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Publicaciones del Departamento de Histología y Embriología
Leukocyte Profiles Reflect Geographic Range Limits in a Widespread Neotropical Bat
Integr Comp Biol 2019 59(5):1176-1189
Daniel J Becker 1 2 3 , Cecilia Nachtmann 1 , Hernan D Argibay 4 , Germán Botto 5 6 , Marina Escalera-Zamudio 7 8 , Jorge E Carrera 9 10 , Carlos Tello 11 12 , Erik Winiarski 13 , Alex D Greenwood 7 14 , Maria L Méndez-Ojeda 15 , Elizabeth Loza-Rubio 16 , Anne Lavergne 17 , Benoit de Thoisy 17 , Gábor Á Czirják 7 , Raina K Plowright 5 , Sonia Altizer 1 2 , Daniel G Streicker 1 18 19
1 Odum School of Ecology, University of Georgia, Athens, GA 30602, USA. 2 Center for the Ecology of Infectious Disease, University of Georgia, Athens, GA 30602, USA. 3 Department of Biology, Indiana University, Bloomington, IN 47405, USA. 4 Departamento de Ecología, Genética y Evolución, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina. 5 Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59715, USA. 6 Departamento de Metodos Cuantitativos, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay. 7 Department of Wildlife Diseases, Leibniz Institute for Zoo and Wildlife Research, Berlin 10315, Germany. 8 Department of Zoology, University of Oxford, Oxford OX1 3SY, UK. 9 Facultad de Ciencias, Universidad Nacional de Piura, Piura 20009, Peru. 10 Programa de Conservación de Murciélagos de Perú, Piura Lima-1, Peru. 11 Association for the Conservation and Development of Natural Resources, Lima 15037, Peru. 12 Yunkawasi, Lima 15049, Peru. 13 Departamento de Histología, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay. 14 Department of Veterinary Medicine, Freie Universität Berlin, Berlin 14163, Germany. 15 Facultad de Medicina Veterinaria y Zootecnia, Universidad Veracruzana, Veracruz 91710, Mexico. 16 Centro Nacional de Investigación Disciplinaria en Microbiología Animal, Instituto Nacional de Investigaciones Forestales, Agrícolas y Pecuarias, Mexico City 05110, Mexico. 17 Laboratoire des Interactions Virus-Hôtes, Institut Pasteur de la Guyane, Cayenne, French Guiana F-97300, France. 18 Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. 19 MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, UK.
DOI: 10.1093/icb/icz007
PMID: 30873523
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30873523
Texto completo: https://academic.oup.com/icb/article-lookup/doi/10.1093/icb/icz007
Abstract:
Quantifying how the environment shapes host immune defense is important for understanding which wild populations may be more susceptible or resistant to pathogens. Spatial variation in parasite risk, food and predator abundance, and abiotic conditions can each affect immunity, and these factors can also manifest at both local and biogeographic scales. Yet identifying predictors and the spatial scale of their effects is limited by the rarity of studies that measure immunity across many populations of broadly distributed species. We analyzed leukocyte profiles from 39 wild populations of the common vampire bat (Desmodus rotundus) across its wide geographic range throughout the Neotropics. White blood cell differentials varied spatially, with proportions of neutrophils and lymphocytes varying up to six-fold across sites. Leukocyte profiles were spatially autocorrelated at small and very large distances, suggesting that local environment and large-scale biogeographic factors influence cellular immunity. Generalized additive models showed that bat populations closer to the northern and southern limits of the species range had more neutrophils, monocytes, and basophils, but fewer lymphocytes and eosinophils, than bats sampled at the core of their distribution. Habitats with access to more livestock also showed similar patterns in leukocyte profiles, but large-scale patterns were partly confounded by time between capture and sampling across sites. Our findings suggest that populations at the edge of their range experience physiologically limiting conditions that predict higher chronic stress and greater investment in cellular innate immunity. High food abundance in livestock-dense habitats may exacerbate such conditions by increasing bat density or diet homogenization, although future spatially and temporally coordinated field studies with common protocols are needed to limit sampling artifacts. Systematically assessing immune function and response over space will elucidate how environmental conditions influence traits relevant to epidemiology and help predict disease risks with anthropogenic disturbance, land conversion, and climate change.
Glutaric Acid Affects Pericyte Contractility and Migration: Possible Implications for GA-I Pathogenesis
Mol Neurobiol 2019 56(11):7694-7707
Eugenia Isasi 1 2 , Nils Korte 3 , Verónica Abudara 4 , David Attwell 3 , Silvia Olivera-Bravo 5
1 Neurobiología Celular y Molecular, Instituto Clemente Estable (IIBCE), 3318, Italia Av, 11600, Montevideo, Uruguay. 2 Departmento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 3 Department of Neuroscience, Physiology and Pharmacology, University College London (UCL), London, UK. 4 Departmento de Fisiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 5 Neurobiología Celular y Molecular, Instituto Clemente Estable (IIBCE), 3318, Italia Av, 11600, Montevideo, Uruguay. solivera2011@gmail.com.
DOI: 10.1007/s12035-019-1620-4
PMID: 31104295
Pubmed: https://pubmed.ncbi.nlm.nih.gov/31104295
Texto completo: https://dx.doi.org/10.1007/s12035-019-1620-4
Abstract:
Glutaric acidemia I (GA-I) is an inherited neurometabolic childhood disease characterized by bilateral striatal neurodegeneration upon brain accumulation of millimolar concentrations of glutaric acid (GA) and related metabolites. Vascular dysfunction, including abnormal cerebral blood flow and blood-brain barrier damage, is an early pathological feature in GA-I, although the affected cellular targets and underlying mechanisms remain unknown. In the present study, we have assessed the effects of GA on capillary pericyte contractility in cerebral cortical slices and pericyte cultures, as well as on the survival, proliferation, and migration of cultured pericytes. GA induced a significant reduction in capillary diameter at distances up to ~ 10 μm from the center of pericyte somata. However, GA did not affect the contractility of cultured pericytes, suggesting that the response elicited in slices may involve GA evoking pericyte contraction by acting on other cellular components of the neurovascular unit. Moreover, GA indirectly inhibited migration of cultured pericytes, an effect that was dependent on soluble glial factors since it was observed upon application of conditioned media from GA-treated astrocytes (CM-GA), but not upon direct GA addition to the medium. Remarkably, CM-GA showed increased expression of cytokines and growth factors that might mediate the effects of increased GA levels not only on pericyte migration but also on vascular permeability and angiogenesis. These data suggest that some effects elicited by GA might be produced by altering astrocyte-pericyte communication, rather than directly acting on pericytes. Importantly, GA-evoked alteration of capillary pericyte contractility may account for the reduced cerebral blood flow observed in GA-I patients.
A novel form of Deleted in breast cancer 1 (DBC1) lacking the N-terminal domain does not bind SIRT1 and is dynamically regulated in vivo
Sci Rep 2019 9(1):14381
Leonardo Santos 1 , Laura Colman 1 , Paola Contreras 1 2 , Claudia C Chini 3 , Adriana Carlomagno 1 , Alejandro Leyva 4 , Mariana Bresque 1 , Inés Marmisolle 5 , Celia Quijano 5 , Rosario Durán 4 , Florencia Irigoín 6 7 , Victoria Prieto-Echagüe 6 , Mikkel H Vendelbo 8 9 , José R Sotelo-Silveira 10 , Eduardo N Chini 3 , Jose L Badano 6 , Aldo J Calliari 1 11 , Carlos Escande 12
1 Laboratory of Metabolic Diseases and Aging, INDICyO Program, Institut Pasteur de Montevideo, Montevideo, Uruguay. 2 Departamento de Fisiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 3 Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, USA. 4 Analytical Biochemistry and Proteomics Unit, Institut Pasteur de Montevideo and Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay. 5 Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 6 Human Molecular Genetics, INDICyO Program, Institut Pasteur de Montevideo, Montevideo, Uruguay. 7 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 8 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark. 9 Department of Biomedicine, Aarhus University, Aarhus, Denmark. 10 Department of Genomics, Instituto de Investigaciones Biológicas Clemente Estable, and Laboratory of Molecular Interactions, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay. 11 Area Biofísica, Departamento de Biología Celular y Molecular, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay. 12 Laboratory of Metabolic Diseases and Aging, INDICyO Program, Institut Pasteur de Montevideo, Montevideo, Uruguay. escande@pasteur.edu.uy.
DOI: 10.1038/s41598-019-50789-7
PMID: 31591441
Pubmed: https://pubmed.ncbi.nlm.nih.gov/31591441
Texto completo: https://doi.org/10.1038/s41598-019-50789-7
Abstract:
The protein Deleted in Breast Cancer-1 is a regulator of several transcription factors and epigenetic regulators, including HDAC3, Rev-erb-alpha, PARP1 and SIRT1. It is well known that DBC1 regulates its targets, including SIRT1, by protein-protein interaction. However, little is known about how DBC1 biological activity is regulated. In this work, we show that in quiescent cells DBC1 is proteolytically cleaved, producing a protein (DN-DBC1) that misses the S1-like domain and no longer binds to SIRT1. DN-DBC1 is also found in vivo in mouse and human tissues. Interestingly, DN-DBC1 is cleared once quiescent cells re-enter to the cell cycle. Using a model of liver regeneration after partial hepatectomy, we found that DN-DBC1 is down-regulated in vivo during regeneration. In fact, WT mice show a decrease in SIRT1 activity during liver regeneration, coincidentally with DN-DBC1 downregulation and the appearance of full length DBC1. This effect on SIRT1 activity was not observed in DBC1 KO mice. Finally, we found that DBC1 KO mice have altered cell cycle progression and liver regeneration after partial hepatectomy, suggesting that DBC1/DN-DBC1 transitions play a role in normal cell cycle progression in vivo after cells leave quiescence. We propose that quiescent cells express DN-DBC1, which either replaces or coexist with the full-length protein, and that restoring of DBC1 is required for normal cell cycle progression in vitro and in vivo. Our results describe for the first time in vivo a naturally occurring form of DBC1, which does not bind SIRT1 and is dynamically regulated, thus contributing to redefine the knowledge about its function.
A novel form of Deleted in breast cancer 1 (DBC1) lacking the N-terminal domain does not bind SIRT1 and is dynamically regulated in vivo
Sci Rep 2019 9(1):14381
Leonardo Santos 1 , Laura Colman 1 , Paola Contreras 1 2 , Claudia C Chini 3 , Adriana Carlomagno 1 , Alejandro Leyva 4 , Mariana Bresque 1 , Inés Marmisolle 5 , Celia Quijano 5 , Rosario Durán 4 , Florencia Irigoín 6 7 , Victoria Prieto-Echagüe 6 , Mikkel H Vendelbo 8 9 , José R Sotelo-Silveira 10 , Eduardo N Chini 3 , Jose L Badano 6 , Aldo J Calliari 1 11 , Carlos Escande 12
1 Laboratory of Metabolic Diseases and Aging, INDICyO Program, Institut Pasteur de Montevideo, Montevideo, Uruguay. 2 Departamento de Fisiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 3 Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, USA. 4 Analytical Biochemistry and Proteomics Unit, Institut Pasteur de Montevideo and Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay. 5 Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 6 Human Molecular Genetics, INDICyO Program, Institut Pasteur de Montevideo, Montevideo, Uruguay. 7 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 8 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark. 9 Department of Biomedicine, Aarhus University, Aarhus, Denmark. 10 Department of Genomics, Instituto de Investigaciones Biológicas Clemente Estable, and Laboratory of Molecular Interactions, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay. 11 Area Biofísica, Departamento de Biología Celular y Molecular, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay. 12 Laboratory of Metabolic Diseases and Aging, INDICyO Program, Institut Pasteur de Montevideo, Montevideo, Uruguay. escande@pasteur.edu.uy.
DOI: 10.1038/s41598-019-50789-7
PMID: 31591441
Pubmed: https://pubmed.ncbi.nlm.nih.gov/31591441
Texto completo: https://doi.org/10.1038/s41598-019-50789-7
Abstract:
The protein Deleted in Breast Cancer-1 is a regulator of several transcription factors and epigenetic regulators, including HDAC3, Rev-erb-alpha, PARP1 and SIRT1. It is well known that DBC1 regulates its targets, including SIRT1, by protein-protein interaction. However, little is known about how DBC1 biological activity is regulated. In this work, we show that in quiescent cells DBC1 is proteolytically cleaved, producing a protein (DN-DBC1) that misses the S1-like domain and no longer binds to SIRT1. DN-DBC1 is also found in vivo in mouse and human tissues. Interestingly, DN-DBC1 is cleared once quiescent cells re-enter to the cell cycle. Using a model of liver regeneration after partial hepatectomy, we found that DN-DBC1 is down-regulated in vivo during regeneration. In fact, WT mice show a decrease in SIRT1 activity during liver regeneration, coincidentally with DN-DBC1 downregulation and the appearance of full length DBC1. This effect on SIRT1 activity was not observed in DBC1 KO mice. Finally, we found that DBC1 KO mice have altered cell cycle progression and liver regeneration after partial hepatectomy, suggesting that DBC1/DN-DBC1 transitions play a role in normal cell cycle progression in vivo after cells leave quiescence. We propose that quiescent cells express DN-DBC1, which either replaces or coexist with the full-length protein, and that restoring of DBC1 is required for normal cell cycle progression in vitro and in vivo. Our results describe for the first time in vivo a naturally occurring form of DBC1, which does not bind SIRT1 and is dynamically regulated, thus contributing to redefine the knowledge about its function.
Mitofusins modulate the increase in mitochondrial length, bioenergetics and secretory phenotype in therapy-induced senescent melanoma cells
Biochem J 2019 476(17):2463-2486
Jennyfer Martínez 1 , Doménica Tarallo 1 , Laura Martínez-Palma 2 , Sabina Victoria 3 , Mariana Bresque 4 , Sebastián Rodríguez-Bottero 2 , Inés Marmisolle 1 , Carlos Escande 4 , Patricia Cassina 2 , Gabriela Casanova 5 , Mariela Bollati-Fogolín 3 , Caroline Agorio 6 , María Moreno 7 , Celia Quijano 8
1 Centro de Investigaciones Biomédicas (CEINBIO) and Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 2 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 3 Cell Biology Unit, Institut Pasteur de Montevideo, Montevideo, Uruguay. 4 Metabolic Diseases and Aging Laboratory, Institut Pasteur de Montevideo, Montevideo, Uruguay. 5 Unidad de Microscopía Electrónica de Transmisión, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay. 6 Cátedra de Dermatología, Hospital de Clínicas Manuel Quintela, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 7 Laboratory for Vaccine Research, Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 8 Centro de Investigaciones Biomédicas (CEINBIO) and Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay celiq@fmed.edu.uy celia.quijano@gmail.com.
DOI: 10.1042/BCJ20190405
PMID: 31431479
Pubmed: https://pubmed.ncbi.nlm.nih.gov/31431479
Texto completo: https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BCJ20190405
Abstract:
Cellular senescence is an endpoint of chemotherapy, and targeted therapies in melanoma and the senescence-associated secretory phenotype (SASP) can affect tumor growth and microenvironment, influencing treatment outcomes. Metabolic interventions can modulate the SASP, and an enhanced mitochondrial energy metabolism supports resistance to therapy in melanoma cells. Herein, we assessed the mitochondrial function of therapy-induced senescent melanoma cells obtained after exposing the cells to temozolomide (TMZ), a methylating chemotherapeutic agent. Senescence induction in melanoma was accompanied by a substantial increase in mitochondrial basal, ATP-linked, and maximum respiration rates and in coupling efficiency, spare respiratory capacity, and respiratory control ratio. Further examinations revealed an increase in mitochondrial mass and length. Alterations in mitochondrial function and morphology were confirmed in isolated senescent cells, obtained by cell-size sorting. An increase in mitofusin 1 and 2 (MFN1 and 2) expression and levels was observed in senescent cells, pointing to alterations in mitochondrial fusion. Silencing mitofusin expression with short hairpin RNA (shRNA) prevented the increase in mitochondrial length, oxygen consumption rate and secretion of interleukin 6 (IL-6), a component of the SASP, in melanoma senescent cells. Our results represent the first in-depth study of mitochondrial function in therapy-induced senescence in melanoma. They indicate that senescence increases mitochondrial mass, length and energy metabolism; and highlight mitochondria as potential pharmacological targets to modulate senescence and the SASP.
Preoptic Area Activation and Vasotocin Involvement in the Reproductive Behavior of a Weakly Pulse-Type Electric Fish, Brachyhypopomus gauderio
Front Integr Neurosci 2019 13:37
Paula Pouso 1 2 , Álvaro Cabana 3 , James L Goodson 4 , Ana Silva 1 5
1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 2 Unidad Bases Neurales de la Conducta, Departamento de Neurofisiología Celular y Molecular, IIBCE, Montevideo, Uruguay. 3 Centro de Investigación Básica en Psicología (CIBPsi) and Instituto de Fundamentos y Métodos, Facultad de Psicología, Universidad de la República, Montevideo, Uruguay. 4 Department of Biology, Indiana University, Bloomington, IN, United States. 5 Laboratorio de Neurociencias, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
DOI: 10.3389/fnint.2019.00037
PMID: 31456670
Pubmed: https://pubmed.ncbi.nlm.nih.gov/31456670
Texto completo: https://doi.org//10.3389/fnint.2019.00037
Abstract:
Social behavior exhibits a wide diversity among vertebrates though it is controlled by a conserved neural network, the social behavior network (SBN). The activity of the SBN is shaped by hypothalamic nonapeptides of the vasopressin-oxytocin family. The weakly electric fish Brachyhypopomus gauderio emits social electrical signals during courtship. Three types of vasotocin (AVT) cells occur in the preoptic area (POA), one of the SBN nodes. In this study, we aimed to test if POA neurons of the nucleus preopticus ventricularis anterior (PPa) and posterior (PPp), and in particular AVT+ cells, were activated by social stimuli using a 2-day behavioral protocol. During the first night, male-female dyads were recorded to identify courting males. During the second night, these males were divided in two experimental conditions: isolated and social (male with a female). Both AVT cells and the cellular activation of the POA neurons (measured by FOS) were identified. We found that the PPa of social males showed more FOS+ cells than the PPa of isolated males, and that the PPa had more AVT+ cells in social males than in isolated males. The double-immunolabeling for AVT and FOS indicated the activation of AVT+ neurons. No significant differences in the activation of AVT+ cells were found between conditions, but a clear association was observed between the number of AVT+ cells and certain behavioral traits. In addition, a different activation of AVT+ cell-types was observed for social vs. isolated males. We conclude that the POA of B. gauderio exhibits changes induced by social stimuli in reproductive context, involving an increase in AVT production and a different profile activation among AVT+ cell populations.
Distribution of sperm antigen 6 (SPAG6) and 16 (SPAG16) in mouse ciliated and non-ciliated tissues
J Mol Histol 2019 50(3):189-202
Jimena Alciaturi 1 , Gabriel Anesetti 1 , Florencia Irigoin 1 2 , Fernanda Skowronek 1 , Rossana Sapiro 3
1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo, Uruguay. 2 Laboratorio de Genética Molecular Humana, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, Uruguay. 3 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo, Uruguay. rsapiro@fmed.edu.uy.
DOI: 10.1007/s10735-019-09817-z
PMID: 30911868
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30911868
Texto completo: https://doi.org/10.1007/s10735-019-09817-z
Abstract:
The cilia and flagella of eukaryotic cells serve many functions, exhibiting remarkable conservation of both structure and molecular composition in widely divergent eukaryotic organisms. SPAG6 and SPAG16 are the homologous in the mice to Chlamydomonas reinhardtii PF16 and PF20. Both proteins are associated with the axonemal central apparatus and are essential for ciliary and flagellar motility in mammals. Recent data derived from high-throughput studies revealed expression of these genes in tissues that do not contain motile cilia. However, the distribution of SPAG6 and SPAG16 in ciliated and non-ciliated tissues is not completely understood. In this work, we performed a quantitative analysis of the expression of Spag6 and Spag16 genes in parallel with the immune-localization of the proteins in several tissues of adult mice. Expression of mRNA was higher in the testis and tissues bearing motile cilia than in the other analyzed tissues. Both proteins were present in ciliated and non-ciliated tissues. In the testis, SPAG6 was detected in spermatogonia, spermatocytes, and in the sperm flagella whereas SPAG16 was found in spermatocytes and in the sperm flagella. In addition, both proteins were detected in the cytoplasm of cells from the brain, spinal cord, and ovary. A small isoform of SPAG16 was localized in the nucleus of germ cells and some neurons. In a parallel set of experiments, we overexpressed EGFP-SPAG6 in cultured cells and observed that the protein co-localized with a subset of acetylated cytoplasmic microtubules. A role of these proteins stabilizing the cytoplasmic microtubules of eukaryotic cells is discussed.
Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth
BMC Med Genomics 2019 12(1):53
Silvana Pereyra 1 , Claudio Sosa 2 , Bernardo Bertoni 1 , Rossana Sapiro 3
1 Departamento de Genética, Facultad de Medicina, Universidad de la República, Av. General Flores 2125, C.P, 11800, Montevideo, Uruguay. 2 Clínica Ginecotologica "C", Centro Hospitalario Pereira Rossell, Facultad de Medicina, Universidad de la República, Bvar. General Artigas 1590, C:P.11600, Montevideo, Uruguay. 3 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Av. General Flores 2125, C.P, 11800, Montevideo, Uruguay. rsapiro@fmed.edu.uy.
DOI: 10.1186/s12920-019-0498-3
PMID: 30935390
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30935390
Texto completo: https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-019-0498-3
Abstract:
Background: Preterm birth (PTB), defined as infant delivery before 37 weeks of completed gestation, results from the interaction of both genetic and environmental components and constitutes a complex multifactorial syndrome. Transcriptome analysis of PTB has proven challenging because of the multiple causes of PTB and the numerous maternal and fetal gestational tissues that must interact to facilitate parturition. The transcriptome of the chorioamnion membranes at the site of rupture in PTB and term fetuses may reflect the molecular pathways of preterm labor.
Methods: In this work, chorioamnion membranes from severe preterm and term fetuses were analyzed using RNA sequencing. Functional annotations and pathway analysis of differentially expressed genes were performed with the GAGE and GOSeq packages. A subset of differentially expressed genes in PTB was validated in a larger cohort using qRT-PCR and by comparing our results with genes and pathways previously reported in the literature.
Results: A total of 270 genes were differentially expressed (DE): 252 were upregulated and 18 were down-regulated in severe preterm births relative to term births. Inflammatory and immunological pathways were upregulated in PTB. Both types of pathways were previously suggested to lead to PTB. Pathways that were not previously reported in PTB, such as the hemopoietic pathway, appeared upregulated in preterm membranes. A group of 18 downregulated genes discriminated between term and severe preterm cases. These genes potentially characterize a severe preterm transcriptome pattern and therefore are candidate genes for understanding the syndrome. Some of the downregulated genes are involved in the nervous system, morphogenesis (WNT1, DLX5, PAPPA2) and ion channel complexes (KCNJ16, KCNB1), making them good candidates as biomarkers of PTB.
Conclusions: The identification of this DE gene pattern will help with the development of a multi-gene disease classifier. These markers were generated in an admixed South American population in which PTB has a high incidence. Since the genetic background may differentially impact different populations, it is necessary to include populations such as those from South America and Africa, which are usually excluded from high-throughput approaches. These classifiers should be compared to those in other populations to obtain a global landscape of PTB.
Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits
Front Pharmacol 2019 10:193
Soledad Marton 1 , Bruno González 2 , Sebastián Rodríguez-Bottero 1 , Ernesto Miquel 1 , Laura Martínez-Palma 1 , Mariana Pazos 2 , José Pedro Prieto 3 , Paola Rodríguez 2 , Dalibor Sames 4 , Gustavo Seoane 2 , Cecilia Scorza 3 , Patricia Cassina 1 , Ignacio Carrera 2
1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 2 Laboratorio de Síntesis Orgánica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay. 3 Departamento de Neurofarmacología Experimental, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay. 4 Department of Chemistry, Columbia University, New York, NY, United States.
DOI: 10.3389/fphar.2019.00193
PMID: 30890941
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30890941
Texto completo: https://doi.org/10.3389/fphar.2019.00193
Abstract:
Ibogaine is an atypical psychedelic alkaloid, which has been subject of research due to its reported ability to attenuate drug-seeking behavior. Recent work has suggested that ibogaine effects on alcohol self-administration in rats are related to the release of Glial cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts the soma of dopaminergic neurons. Although previous reports have shown ibogaine's ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF and other neurotrophic factors (NFs) such as Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct brain regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Rats were i.p. treated with ibogaine 20 mg/kg (I20), 40 mg/kg (I40) or vehicle, and NFs expression was analyzed after 3 and 24 h. At 24 h an increase of the expression of the NFs transcripts was observed in a site and dose dependent manner. Only for I40, GDNF was selectively upregulated in the VTA and SN. Both doses elicited a large increase in the expression of BDNF transcripts in the NAcc, SN and PFC, while in the VTA a significant effect was found only for I40. Finally, NGF mRNA was upregulated in all regions after I40, while I20 showed a selective upregulation in PFC and VTA. Regarding protein levels, an increase of GDNF was observed in the VTA only for I40 but no significant increase for BDNF was found in all the studied areas. Interestingly, an increase of proBDNF was detected in the NAcc for both doses. These results show for the first time a selective increase of GDNF specifically in the VTA for I40 but not for I20 after 24 h of administration, which agrees with the effective dose found in previous self-administration studies in rodents. Further research is needed to understand the contribution of these changes to ibogaine's ability to attenuate drug-seeking behavior.
Experimental polycystic ovarian syndrome is associated with reduced expression and function of P2Y2 receptors in rat theca cells
Mol Reprod Dev 2019 86(3):308-318
Anaí Del Rocío Campos-Contreras 1 , Ana Patricia Juárez-Mercado 1 , Adriana González-Gallardo 2 , Rebeca Chávez-Genaro 3 , Edith Garay 1 , Dalia Luz De Ita-Pérez 1 , Mauricio Díaz-Muñoz 1 , Francisco Gabriel Vázquez-Cuevas 1
1 Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla Querétaro, México. 2 Unidad de Proteogenómica. Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla Querétaro, México. 3 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
DOI: 10.1002/mrd.23106
PMID: 30624816
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30624816
Texto completo: https://doi.org/10.1002/mrd.23106
Abstract:
Extracellular purines through specific receptors have been recognized as new regulators of ovarian function. It is known that P2Y2 receptor activity induces theca cell proliferation, we hypothesized that purinergic signaling controls the changes related to hyperthecosis in polycystic ovarian syndrome (PCOS). The aim of this study was to analyze the expression of UTP-sensitive P2Y receptors and their role in theca cells (TC) proliferation in experimentally-induced PCOS (EI-PCOS). In primary cultures of TC from intact rats, all the transcripts of P2Y receptors were detected by polymerase chain reaction; in these cells, UTP (10 μM) induced extracellular signal-regulated kinases (ERK) phosphorylation. Rats with EI-PCOS showed a reduced expression of P2Y2R in TC whereas P2Y4R did not change. By analyzing ERK phosphorylation, it was determined that P2Y2R is the most relevant receptor in TC. UTP promoted cell proliferation in TC from control but not from EI-PCOS rats. The in silico analysis of P2yr2 promoter indicated the presence of androgen response elements; the stimulation of TC primary cultures with testosterone promoted a significant reduction in the expression of the P2yr2 transcript. We concluded that P2Y2R participates in controlling the proliferative rate of TCs from healthy ovaries, but this regulation is lost during EI-PCOS.