Publicaciones por año
Publicaciones del Departamento de Histología y Embriología
Ciliary Entry of the Hedgehog Transcriptional Activator Gli2 Is Mediated by the Nuclear Import Machinery but Differs from Nuclear Transport in Being Imp-α/β1-Independent
PLoS One 2016 11(8):e0162033
Belén Torrado 1 , Martín Graña 2 , José L Badano 1 , Florencia Irigoín 1 3
1 Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo CP11400, Uruguay. 2 Bioinformatics Unit, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo CP11400, Uruguay. 3 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo CP11800, Uruguay.
DOI: 10.1371/journal.pone.0162033
PMID: 27579771
Pubmed: https://pubmed.ncbi.nlm.nih.gov/27579771
Texto completo: https://dx.plos.org/10.1371/journal.pone.0162033
Abstract:
Gli2 is the primary transcriptional activator of Hedgehog signalling in mammals. Upon stimulation of the pathway, Gli2 moves into the cilium before reaching the nucleus. However, the mechanisms underlying its entry into the cilium are not completely understood. Since several similarities have been reported between nuclear and ciliary import, we investigated if the nuclear import machinery participates in Gli2 ciliary entry. Here we show that while two conserved classical nuclear localization signals mediate Gli2 nuclear localization via importin (Imp)-α/β1, these sequences are not required for Gli2 ciliary import. However, blocking Imp-mediated transport through overexpression of GTP-locked Ran reduced the percentage of Gli2 positive cilia, an effect that was not explained by increased CRM1-dependent export of Gli2 from the cilium. We explored the participation of Imp-β2 in Gli2 ciliary traffic and observed that this transporter is involved in moving Gli2 into the cilium, as has been described for other ciliary proteins. In addition, our data indicate that Imp-β2 might also collaborate in Gli2 nuclear entry. How does Imp-β2 determine the final destination of a protein that can localize to two distinct subcellular compartments remains an open question. Therefore, our data shows that the nuclear-cytoplasmic shuttling machinery plays a critical role mediating the subcellular distribution of Gli2 and the activation of the pathway, but distinct importins likely play a differential role mediating its ciliary and nuclear translocation.
A Natural Cattle Immune Response Against Horn Fly (Diptera: Muscidae) Salivary Antigens May Regulate Parasite Blood Intake
J Econ Entomol 2016 109(4):1951-6
M Breijo 1 , L Pastro 2 , S Rocha 3 , X Ures 3 , P Alonzo 3 , M Santos 3 , C Bolatto 4 , C Fernández 5 , A Meikle 6
1 Unidad de Reactivos y Biomodelos de Experimentación, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo, Uruguay (mbreijo@fmed.edu.uy; gabrielrocha85@gmail.com; ximenaures@gmail.com; palonzo@higiene.edu.uy; msantos@fmed.edu.uy) mbreijo@fmed.edu.uy. 2 Laboratorio de Interacciones Moleculares, Facultad de Ciencias, Iguá 4225, 11400 Montevideo, Uruguay (lpastro@fcien.edu.uy). 3 Unidad de Reactivos y Biomodelos de Experimentación, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo, Uruguay (mbreijo@fmed.edu.uy; gabrielrocha85@gmail.com; ximenaures@gmail.com; palonzo@higiene.edu.uy; msantos@fmed.edu.uy). 4 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo, Uruguay (cbolatto@fmed.edu.uy). 5 Cátedra de Inmunología, Facultad de Química, Instituto de Higiene, Universidad de la República, Av. Alfredo Navarro 3051, 11600 Montevideo, Uruguay (cfernan@fq.edu.uy). 6 Laboratorio de Técnicas Nucleares, Facultad de Veterinaria, Universidad de la República, Lasplaces 1550, Montevideo, Uruguay (meikleana@gmail.com).
DOI: 10.1093/jee/tow133
PMID: 27329632
Pubmed: https://pubmed.ncbi.nlm.nih.gov/27329632
Texto completo: https://academic.oup.com/jee/article-lookup/doi/10.1093/jee/tow133
Abstract:
The horn fly, Haematobia irritans (L.), is a blood-sucking ectoparasite that is responsible for sizeable economic losses in livestock. The salivary gland products facilitate blood intake. Taking advantage of the identification of novel H. irritans salivary antigens (Hematobin, HTB and Irritans 5, IT5), we investigated the parasite loads, H. irritans blood intake, and antibody response of naturally infected bovines during the fly season. Fly loads and fly hemoglobin content fluctuated during the trial. Each time horn fly loads exceeded 200 flies per cattle, a reduction in horn fly blood intake was observed three weeks later. All of the cattle elicited an antibody response against HTB and IT5 that declined once the fly season was over. Cattle anti-IT5 titers were positively correlated with parasite loads and negatively correlated with fly blood intake. These results suggest that the natural changes in the H. irritans blood intake observed in this study were associated with a natural host response against horn fly salivary antigens.
Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis
J Neuroinflammation 2016 13(1):177
Emiliano Trias 1 , Sofía Ibarburu 1 , Romina Barreto-Núñez 1 , Joël Babdor 2 3 4 5 , Thiago T Maciel 2 3 4 5 6 7 , Matthias Guillo 2 3 4 5 , Laurent Gros 8 , Patrice Dubreuil 7 8 9 , Pablo Díaz-Amarilla 10 , Patricia Cassina 11 , Laura Martínez-Palma 11 , Ivan C Moura 2 3 4 5 6 7 , Joseph S Beckman 12 , Olivier Hermine 13 14 15 16 17 18 19 20 21 , Luis Barbeito 22
1 Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay. 2 Imagine Institute, Hôpital Necker, 24 boulevard du Montparnasse, 75015, Paris, France. 3 INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France. 4 Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. 5 CNRS ERL 8254, Paris, France. 6 Laboratory of Excellence GR-Ex, Paris, France. 7 Equipe Labélisée par la Ligue Nationale contre le cancer, Paris, Cedex, France. 8 AB Science, 3 Avenue Georges V, 75008, Paris, France. 9 CRCM, [Signaling, Hematopoiesis and Mechanism of Oncogenesis], Inserm, U1068, Institut Paoli-Calmettes, Aix-Marseille Univ, UM105, CNRS, UMR7258, Marseille, F-13009, France. 10 Laboratorio de Neurobiología Celular y Molecular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay. 11 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 12 Linus Pauling Institute, Department of Biochemistry and Biophysics, Environmental Health Sciences Center, Oregon State University, Corvallis, USA. 13 Imagine Institute, Hôpital Necker, 24 boulevard du Montparnasse, 75015, Paris, France. ohermine@gmail.com. 14 INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France. ohermine@gmail.com. 15 Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. ohermine@gmail.com. 16 CNRS ERL 8254, Paris, France. ohermine@gmail.com. 17 Laboratory of Excellence GR-Ex, Paris, France. ohermine@gmail.com. 18 Equipe Labélisée par la Ligue Nationale contre le cancer, Paris, Cedex, France. ohermine@gmail.com. 19 AB Science, 3 Avenue Georges V, 75008, Paris, France. ohermine@gmail.com. 20 Department of Hematology, Necker Hospital, Paris, France. ohermine@gmail.com. 21 Centre national de référence des mastocytoses (CEREMAST), Paris, France. ohermine@gmail.com. 22 Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay. barbeito@pateur.edu.uy.
DOI: 10.1186/s12974-016-0620-9
PMID: 27400786
Pubmed: https://pubmed.ncbi.nlm.nih.gov/27400786
Texto completo: https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-016-0620-9
Abstract:
Background: In the SOD1(G93A) mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS.
Methods: The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1(G93A) rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset.
Results: We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1(G93A) spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1(G93A) rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %.
Conclusions: These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.
Interactions between environmental factors and maternal-fetal genetic variations: strategies to elucidate risks of preterm birth
Eur J Obstet Gynecol Reprod Biol 2016 202:20-5
Silvana Pereyra 1 , Bernardo Bertoni 2 , Rossana Sapiro 3
1 Departamento de Genética, Facultad de Medicina, Universidad de la República, Av. General Flores 2125, C.P. 11800 Montevideo, Uruguay. Electronic address: spereyra@fmed.edu.uy. 2 Departamento de Genética, Facultad de Medicina, Universidad de la República, Av. General Flores 2125, C.P. 11800 Montevideo, Uruguay. Electronic address: bbertoni@fmed.edu.uy. 3 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Av. General Flores 2125, C.P. 11800 Montevideo, Uruguay. Electronic address: rsapiro@fmed.edu.uy.
DOI: 10.1016/j.ejogrb.2016.04.030
PMID: 27156152
Pubmed: https://pubmed.ncbi.nlm.nih.gov/27156152
Texto completo: https://linkinghub.elsevier.com/retrieve/pii/S0301-2115(16)30181-6
Abstract:
Context: Preterm birth (PTB) is a complex disease in which medical, social, cultural, and hereditary factors contribute to the pathogenesis of this adverse event. Interactions between genes and environmental factors may complicate our understanding of the relative influence of both effects on PTB. To overcome this, we combined data obtained from a cohort of newborns and their mothers with multiplex analysis of inflammatory-related genes and several environmental risk factors of PTB to describe the environmental-genetic influence on PTB.
Objective: The study aimed to investigate the association between maternal and fetal genetic variations in genes related to the inflammation pathway with PTB and to assess the interaction between environmental factors with these variations.
Study design: We conducted a case-control study at the Pereira Rossell Hospital Center, Montevideo, Uruguay. The study included 143 mother-offspring dyads who delivered at preterm (gestational age<37 weeks) and 108 mother-offspring dyads who delivered at term. We used real-time PCR followed by a high-resolution melting analysis to simultaneously identify gene variations involved in inflammatory pathways in the context of environmental variables. The genes analyzed were: Toll-like receptor 4 (TLR4), Interleukin 6 (IL6), Interleukin 1 beta (IL1B) and Interleukin 12 receptor beta (IL12RB).
Results: We detected a significant interaction between IL1B rs16944 polymorphism in maternal samples and IL6 rs1800795 polymorphism in newborns, emphasizing the role of the interaction of maternal and fetal genomes in PTB. In addition, smoke exposure and premature rupture of membranes (PROM) were significantly different between the premature group and controls. IL1B and IL6 polymorphisms in mothers were significantly associated with PTB when controlling for smoke exposure. TLR4 polymorphism and PROM were significantly associated with PTB when controlling for PROM, but only in the case of severe PTB.
Conclusions: Interactions between maternal and fetal genomes may influence the timing of birth. By incorporating environmental data, we revealed genetic associations with PTB, a finding not found when we analyzed genetic data alone. Our results stress the importance of studying the effect of genotype interactions between mothers and children in the context of environmental factors because they substantially contribute to phenotype variability.
Electrophilic nitro-fatty acids prevent astrocyte-mediated toxicity to motor neurons in a cell model of familial amyotrophic lateral sclerosis via nuclear factor erythroid 2-related factor activation
Free Radic Biol Med 2016 95:112-20
Pablo Diaz-Amarilla 1 * , Ernesto Miquel 2 * , Andrés Trostchansky 3 , Emiliano Trias 4 , Ana M Ferreira 5 , Bruce A Freeman 6 , Patricia Cassina 2 , Luis Barbeito 4 , Marcelo R Vargas 7 , Homero Rubbo 8
1 Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay. 2 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 3 Departamento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 4 Institut Pasteur of Montevideo, Montevideo, Uruguay. 5 Catedra de Inmunología, Facultad de Quimica y Ciencias, Universidad de la República, Montevideo, Uruguay. 6 Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA, USA. 7 Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA. 8 Departamento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. Electronic address: hrubbo@fmed.edu.uy. * These authors contributed equally to this work
DOI: 10.1016/j.freeradbiomed.2016.03.013
PMID: 27012417
Pubmed: https://pubmed.ncbi.nlm.nih.gov/27012417
Texto completo: https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(16)00119-2
Abstract:
Nitro-fatty acids (NO2-FA) are electrophilic signaling mediators formed in tissues during inflammation, which are able to induce pleiotropic cytoprotective and antioxidant pathways including up regulation of Nuclear factor erythroid 2-related factor 2 (Nrf2) responsive genes. Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons associated to an inflammatory process that usually aggravates the disease progression. In ALS animal models, the activation of the transcription factor Nrf2 in astrocytes confers protection to neighboring neurons. It is currently unknown whether NO2-FA can exert protective activity in ALS through Nrf2 activation. Herein we demonstrate that nitro-arachidonic acid (NO2-AA) or nitro-oleic acid (NO2-OA) administrated to astrocytes expressing the ALS-linked hSOD1(G93A) induce antioxidant phase II enzyme expression through Nrf2 activation concomitant with increasing intracellular glutathione levels. Furthermore, treatment of hSOD1(G93A)-expressing astrocytes with NO2-FA prevented their toxicity to motor neurons. Transfection of siRNA targeted to Nrf2 mRNA supported the involvement of Nrf2 activation in NO2-FA-mediated protective effects. Our results show for the first time that NO2-FA induce a potent Nrf2-dependent antioxidant response in astrocytes capable of preventing motor neurons death in a culture model of ALS.
Selenoproteins of African trypanosomes are dispensable for parasite survival in a mammalian host
Mol Biochem Parasitol 2016 206(1-2):13-9
Mariana Bonilla 1 , Erika Krull 1 , Florencia Irigoín 2 , Gustavo Salinas 3 , Marcelo A Comini 4
1 Redox Biology of Trypanosomes Laboratory, Institut Pasteur de Montevideo, Uruguay. 2 Molecular Human Genetics Laboratory, Institut Pasteur de Montevideo, Uruguay; Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 3 Worm Biology Laboratory, Institut Pasteur de Montevideo, Uruguay; Cátedra de Inmunología, Departamento de Biociencias, Facultad de Química, Universidad de la República, Montevideo, Uruguay. Electronic address: gsalin@fq.edu.uy. 4 Redox Biology of Trypanosomes Laboratory, Institut Pasteur de Montevideo, Uruguay. Electronic address: mcomini@pasteur.edu.uy.
DOI: 10.1016/j.molbiopara.2016.03.002
PMID: 26975431
Pubmed: https://pubmed.ncbi.nlm.nih.gov/26975431
Texto completo: https://linkinghub.elsevier.com/retrieve/pii/S0166-6851(16)30018-4
Abstract:
The trace element selenium is found in polypeptides as selenocysteine, the 21(st) amino acid that is co-translationally inserted into proteins at a UGA codon. In proteins, selenocysteine usually plays a role as an efficient redox catalyst. Trypanosomatids previously examined harbor a full set of genes encoding the machinery needed for selenocysteine biosynthesis and incorporation into three selenoproteins: SelK, SelT and, the parasite-specific, Seltryp. We investigated the selenoproteome of kinetoplastid species in recently sequenced genomes and assessed the in vivo relevance of selenoproteins for African trypanosomes. Database mining revealed that SelK, SelT and Seltryp genes are present in most kinetoplastids, including the free-living species Bodo saltans, and Seltryp was lost in the subgenus Viannia from the New World Leishmania. Homology and sinteny with bacterial sulfur dioxygenases and sulfur transferases suggest a putative role for Seltryp in sulfur metabolism. A Trypanosoma brucei selenocysteine synthase (SepSecS) null-mutant, in which selenoprotein synthesis is abolished, displayed similar sensitivity to oxidative stress induced by a short-term exposure to high concentrations of methylglyoxal or H2O2 to that of the parental wild-type cell line. Importantly, the infectivity of the SepSecS knockout cell line was not impaired when tested in a mouse infection model and compensatory effects via up-regulation of proteins involved in thiol-redox metabolism were not observed. Collectively, our data show that selenoproteins are not required for survival of African trypanosomes in a mammalian host and exclude a role for selenoproteins in parasite antioxidant defense and/or virulence. On this basis, selenoproteins can be disregarded as drug target candidates.
Increase in the expression of leukocyte elastase inhibitor during wound healing in corneal endothelial cells
Cell Tissue Res 2015 362(3):557-68
Cristian Justet 1 , Frances Evans 1 2 , Alicia Torriglia 3 4 5 , Silvia Chifflet 6
1 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, 11800, Montevideo, Uruguay. 2 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, 11800, Montevideo, Uruguay. 3 INSERM U1138, Centre de Recherche des Cordeliers, Paris, France. alicia.torriglia@inserm.fr. 4 Université Paris Descartes, Paris, France. alicia.torriglia@inserm.fr. 5 Université Pierre et Marie Curie, Paris, France. alicia.torriglia@inserm.fr. 6 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, 11800, Montevideo, Uruguay. schiffle@mednet.org.uy.
DOI: 10.1007/s00441-015-2223-7
PMID: 26085342
Pubmed: https://pubmed.ncbi.nlm.nih.gov/26085342
Texto completo: https://dx.doi.org/10.1007/s00441-015-2223-7
Abstract:
Tissue injury triggers a complex network of cellular and molecular responses. Although cell migration and proliferation are the most conspicuous, several other responses, such as apoptosis and increased protease activity, are necessary for a proper restitution of the tissue. In this work, we study the leukocyte elastase inhibitor (LEI) expression during wound healing of bovine corneal endothelial monolayers in culture. LEI is a multifunctional protein with anti-protease and anti-apoptotic activity. When properly cleaved, it is transformed into L-DNase II, a pro-apoptotic enzyme and translocated to the nucleus. We found that early after injury LEI increases its protein and mRNA expressions, without nuclear translocation and returns to basal levels immediately after wound closure. This increase is blocked by N-acetylcysteine, suggesting that production of reactive oxygen species immediately after wounding is involved in the LEI increase. Another finding of this work is that there is an acidification of the cells at the wound border which, in contrast to other cell types, does not determine nuclear translocation of the protein. Taken together, the results of this work suggest that the function of LEI during wound healing is related to its activity as a protease inhibitor and/or to its anti-apoptotic activity.
Bardet-Biedl syndrome: Is it only cilia dysfunction?
FEBS Lett 2015 589(22):3479-91
Rossina Novas 1 , Magdalena Cardenas-Rodriguez 1 , Florencia Irigoín 2 , Jose L Badano 3
1 Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo CP11400, Uruguay. 2 Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo CP11400, Uruguay; Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Gral. Flores 2125, Montevideo CP11800, Uruguay. 3 Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo CP11400, Uruguay
DOI: 10.1016/j.febslet.2015.07.031
PMID: 26231314
Pubmed: https://pubmed.ncbi.nlm.nih.gov/26231314
Texto completo: https://onlinelibrary.wiley.com/doi/10.1016/j.febslet.2015.07.031
Abstract:
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic disorder, characterized by both congenital and late onset defects. From the analysis of the mutational burden in patients to the functional characterization of the BBS proteins, this syndrome has become a model for both understanding oligogenic patterns of inheritance and the biology of a particular cellular organelle: the primary cilium. Here we briefly review the genetics of BBS to then focus on the function of the BBS proteins, not only in the context of the cilium but also highlighting potential extra-ciliary roles that could be relevant to the etiology of the disorder. Finally, we provide an overview of how the study of this rare syndrome has contributed to the understanding of cilia biology and how this knowledge has informed on the cellular basis of different clinical manifestations that characterize BBS and the ciliopathies.
Defective Human Sperm Cells Are Associated with Mitochondrial Dysfunction and Oxidant Production
Biol Reprod 2015 93(5):119
Adriana Cassina 1 , Patricia Silveira 2 , Lidia Cantu 3 , Jose Maria Montes 3 , Rafael Radi 1 , Rossana Sapiro 4
1 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay. 2 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay. 3 Andrology Clinic Fertilab, Montevideo, Uruguay. 4 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay
DOI: 10.1095/biolreprod.115.130989
PMID: 26447142
Pubmed: https://pubmed.ncbi.nlm.nih.gov/26447142
Texto completo: https://academic.oup.com/biolreprod/article-lookup/doi/10.1095/biolreprod.115.130989
Abstract:
Infertility affects about 15% of couples of reproductive age. The male factor is involved in nearly 50% of infertility cases. Defective human sperm function has been associated with evidence of high levels of reactive oxygen species (ROS) and a resultant loss of fertilizing potential in vivo and in vitro. Analogous to what has been observed in somatic cells, mitochondria are likely the major sources of ROS in sperm cells. In this study, we analyzed mitochondrial function using high-resolution respirometry, ROS production, and footprints of oxidative and nitrative stress processes in intact human sperm cells. We showed that mitochondrial dysfunction (measured through the respiratory control ratio) was correlated with a decrease in human sperm motility. The samples analyzed presented nitro-oxidative modifications of proteins, such as protein 3-nitrotyrosine, that were observed mainly in the mid-piece (where mitochondria are localized) and in the sperm head. Semen samples presenting lower percentage of motile sperm showed higher amounts of nitro-oxidative protein modifications than those with larger quantities of motile sperm. When spermatozoa were exposed to inhibitors of the respiratory mitochondrial function, in the presence of a nitric oxide flux, sperm produced potent nitro-oxidative species (i.e., peroxynitrite). This effect was observed in more than 90% of intact living sperm cells and in sperm mitochondrial fractions. These data suggest that dysfunctional mitochondria in sperm cells produce oxidants that may contribute to male infertility. These data provide the rationale for testing the potential of compounds that improve sperm mitochondrial function to treat male infertility.
The secretogranin-II derived peptide secretoneurin modulates electric behavior in the weakly pulse type electric fish, Brachyhypopomus gauderio
Gen Comp Endocrinol 2015 222:158-66
Paula Pouso 1 , Laura Quintana 2 , Gabriela C López 3 , Gustavo M Somoza 3 , Ana C Silva 4 , Vance L Trudeau 5
1 Depto Histología y Embriología, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay; Unidad Bases Neurales de la Conducta, Departamento de Neurofisiología Celular y Molecular, IIBCE, 11600 Montevideo, Uruguay. 2 Unidad Bases Neurales de la Conducta, Departamento de Neurofisiología Celular y Molecular, IIBCE, 11600 Montevideo, Uruguay. 3 Laboratorio de Ictiofisiología y Acuicultura, Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús (IIBINTECH), Provincia de Buenos Aires, Argentina. 4 Unidad Bases Neurales de la Conducta, Departamento de Neurofisiología Celular y Molecular, IIBCE, 11600 Montevideo, Uruguay; Laboratorio de Neurociencias, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay. 5 Centre for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.
DOI: 10.1016/j.ygcen.2015.06.015
PMID: 26141148
Pubmed: https://pubmed.ncbi.nlm.nih.gov/26141148
Texto completo: https://linkinghub.elsevier.com/retrieve/pii/S0016-6480(15)00183-5
Abstract:
Secretoneurin (SN) in the preoptic area and pituitary of mammals and fish has a conserved close association with the vasopressin and oxytocin systems, members of a peptide family that are key in the modulation of sexual and social behaviors. Here we show the presence of SN-immunoreactive cells and projections in the brain of the electric fish, Brachyhypopomus gauderio. Secretoneurin colocalized with vasotocin (AVT) and isotocin in cells and fibers of the preoptic area. In the rostral pars distalis of the pituitary, many cells were both SN and prolactin-positive. In the hindbrain, at the level of the command nucleus of the electric behavior (pacemaker nucleus; PN), some of SN-positive fibers colocalized with AVT. We also explored the potential neuromodulatory role of SN on electric behavior, specifically on the rate of the electric organ discharge (EOD) that signals arousal, dominance and subordinate status. Each EOD is triggered by the command discharge of the PN, ultimately responsible for the basal EOD rate. SN modulated diurnal basal EOD rate in freely swimming fish in a context-dependent manner; determined by the initial value of EOD rate. In brainstem slices, SN partially mimicked the in vivo behavioral effects acting on PN firing rate. Taken together, our results suggest that SN may regulate electric behavior, and that its effect on EOD rate may be explained by direct action of SN at the PN level through either neuroendocrine and/or endocrine mechanisms.