, Neovascularization, Physiologic drug effects, Ovary drug effects
Abstract

An adequate vascular supply is important to provide endocrine and paracrine signals during follicular development. We evaluated the direct in vivo effects of both the GnRH-agonist Leuprolide acetate (LA) and the GnRH-antagonist Antide (Ant) on the expression of VEGF-A and ANPT-1 and their receptors in ovarian follicles from prepubertal eCG-treated rats. We also examined whether the changes observed in apoptosis by GnRH-I analogs have an effect on the caspase cascade. LA significantly decreased the levels of VEGF-A, its receptor Flk-1, and ANPT-1 when compared to controls, while the co-injection of Ant interfered with this effect. No changes were observed in the levels of Tie-2 after treatment with these analogs. When we measured the follicular content of caspase-3 protein, we observed that LA significantly increased the level of the active form. The co-injection of Ant interfered with this effect and Ant alone significantly decreased caspase-3 cleavage. IHC analyses corroborated these data. Notably, while LA increased caspase-3 activity levels, Ant decreased them when compared to controls. In follicles obtained from LA-treated rats, cleavage of PARP (a substrate of caspase-3) from the intact 113-kDa protein showed a significant enhancement in an 85-kDa fragment. The co-injection of Ant interfered with this effect. Ant alone significantly decreased PARP cleavage as compared to controls. We conclude that the decrease in VEGF-A, its receptor Flk-1/KDR, and ANPT-1 produced by the administration of GnRH-I agonist is one of the mechanisms involved in ovarian cell apoptosis. This suggests an intraovarian role of an endogenous GnRH-like peptide in gonadotropin-induced follicular development., ((c) 2007 Wiley-Liss, Inc.)

Published
2008
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