A dual death/survival role of autophagy in the adult ovary of Lagostomus maximus (Mammalia- Rodentia)

Follicular atresia is a cell death event that occurs in the great majority of follicles before ovulation in the mature mammalian ovary. Germ cell loss has been mainly associated to apoptosis although autophagy also seems to be at play. Aimed to increase our understanding on the possible cooperating role of autophagy and apoptosis in follicular atresia and/or follicular survival, we analyzed both programmed cell death mechanisms in a rodent model, the South American plains vizcacha, Lagostomus maximus. Female vizcacha shows highly suppressed apoptosis-dependent follicular atresia in the adult ovary, with continuous folliculogenesis and massive polyovulation. This strategy of massive ovulation requires a permanent remodeling of the ovarian architecture to maintain the availability of quiescent primordial follicles throughout the individual's reproductive lifespan. We report here our analysis of autophagy (BECN1, LAMP1 and LC3B-I/II) and apoptosis (BCL2 and ACTIVE CASPASE- 3) markers which revealed interactive behaviors between both processes, with autophagy promoting survival or cell death depending on the ovarian structure. Strong BECN1, LC3B-II and LAMP1 staining was observed in atretic follicles and degenerating corpora lutea that also expressed nuclear ACTIVE CASPASE-3. Healthy follicles showed a slight expression of autophagy proteins but a strong expression of BCL2 and no detectable ACTIVE CASPASE-3. Transmission electron microscopy revealed a high formation of autophagosomes, autolysosomes and lysosomes in atretic follicles and degenerating corpora lutea and a low number of autophagic vesicles in normal follicles. The co-expression of LC3B-BECN1, LC3B-LAMP1 and LC3B-ACTIVE CASPASE-3 was only detected in atretic follicles and degenerating corpora lutea, while co-expression of BCL2-BECN1 was only observed in normal follicles. We propose that autophagy could act as a mechanism to eliminate altered follicles and remnant corpora lutea providing the necessary space for maturation of primordial follicles that continuously enter the growing follicular pool to sustain massive ovulation.Fil: Leopardo, Noelia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Velazquez, Mariela Edith. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Cortasa, Santiago Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Gonzalez, Candela Rocio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Vitullo, Alfredo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentin

Assessment of future groundwater recharge in semi-arid regions under climate change scenarios (Serral-Salinas aquifer, SE Spain). Could increased rainfall variability increase the recharge rate?

The projected impact of climate change on groundwater recharge is a challenge in hydrogeological research because substantial doubts still remain, particularly in arid and semi-arid zones. We present a methodology to generate future groundwater recharge scenarios using available information about regional climate change projections developed in European Projects. It involves an analysis of regional climate model (RCM) simulations and a proposal for ensemble models to assess the impacts of climate change. Future rainfall and temperature series are generated by modifying the mean and standard deviation of the historical series in accordance with estimates of their change provoked by climate change. Future recharge series will be obtained by simulating these new series within a continuous balance model of the aquifer. The proposed method is applied to the Serral-Salinas aquifer, located in a semi-arid zone of south-east Spain. The results show important differences depending on the RCM used. Differences are also observed between the series generated by imposing only the changes in means or also in standard deviations. An increase in rainfall variability, as expected under future scenarios, could increase recharge rates for a given mean rainfall because the number of extreme events increases. For some RCMs, the simulations predict total recharge increases over the historical values, even though climate change would produce a reduction in the mean rainfall and an increased mean temperature. A method based on a multi-objective analysis is proposed to provide ensemble predictions that give more value to the information obtained from the best calibrated models. The ensemble of predictions estimates a reduction in mean annual recharge of 14% for scenario A2 and 58% for scenario A1B. Lower values of future recharge are obtained if only the change in the mean is imposed.This work has been developed under the framework of the CGL-2009-13238-C02-01 and CGL2009-13238-C02-02 research projects, financed by the Plan Nacional I+D+I 2008-2011 (Ministry of Science and Innovation, Spain). The study was also partially supported by the European Community 7th Framework Project GENESIS (226536) on groundwater systems. We also thank the PRUDENCE and ENSEMBLES Projects, as some public data of this project have been applied.Pulido Velázquez, D.; García-Arostegui, J.; Molina González, JL.; Pulido-Velazquez, M. (2015). Assessment of future groundwater recharge in semi-arid regions under climate change scenarios (Serral-Salinas aquifer, SE Spain). Could increased rainfall variability increase the recharge rate?. Hydrological Processes. 29(6):828-844. https://doi.org/10.1002/hyp.10191S828844296AEMet 2009 Generación de escenarios regionalizados de cambio climático para España www.aemet.es/documentos/es/elclima/cambio_climat/escenarios/Informe_Escenarios.pdfAguilera, H., & Murillo, J. M. (2008). The effect of possible climate change on natural groundwater recharge based on a simple model: a study of four karstic aquifers in SE Spain. Environmental Geology, 57(5), 963-974. doi:10.1007/s00254-008-1381-2Bell, V. A., Kay, A. L., Jones, R. G., & Moore, R. J. (2007). Development of a high resolution grid-based river flow model for use with regional climate model output. Hydrology and Earth System Sciences, 11(1), 532-549. doi:10.5194/hess-11-532-2007Bouraoui, F., Vachaud, G., Li, L. Z. X., Le Treut, H., & Chen, T. (1999). Evaluation of the impact of climate changes on water storage and groundwater recharge at the watershed scale. Climate Dynamics, 15(2), 153-161. doi:10.1007/s003820050274Candela, L., von Igel, W., Javier Elorza, F., & Aronica, G. (2009). Impact assessment of combined climate and management scenarios on groundwater resources and associated wetland (Majorca, Spain). Journal of Hydrology, 376(3-4), 510-527. doi:10.1016/j.jhydrol.2009.07.057Candela, L., Tamoh, K., Olivares, G., & Gomez, M. (2012). Modelling impacts of climate change on water resources in ungauged and data-scarce watersheds. Application to the Siurana catchment (NE Spain). Science of The Total Environment, 440, 253-260. doi:10.1016/j.scitotenv.2012.06.062Cayan, D. R., Maurer, E. P., Dettinger, M. D., Tyree, M., & Hayhoe, K. (2008). Climate change scenarios for the California region. Climatic Change, 87(S1), 21-42. doi:10.1007/s10584-007-9377-6Christensen, N. S., & Lettenmaier, D. P. (2007). A multimodel ensemble approach to assessment of climate change impacts on the hydrology and water resources of the Colorado River Basin. Hydrology and Earth System Sciences, 11(4), 1417-1434. doi:10.5194/hess-11-1417-2007Döll, P. (2009). Vulnerability to the impact of climate change on renewable groundwater resources: a global-scale assessment. Environmental Research Letters, 4(3), 035006. doi:10.1088/1748-9326/4/3/035006Dragoni, W., & Sukhija, B. S. (2008). Climate change and groundwater: a short review. Geological Society, London, Special Publications, 288(1), 1-12. doi:10.1144/sp288.1ENSEMBLES PROJECT 2009 European Commission's 6th Framework Integrated Project from 2004-2009 (through the contract GOCE-CT-2003-505539) under the Thematic Sub-Priority ‘Global Change and Ecosystems’ http://ensembles-eu.metoffice.com/FAO 2008 Climate change water and flood securityFowler, H. J., Blenkinsop, S., & Tebaldi, C. (2007). Linking climate change modelling to impacts studies: recent advances in downscaling techniques for hydrological modelling. International Journal of Climatology, 27(12), 1547-1578. doi:10.1002/joc.1556Fowler, H. J., Kilsby, C. G., & Stunell, J. (2007). Modelling the impacts of projected future climate change on water resources in north-west England. Hydrology and Earth System Sciences, 11(3), 1115-1126. doi:10.5194/hess-11-1115-2007Green, T. R., Bates, B. C., Charles, S. P., & Fleming, P. M. (2007). Physically Based Simulation of Potential Effects of Carbon Dioxide–Altered Climates on Groundwater Recharge. Vadose Zone Journal, 6(3), 597. doi:10.2136/vzj2006.0099Green, T. R., Taniguchi, M., Kooi, H., Gurdak, J. J., Allen, D. M., Hiscock, K. M., … Aureli, A. (2011). Beneath the surface of global change: Impacts of climate change on groundwater. Journal of Hydrology, 405(3-4), 532-560. doi:10.1016/j.jhydrol.2011.05.002Gurdak, J. J., & Roe, C. D. (2010). Review: Recharge rates and chemistry beneath playas of the High Plains aquifer, USA. Hydrogeology Journal, 18(8), 1747-1772. doi:10.1007/s10040-010-0672-3Haylock, M. R., Hofstra, N., Klein Tank, A. M. G., Klok, E. J., Jones, P. D., & New, M. (2008). A European daily high-resolution gridded data set of surface temperature and precipitation for 1950–2006. Journal of Geophysical Research, 113(D20). doi:10.1029/2008jd010201Hernandez-Barrios L 2007 Efectos del cambio climático en los sistemas complejos de recursos hídricos. Aplicación a la cuenca del Júcar. (Effects of climate change on complex water resources systems. Application to the Jucar River Basin)Herrera-Pantoja, M., & Hiscock, K. M. (2007). The effects of climate change on potential groundwater recharge in Great Britain. Hydrological Processes, 22(1), 73-86. doi:10.1002/hyp.6620Iglesias, A., Garrote, L., Flores, F., & Moneo, M. (2006). Challenges to Manage the Risk of Water Scarcity and Climate Change in the Mediterranean. Water Resources Management, 21(5), 775-788. doi:10.1007/s11269-006-9111-6IPCC 2007 Four assessment report: impacts, adaptation and vulnerabilityJiménez-Martínez, J., Candela, L., Molinero, J., & Tamoh, K. (2010). Groundwater recharge in irrigated semi-arid areas: quantitative hydrological modelling and sensitivity analysis. Hydrogeology Journal, 18(8), 1811-1824. doi:10.1007/s10040-010-0658-1Jyrkama, M. I., & Sykes, J. F. (2007). The impact of climate change on spatially varying groundwater recharge in the grand river watershed (Ontario). Journal of Hydrology, 338(3-4), 237-250. doi:10.1016/j.jhydrol.2007.02.036Kovalevskii, V. S. (2007). Effect of climate changes on groundwater. Water Resources, 34(2), 140-152. doi:10.1134/s0097807807020042Lautenbach, S., Jürgen Berlekamp, Graf, N., Seppelt, R., & Matthies, M. (2009). Scenario analysis and management options for sustainable river basin management: Application of the Elbe DSS. Environmental Modelling & Software, 24(1), 26-43. doi:10.1016/j.envsoft.2008.05.001Lopez, A., Fung, F., New, M., Watts, G., Weston, A., & Wilby, R. L. (2009). From climate model ensembles to climate change impacts and adaptation: A case study of water resource management in the southwest of England. Water Resources Research, 45(8). doi:10.1029/2008wr007499Merritt, W. S., Alila, Y., Barton, M., Taylor, B., Cohen, S., & Neilsen, D. (2006). Hydrologic response to scenarios of climate change in sub watersheds of the Okanagan basin, British Columbia. Journal of Hydrology, 326(1-4), 79-108. doi:10.1016/j.jhydrol.2005.10.025Molina JL García Aróstegui JL 2007 Identificación preliminar de impactos del uso intensivo del agua subterránea en el sureste español: Acuífero Serral-Salinas (Murcia-Alicante)Molina, J. L., García Aróstegui, J. L., Benavente, J., Varela, C., de la Hera, A., & López Geta, J. A. (2009). Aquifers Overexploitation in SE Spain: A Proposal for the Integrated Analysis of Water Management. Water Resources Management, 23(13), 2737-2760. doi:10.1007/s11269-009-9406-5Molina, J.-L., García-Aróstegui, J. L., Bromley, J., & Benavente, J. (2011). Integrated Assessment of the European WFD Implementation in Extremely Overexploited Aquifers Through Participatory Modelling. Water Resources Management, 25(13), 3343-3370. doi:10.1007/s11269-011-9859-1Molina, J.-L., Pulido-Velázquez, D., García-Aróstegui, J. L., & Pulido-Velázquez, M. (2013). Dynamic Bayesian Networks as a Decision Support tool for assessing Climate Change impacts on highly stressed groundwater systems. Journal of Hydrology, 479, 113-129. doi:10.1016/j.jhydrol.2012.11.038PRUDENCE PROJECT 2004 Prediction of regional scenarios and uncertainties for defining European climate change risks and effects http://prudence.dmi.dk/Pulido-Velazquez, D., Garrote, L., Andreu, J., Martin-Carrasco, F.-J., & Iglesias, A. (2011). A methodology to diagnose the effect of climate change and to identify adaptive strategies to reduce its impacts in conjunctive-use systems at basin scale. Journal of Hydrology, 405(1-2), 110-122. doi:10.1016/j.jhydrol.2011.05.014Romero, R., Guijarro, J. A., Ramis, C., & Alonso, S. (1998). A 30-year (1964–1993) daily rainfall data base for the Spanish Mediterranean regions: first exploratory study. International Journal of Climatology, 18(5), 541-560. doi:10.1002/(sici)1097-0088(199804)18:53.0.co;2-nSamper J Huguet Ll Ares J García Vera MA 1999 Manual del usuario del programa VISUAL BALAN v.1.0: Código interactivo para la realización de balances hidrológicos y la estimación de la recargaSamper J Huguet Ll Ares J García-Vera MA 2005 User's guide VisualBALAN v.2.0: código interactivo para la realización de balances hidrológicos y la estimación de la recarga [Visual-BALAN v.2.0: interactive code to establish water balance and aquifer recharge]Taylor, R. G., Scanlon, B., Döll, P., Rodell, M., van Beek, R., Wada, Y., … Treidel, H. (2012). Ground water and climate change. Nature Climate Change, 3(4), 322-329. doi:10.1038/nclimate1744Vaccaro, J. J. (1992). Sensitivity of groundwater recharge estimates to climate variability and change, Columbia Plateau, Washington. Journal of Geophysical Research, 97(D3), 2821. doi:10.1029/91jd01788Werner, A. D., Zhang, Q., Xue, L., Smerdon, B. D., Li, X., Zhu, X., … Li, L. (2012). An Initial Inventory and Indexation of Groundwater Mega-Depletion Cases. Water Resources Management, 27(2), 507-533. doi:10.1007/s11269-012-0199-6WRF (Water Resources Foundation) 2009 Climate change impacts http://www.theclimatechangeclearinghouse.org/ClimateChangeImpacts/ChangesStormIntensityFrequency/Pages/default.asp

A CUPID Li2100MoO4scintillating bolometer tested in the CROSS underground facility

A scintillating bolometer based on a large cubic Li2100MoO4 crystal (45 mm side) and a Ge wafer (scintillation detector) has been operated in the CROSS cryogenic facility at the Canfranc underground laboratory in Spain. The dual-readout detector is a prototype of the technology that will be used in the next-generation 0¿2ß experiment CUPID . The measurements were performed at 18 and 12 mK temperature in a pulse tube dilution refrigerator. This setup utilizes the same technology as the CUORE cryostat that will host CUPID and so represents an accurate estimation of the expected performance. The Li2100MoO4 bolometer shows a high energy resolution of 6 keV FWHM at the 2615 keV ¿ line. The detection of scintillation light for each event triggered by the Li2100MoO4 bolometer allowed for a full separation (~8s) between ¿(ß) and a events above 2 MeV . The Li2100MoO4 crystal also shows a high internal radiopurity with 228Th and 226Ra activities of less than 3 and 8 µBq/kg, respectively. Taking also into account the advantage of a more compact and massive detector array, which can be made of cubic-shaped crystals (compared to the cylindrical ones), this test demonstrates the great potential of cubic Li2100MoO4 scintillating bolometers for high-sensitivity searches for the 100Mo 0¿2ß decay in CROSS and CUPID projects

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Resveratrol alleviates doxorubicin-induced damage in mice ovary

While oocytes and embryos cryopreservation can favor some patients with cancer-induced infertility to achieve pregnancy, the development of effective therapeutic strategies to preserve ovarian function during chemotherapy would be a significant advantage. The aim of the present study is to analyze whether Resveratrol treatment (Res) can preserve ovarian function from doxorubicin (Doxo)-induced gonadotoxicity using a mice model of premature ovarian failure. Res (7 and 15 mg/kg) increased the percentage of primary and antral follicles whilst decreasing the percentage of atretic follicles compared to Doxo alone. Res preserved the number of primordial follicles compared with those in the Doxo group but they did not change from those in the control group. Res treatment increased the number of AMH positive follicles compared to Doxo alone. Res increased proliferation index in follicular cells and reduced the DNA damage and apoptosis in preantral and early antral follicles compared to Doxo alone. Additionally, Doxo administration caused a severe endothelial damage and affected microvasculature stability in the ovary. However, Res was able to increase the recruitment of pericytes and smooth muscle cells in the Doxo-treated group. We also found that Res increased the expression of VEGF compared to Doxo alone. By H&E staining, Doxo-treated mice demonstrated endometrial alterations compared to controls, affecting both epithelial and stromal compartments. Nonetheless, Res restored the architecture of uterine tissue. Moreover, we also showed that Res administration is able to maintain antioxidant defenses through the increase of SOD expression in the Doxo-induced POF model. In conclusion, Res administration prior to and during Doxo treatment might serve as a noninvasive and low-cost protocol to preserve ovarian function in female cancer survivors.Fil: Herrero, Yamila. 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; ArgentinaFil: Velazquez, Candela. 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; ArgentinaFil: Pascuali, Natalia Marisa. 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; ArgentinaFil: May, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: 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; ArgentinaFil: Scotti, Leopoldina. 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; ArgentinaFil: 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; Argentin

Promoting early neovascularization by allotransplanted adipose-derived Muse cells in an ovine model of acute myocardial infarction.

BackgroundRecent preclinical studies have demonstrated that bone marrow (BM)-derived Muse cells have a homing mechanism to reach damaged cardiac tissue while also being able to reduce myocardial infarct size and improve cardiac function; however, the potential of BM-Muse cells to foster new blood-vessel formation has not been fully assessed. Up to date, adipose tissue (AT)-derived Muse cells remain to be studied in acute myocardial infarction (AMI). The aim of the present study was to analyze in vitro and in vivo the neovascularization capacity of AT-Muse cells while exploring their biodistribution and differentiation potential in a translational ovine model of AMI.Methods and resultsAT-Muse cells were successfully isolated from ovine adipose tissue. In adult sheep, one or more diagonal branches of the left anterior descending coronary artery were permanently ligated for thirty minutes. Sheep were randomized in two groups and treated with intramyocardial injections: Vehicle (PBS, n = 4) and AT-Muse (2x107 AT-Muse cells labeled with PKH26 Red Fluorescent Dye, n = 4). Molecular characterization showed higher expression of angiogenic genes (VEGF, PGF and ANG) and increased number of tube formation in AT-Muse cells group compared to Adipose-derived mesenchymal stromal cells (ASCs) group. At 7 days post-IAM, the AT-Muse group showed significantly more arterioles and capillaries than the Vehicle group. Co-localization of PKH26+ cells with desmin, sarcomeric actin and troponin T implied the differentiation of Muse cells to a cardiac fate; moreover, PKH26+ cells also co-localized with a lectin marker, suggesting a possible differentiation to a vascular lineage.ConclusionIntramyocardially administered AT-Muse cells displayed a significant neovascularization activity and survival capacity in an ovine model of AMI

Beneficial effects of metformin on mice female fertility after a high-fat diet intake

Female fertility is highly dependent on energy balance. High fat diet (HFD) intake entails a risk of infertility and ovulatory disorders. Considering the increase in the prevalence of overweight and obesity over the last decades, it is crucial to understand the mechanisms involved in overweight-associated infertility. In this study, we evaluated the reproductive performance of female mice fed with a HFD and the effects of metformin administration on ovarian function in these mice. We hypothesized that one of the mechanisms involved in subfertility due to a HFD intake is the alteration of ovarian blood vessel formation. We found that mice fed with HFD had altered estrous cycles and steroidogenesis, increased ovarian fibrosis, fewer pups per litter and require more time to achieve pregnancy. HFD-fed mice also presented dysregulated ovarian angiogenesis and an increase in nuclear DNA damage in ovarian cells. Ovulation rates were lower in these animals, as evidenced both in natural mating and after ovulation induction with gonadotropins. Metformin ameliorated ovarian angiogenesis, improved steroidogenesis, fibrosis, and ovulation, decreased the time to pregnancy and increased litter sizes in HFD-fed mice. We conclude that ovarian angiogenesis is one of the mechanisms detrimentally affected by HFD intake. Since metformin could improve ovarian microvasculature, it may be an interesting strategy to study in women to shed light on new targets for patients with metabolic disturbances.Fil: Velazquez, Candela. 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; ArgentinaFil: Herrero, Yamila. 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; ArgentinaFil: Bianchi, Maria Silvia. 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; ArgentinaFil: Cohen, Debora Juana. 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; ArgentinaFil: Cuasnicu, Patricia Sara. 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; ArgentinaFil: Prost, Katherine. Hospital de Agudos Doctor Pedro Fiorito ; Gobierno de la Provincia de Buenos Aires;Fil: Marinoni, Rocío Celeste. 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; ArgentinaFil: Pascuali, Natalia Marisa. 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; ArgentinaFil: 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; ArgentinaFil: 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; Argentin

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

Metformin (MET) is the most widely prescribed hypoglycemic drug in type 2 diabetes and Polycystic Ovary Syndrome. Besides its effects on glucose metabolism, MET exerts beneficial effects on these patients? fertility. However, the exact mechanisms of action of MET on female fertility are still unclear. In this work, we analyzed a possible direct effect of MET on ovarian cells. We found expression of the organic cation transporters OCT1, OCT2 and OCT3, responsible for MET uptake into the cells, in rat granulosa cells and human cumulus cells. Furthermore, MET increased pAMPK and decreased VEGF levels both in vivo and in rat granulosa cells in culture. These last effects were reversed when OCTs were inhibited. Our results suggest that MET acts directly on ovarian cells regulating cell metabolism and VEGF expression. Our findings are relevant to optimize PCOS fertility treatment and to explore ovarian MET actions in other female pathologies.Fil: Di Pietro, Mariana. 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; ArgentinaFil: Velazquez, Candela. 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; ArgentinaFil: Matzkin, María Eugenia. 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; ArgentinaFil: Frungieri, Mónica Beatriz. Universidad de Buenos Aires; 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; ArgentinaFil: Peña, Mariana Gómez. Centro Médico Pregna Medicina Reproductiva; ArgentinaFil: de Zúñiga, Ignacio Javier. Centro Médico Pregna Medicina Reproductiva; ArgentinaFil: Pascuali, Natalia Marisa. 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; ArgentinaFil: 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; ArgentinaFil: Bianchi, Silvia María. 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; ArgentinaFil: 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; ArgentinaFil: 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; Argentin