Tania Maria Ruffoni Ortiga


Universidade Federal do Rio de Janeiro


Scopus Publications

Scopus Publications

  • Metabolomic analysis of follicular fluid from women with Hashimoto thyroiditis
    Diana Caroline da Silva Bastos, Maria Izabel Chiamolera, Renata Elen Silva, Maria Do Carmo Borges de Souza, Roberto Azevedo Antunes, Marcelo Marinho Souza, Ana Cristina Allemand Mancebo, Patrícia Cristina Fernandes Arêas, Fernando M. Reis, Edson Guimarães Lo Turco,et al.

    Springer Science and Business Media LLC
    AbstractHashimoto thyroiditis is an autoimmune disease characterized by hypothyroidism and a high level of anti-thyroid autoantibodies. It has shown to negatively impact female fertility; however, the mechanisms are unclear. Ovarian follicular fluid appears to be the key to understanding how Hashimoto thyroiditis affecst fertility. Thus, we aimed to evaluated the metabolic profile of follicular fluid and antithyroid autoantibody levels in the context of Hashimoto thyroiditis. We collected follicular fluid from 61 patients, namely 38 women with thyroid autoantibody positivity and 23 women as negative controls, undergoing in vitro fertilization treatment. Follicular fluid samples were analyzed using metabolomics, and thyroid autoantibodies were measured. Fifteen metabolites with higher concentrations in the follicular fluid samples from Hashimoto thyroiditis were identified, comprising five possible affected pathways: the glycerophospholipid, arachidonic acid, linoleic acid, alpha-linolenic acid, and sphingolipid metabolism pathways. These pathways are known to regulate ovarian functions. In addition, antithyroglobulin antibody concentrations in both serum and follicular fluid were more than tenfold higher in women with Hashimoto thyroiditis than in controls. Our data showed that the metabolic profile of follicular fluid is altered in women with Hashimoto thyroiditis, suggesting a potential mechanistic explanation for the association of this disease with female infertility.

  • Combined effects of intermittent fasting with swimming-based high intensity intermittent exercise training in Wistar rats
    Everton Luis dos Santos Cardoso, Fábio Cahuê, Iordan Emanuel Ferreira Miranda, Marcelo de Lima Sant’Anna, Cherley Borba Vieira Andrade, Raiana Andrade Quintanilha Barbosa, Tania Maria Ortiga-Carvalho, Mário Vaisman, and Verônica Pinto Salerno

    Elsevier BV

  • Immunostaining of βA-Activin and Follistatin Is Decreased in HPV(+) Cervical Pre-Neoplastic and Neoplastic Lesions
    Victor Jesus Huaringa Payano, Lara Verônica de Araújo Lopes, Larissa Rodrigues Peixoto, Keila Alves da Silva, Tania Maria Ortiga-Carvalho, Alexandre Tafuri, Annamaria Ravara Vago, and Enrrico Bloise

    The activin–follistatin system regulates several cellular processes, including differentiation and tumorigenesis. We hypothesized that the immunostaining of βA-activin and follistatin varies in neoplastic cervical lesions. Cervical paraffin-embedded tissues from 162 patients sorted in control (n = 15), cervical intraepithelial neoplasia (CIN) grade 1 (n = 38), CIN2 (n = 37), CIN3 (n = 39), and squamous cell carcinoma (SCC; n = 33) groups were examined for βA-activin and follistatin immunostaining. Human papillomavirus (HPV) detection and genotyping were performed by PCR and immunohistochemistry. Sixteen samples were inconclusive for HPV detection. In total, 93% of the specimens exhibited HPV positivity, which increased with patient age. The most detected high-risk (HR)-HPV type was HPV16 (41.2%) followed by HPV18 (16%). The immunostaining of cytoplasmatic βA-activin and follistatin was higher than nuclear immunostaining in all cervical epithelium layers of the CIN1, CIN2, CIN3, and SCC groups. A significant decrease (p < 0.05) in the cytoplasmic and nuclear immunostaining of βA-activin was detected in all cervical epithelial layers from the control to the CIN1, CIN2, CIN3, and SCC groups. Only nuclear follistatin immunostaining exhibited a significant reduction (p < 0.05) in specific epithelial layers of cervical tissues from CIN1, CIN2, CIN3, and SCC compared to the control. Decreased immunostaining of cervical βA-activin and follistatin at specific stages of CIN progression suggests that the activin–follistatin system participates in the loss of the differentiation control of pre-neoplastic and neoplastic cervical specimens predominantly positive for HPV.

  • Yerba mate consumption by ovariectomized rats alters white adipose tissue
    Victor Machado de Mello Andrade, Amanda Fernandes de Moura, Katlen da Costa Chaves, Camilla Pereira Dias da Rocha, Cherley Borba Vieira de Andrade, Isis Hara Trevenzoli, Tania Maria Ortiga-Carvalho, Luciane Cláudia Barcellos, Mário Vaisman, and Verônica Pinto Salerno

    Elsevier BV

  • Infection and disruption of placental multidrug resistance (MDR) transporters: Implications for fetal drug exposure
    C.B.V. Andrade, L.V.A. Lopes, T.M. Ortiga-Carvalho, S.G. Matthews, and E. Bloise

    Elsevier BV

  • Randomized prospective study comparing conventional In Vitro Fertilization technique to Intravaginal Culture with the INVOCELL™ device for 3 and 5 days
    Lilian de Freitas Aguiar, Gisele dos Santos Pessanha da Cunha, Karoll Andrea Alfonso Torres Cordido, Francisco Augusto Colucci Coelho, and Tânia Maria Ortiga Carvalho

    GN1 Sistemas e Publicacoes Ltd.

  • Mid-pregnancy poly(I:C) viral mimic disrupts placental ABC transporter expression and leads to long-term offspring motor and cognitive dysfunction
    V. R. S. Monteiro, C. B. V. Andrade, H. R. Gomes, M. W. Reginatto, G. E. Império, K. N. Fontes, D. A. Spiess, W. S. Rangel-Junior, V. M. O. Nascimento, C. O. S. Lima,et al.

    Springer Science and Business Media LLC
    AbstractLimited information is available about the effect of mid-pregnancy viral infections on the placental expression of efflux transporters and offspring behavior. We hypothesized that maternal exposure to polyinosinic-polycytidylic acid [poly(I:C)], a synthetic double-stranded RNA viral mimic, would impair placental cell turnover, the expression of selected ABC transporters and adult offspring behavior. C57BL/6 mice were administered poly(I:C) (10 mg/Kg;ip) or vehicle at gestational day (GD) 13.5 (mid-pregnancy). Dams were euthanized for blood collection 4 h after injection, fetal and placental collection at GD18.5 or allowed to deliver spontaneously at term. At GD 13.5, poly(I:C) induced an acute pro-inflammatory response characterized by an increase in maternal plasma levels of IL-6, CXCL-1 and CCL-2/MCP-1. At GD 18.5, poly(I:C) decreased cell proliferation/death in the labyrinthine and increased cell death in the junctional zones, characterizing a disruption of placental cell turnover. Abca1 and Abcg1 immunolabelling was decreased in the labyrinthine zone, whereas Abca1, Abcg1 and breast cancer resistance transporter (Bcrp) expression increased in the junctional zone. Moreover, adult offspring showed motor and cognitive impairments in the Rotarod and T-water maze tests. These results indicate that viral infection during mid-pregnancy may disrupt relevant placental efflux transporters, as well as placental cell turnover and offspring behavior in adult life.

  • Cylindrospermopsin Disrupts Estrous Cycle and Increases Spermatogenesis in Mice
    Adriana Carvalho Natal de Moraes, Fernanda Oliveira Caires, Guinever Eustaquio Imperio, Rafael Henrique Nóbrega, Tania Maria Ortiga-Carvalho, and Valéria Freitas de Magalhães

    Springer Science and Business Media LLC

  • Gaps in the knowledge of thyroid hormones and placental biology†
    Daniela Pereira Carvalho, Ariane Fontes Dias, Amanda Nancy Sferruzzi-Perri, and Tania Maria Ortiga-Carvalho

    Oxford University Press (OUP)
    Abstract Thyroid hormones (THs) are required for the growth and development of the fetus, stimulating anabolism, and oxygen consumption from the early stages of pregnancy to the period of fetal differentiation close to delivery. Maternal changes in the hypothalamic–pituitary–thyroid axis are also well known. In contrast, several open questions remain regarding the relationships between the placenta and the maternal and fetal TH systems. The exact mechanism by which the placenta participates in regulating the TH concentration in the fetus and mother and the role of TH in the placenta are still poorly studied. In this review, we aim to summarize the available data in the area and highlight significant gaps in our understanding of the ontogeny and cell-specific localization of TH transporters, TH receptors, and TH metabolic enzymes in the placenta in both human and rodent models. Significant deficiencies also exist in the knowledge of the contribution of genomic and nongenomic effects of TH on the placenta and finally, how the placenta reacts during pregnancy when the mother has thyroid disease. By addressing these key knowledge gaps, improved pregnancy outcomes and management of women with thyroid alterations may be possible.

  • Low Inflammatory Stimulus Increases D2 Activity and Modulates Thyroid Hormone Metabolism during Myogenesis In Vitro
    Thamires Siqueira de Oliveira, Marilia Kimie Shimabukuro, Victoria Regina Siqueira Monteiro, Cherley Borba Vieira Andrade, Anita Boelen, Simone Magagnin Wajner, Ana Luiza Maia, Tania Maria Ortiga-Carvalho, and Flavia Fonseca Bloise

    Thyroid hormone (TH) signaling controls muscle progenitor cells differentiation. However, inflammation can alter muscle TH signaling by modulating the expression of TH transporters (Slc16a2), receptors (Thra1), and deiodinase enzymes (Dio2 and Dio3). Thus, a proinflammatory environment could affect myogenesis. The role of a low-grade inflammatory milieu in TH signaling during myogenesis needs further investigation. Herein, we aimed to study the impact of the bacterial lipopolysaccharide (LPS)-induced inflammatory stimulus on the TH signaling during myogenesis. C2C12 myoblasts differentiation was induced without (CTR) or with 10 ng/mL LPS presence. The myoblasts under LPS stimulus release the proinflammatory cytokines (IL-6 and IL-1β) and chemokines (CCL2 and CXCL-1). LPS decreases Myod1 expression by 28% during the initial myogenesis, thus reducing the myogenic stimulus. At the same time, LPS reduced the expression of Dio2 by 41% but doubled the D2 enzymatic activity. The late differentiation was not affected by inflammatory milieu, which only increased the Slc16a2 gene expression by 38%. LPS altered the intracellular metabolism of TH and reduced the initial myogenic stimulus. However, it did not affect late differentiation. Increased intracellular TH activation may be the compensatory pathway involved in the recovery of myogenic differentiation under a low-grade inflammatory milieu.

  • Sepsis Disrupts Mitochondrial Function and Diaphragm Morphology
    Thamires Siqueira Oliveira, Anderson Teixeira Santos, Cherley Borba Vieira Andrade, Johnatas Dutra Silva, Natália Blanco, Nazareth de Novaes Rocha, Juliana Woyames, Pedro Leme Silva, Patricia Rieken Macedo Rocco, Wagner Seixas da-Silva,et al.

    Frontiers Media SA
    Graphical AbstractSeptic diaphragm has impaired morphology and increased thickness that seems to be associated, at least in part, with decreased mitochondrial function related to reducing in Pgc1α expression, ATP production, mitochondrial number, and quality in the CLP mice compared with the control group.

  • Altered umbilical cord blood nutrient levels, placental cell turnover and transporter expression in human term pregnancies conceived by intracytoplasmic sperm injection (Icsi)
    Enrrico Bloise, Jair R. S. Braga, Cherley B. V. Andrade, Guinever E. Imperio, Lilian M. Martinelli, Roberto A. Antunes, Karina R. Silva, Cristiana B. Nunes, Luigi Cobellis, Flavia F. Bloise,et al.

    Assisted reproductive technologies (ART) may increase risk for abnormal placental development, preterm delivery and low birthweight. We investigated placental morphology, transporter expression and paired maternal/umbilical fasting blood nutrient levels in human term pregnancies conceived naturally (n = 10) or by intracytoplasmic sperm injection (ICSI; n = 11). Maternal and umbilical vein blood from singleton term (>37 weeks) C-section pregnancies were assessed for levels of free amino acids, glucose, free fatty acids (FFA), cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), very low-density lipoprotein (VLDL) and triglycerides. We quantified placental expression of GLUT1 (glucose), SNAT2 (amino acids), P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) (drug) transporters, and placental morphology and pathology. Following ICSI, placental SNAT2 protein expression was downregulated and umbilical cord blood levels of citrulline were increased, while FFA levels were decreased at term (p < 0.05). Placental proliferation and apoptotic rates were increased in ICSI placentae (p < 0.05). No changes in maternal blood nutrient levels, placental GLUT1, P-gp and BCRP expression, or placental histopathology were observed. In term pregnancies, ICSI impairs placental SNAT2 transporter expression and cell turnover, and alters umbilical vein levels of specific nutrients without changing placental morphology. These may represent mechanisms through which ICSI impacts pregnancy outcomes and programs disease risk trajectories in offspring across the life course.

  • Effect of Sublethal Prenatal Endotoxaemia on Murine Placental Transport Systems and Lipid Homeostasis
    Mila W. Reginatto, Klaus Novaes Fontes, Victoria R. S. Monteiro, Natalia L. Silva, Cherley Borba Vieira Andrade, Hanailly Ribeiro Gomes, Guinever E. Imperio, Flavia Fonseca Bloise, George Eduardo Gabriel Kluck, Georgia Correa Atella,et al.

    Frontiers Media SA
    Infection alters the expression of transporters that mediate the placental exchange of xenobiotics, lipids and cytokines. We hypothesized that lipopolysaccharide (LPS) modifies the expression of placental transport systems and lipid homeostasis. LPS (150 μg/kg; i.p.) treatments were administered for 4 h or 24 h, animals were euthanized at gestational days (GD) 15.5 or 18.5, and maternal blood, fetuses and placentae were collected. Increased rates of fetal demise were observed at GD15.5 following LPS treatment, whereas at GD18.5, high rates of early labour occurred and were associated with distinct proinflammatory responses. Lipopolysaccharide did not alter ATP-binding cassette (ABC) transporter mRNA expression but decreased fatty acid binding protein associated with plasma membrane (Fabppm) at GD15.5 (LPS-4 h) and increased fatty acid translocase (Fat/Cd36) mRNA at GD18.5 (LPS-4 h). At the protein level, breast cancer-related protein (Bcrp) and ABC sub-family G member 1 (Abcg1) levels were decreased in the placental labyrinth zone (Lz) at GD15.5, whereas P-glycoprotein (P-gp) and Bcrp Lz-immunostaining was decreased at GD18.5. In the placental junctional zone (Jz), P-gp, Bcrp and Abcg1 levels were higher at GD18.5. Specific maternal plasma and placental changes in triacylglycerol, free fatty acid, cholesterol, cholesterol ester and monoacylglycerol levels were detected in a gestational age-dependent manner. In conclusion, LPS-increased risk of fetal death and early labour were associated with altered placental ABC and lipid transporter expression and deranged maternal plasma and placental lipid homeostasis. These changes may potentially modify fetal xenobiotic exposure and placental lipid exchange in cases of bacterial infection.

  • ZIKV Disrupts Placental Ultrastructure and Drug Transporter Expression in Mice
    Cherley Borba Vieira Andrade, Victoria Regina de Siqueira Monteiro, Sharton Vinicius Antunes Coelho, Hanailly Ribeiro Gomes, Ronny Paiva Campos Sousa, Veronica Muller de Oliveira Nascimento, Flavia Fonseca Bloise, Stephen Giles Matthews, Enrrico Bloise, Luciana Barros Arruda,et al.

    Frontiers Media SA
    Congenital Zika virus (ZIKV) infection can induce fetal brain abnormalities. Here, we investigated whether maternal ZIKV infection affects placental physiology and metabolic transport potential and impacts the fetal outcome, regardless of viral presence in the fetus at term. Low (103 PFU-ZIKVPE243; low ZIKV) and high (5x107 PFU-ZIKVPE243; high ZIKV) virus titers were injected into immunocompetent (ICompetent C57BL/6) and immunocompromised (ICompromised A129) mice at gestational day (GD) 12.5 for tissue collection at GD18.5 (term). High ZIKV elicited fetal death rates of 66% and 100%, whereas low ZIKV induced fetal death rates of 0% and 60% in C57BL/6 and A129 dams, respectively. All surviving fetuses exhibited intrauterine growth restriction (IUGR) and decreased placental efficiency. High-ZIKV infection in C57BL/6 and A129 mice resulted in virus detection in maternal spleens and placenta, but only A129 fetuses presented virus RNA in the brain. Nevertheless, pregnancies in both strains produced fetuses with decreased head sizes (p<0.05). Low-ZIKV-A129 dams had higher IL-6 and CXCL1 levels (p<0.05), and their placentas showed increased CCL-2 and CXCL-1 contents (p<0.05). In contrast, low-ZIKV-C57BL/6 dams had an elevated CCL2 serum level and increased type I and II IFN expression in the placenta. Notably, less abundant microvilli and mitochondrial degeneration were evidenced in the placental labyrinth zone (Lz) of ICompromised and high-ZIKV-ICompetent mice but not in low-ZIKV-C57BL/6 mice. In addition, decreased placental expression of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) and the lipid transporter Abca1 was detected in all ZIKV-infected groups, but Bcrp and Abca1 were only reduced in ICompromised and high-ZIKV ICompetent mice. Our data indicate that gestational ZIKV infection triggers specific proinflammatory responses and affects placental turnover and transporter expression in a manner dependent on virus concentration and maternal immune status. Placental damage may impair proper fetal-maternal exchange function and fetal growth/survival, likely contributing to congenital Zika syndrome.

  • Breast cancer resistance protein (Bcrp/Abcg2) is selectively modulated by lipopolysaccharide (LPS) in the mouse yolk sac
    L.M. Martinelli, M.W. Reginatto, K.N. Fontes, C.B.V. Andrade, V.R.S. Monteiro, H.R. Gomes, F.R.C.L. Almeida, F.F. Bloise, S.G. Matthews, T.M. Ortiga-Carvalho,et al.

    Elsevier BV

  • Malaria in pregnancy regulates P-glycoprotein (P-gp/Abcb1a) and ABCA1 efflux transporters in the Mouse Visceral Yolk Sac
    Lilian M. Martinelli, Klaus N. Fontes, Mila W. Reginatto, Cherley B. V. Andrade, Victoria R. S. Monteiro, Hanailly R. Gomes, Joao L. Silva‐Filho, Ana A. S. Pinheiro, Annamaria R. Vago, Fernanda R. C. L. Almeida,et al.

    Malaria in pregnancy (MiP) induces intrauterine growth restriction (IUGR) and preterm labour (PTL). However, its effects on yolk sac morphology and function are largely unexplored. We hypothesized that MiP modifies yolk sac morphology and efflux transport potential by modulating ABC efflux transporters. C57BL/6 mice injected with Plasmodium berghei ANKA (5 × 105 infected erythrocytes) at gestational day (GD) 13.5 were subjected to yolk sac membrane harvesting at GD 18.5 for histology, qPCR and immunohistochemistry. MiP did not alter the volumetric proportion of the yolk sac's histological components. However, it increased levels of Abcb1a mRNA (encoding P‐glycoprotein) and macrophage migration inhibitory factor (Mif chemokine), while decreasing Abcg1 (P < 0.05); without altering Abca1, Abcb1b, Abcg2, Snat1, Snat2, interleukin (Il)‐1β and C‐C Motif chemokine ligand 2 (Ccl2). Transcripts of Il‐6, chemokine (C‐X‐C motif) ligand 1 (Cxcl1), Glut1 and Snat4 were not detectible. ABCA1, ABCG1, breast cancer resistance protein (BCRP) and P‐gp were primarily immunolocalized to the cell membranes and cytoplasm of endodermic epithelium but also in the mesothelium and in the endothelium of mesodermic blood vessels. Intensity of P‐gp labelling was stronger in both endodermic epithelium and mesothelium, whereas ABCA1 labelling increased in the endothelium of the mesodermic blood vessels. The presence of ABC transporters in the yolk sac wall suggests that this fetal membrane acts as an important protective gestational barrier. Changes in ABCA1 and P‐gp in MiP may alter the biodistribution of toxic substances, xenobiotics, nutrients and immunological factors within the fetal compartment and participate in the pathogenesis of malaria‐induced IUGR and PTL.

  • Human Menstrual Blood-Derived Mesenchymal Cells Improve Mouse Embryonic Development
    Marianna Ferreira Gonçalves, Karina Dutra Asensi, Anna Luiza Lima Nascimento, Julia Helena Oliveira de Barros, Rosana de Almeida Santos, Cherley Borba Vieira de Andrade, Tais Hanae Kasai-Brunswick, Marcel Frajblat, Tania M. Ortiga-Carvalho, and Regina Coeli dos Santos Goldenberg

    Mary Ann Liebert Inc
    There is a constant need for improving embryo culture conditions in assisted reproduction. One possibility is to use mesenchymal stem/stromal cells derived from menstrual blood (mbMSCs), with an endometrial origin. In this study, we sought to analyze the expansion of mouse embryos in a direct coculture model with mbMSCs. Our results showed that after five passages, mbMSCs presented a spindle-shaped morphology, with surface markers that were comparable with the normal mesenchymal cell phenotype. mbMSCs could differentiate into adipogenic and osteogenic lineages and secrete angiopoetin-2 and hepatocyte growth factor. The coculture experiments employed 103 two-cell-stage embryos that were randomly divided into two groups: control (n = 50), embryos cultured in GV-Blast medium, and cocultured mbMSCs (n = 53), embryos cocultured with GV-Blast and mbMSCs. Typically, two to three embryos were placed in a well with 200 μL of culture medium and observed until developmental day 5. After 5 days, the cocultured group had more embryos in the blastocyst stage (69.8%) when compared with the control group (30%) (p < 0.001). It was also found that nearly 57% of blastocysts in the cocultured group reached the hatching stage, while only 13% achieved this stage in the control group (p < 0.001). Analyses of cultured mbMSCs and growth media, in the presence or absence of an embryo, were also performed. Immunofluorescence detected similar levels of collagen I and III and fibronectin in both mbMSCs and cocultured mbMSCs, and similar amounts of growth factors, VEGF, PDGF-AA, and PDGF-BB, were also observed in the conditioned medium, regardless of embryo presence. The present study describes, for the first time, an easy, noninvasive, and autologous method that could potentially increase blastocyst growth rates during assisted reproductive procedures (i.e., in vitro fertilization). It is proposed that this mbMSC coculture strategy enriches the embryonic microenvironment and promotes embryo development. This technique may complement or replace existing assisted reproduction methods and is directly relevant to the field of personalized medicine. Impact statement The study demonstrates a novel and potentially personalized assisted reproduction approach. The search for alternative and autologous methods provides assisted reproduction patients with a better chance of a successful pregnancy. In this study, mesenchymal cells derived from menstrual blood resembled the outside uterine surface and could potentially be employed for improving embryo outgrowth. Our protocol enriches the embryonic microenvironment and facilitates high-quality single-embryo transfer.

  • Sepsis Impairs Thyroid Hormone Signaling and Mitochondrial Function in the Mouse Diaphragm
    Flavia Fonseca Bloise, Anderson Teixeira Santos, Juliana de Brito, Cherley Borba Vieira de Andrade, Thamires Siqueira Oliveira, Aline Fonseca Pereira de Souza, Klaus Novaes Fontes, Johnatas D Silva, Natália Blanco, Pedro Leme Silva,et al.

    Mary Ann Liebert Inc
    BACKGROUND Sepsis can cause the nonthyroidal illness syndrome (NTIS), resulting in perturbed thyroid hormone (TH) signaling and reduced thyroxine (T4) levels. TH is a major regulator of muscle function, via its influence on mitochondria. The present study aimed to evaluate the relationship among TH signaling, mitochondrial function and the antioxidant defense system in the diaphragms of septic mice. METHODS Male C57Bl/6 mice were divided into two groups: cecal ligation and puncture (CLP) and sham. Twenty-four hours after surgery, plasma, diaphragms and livers were collected. TH metabolism and responses were analyzed by measuring mRNA expression of Dio1 in the liver, and Thra, Thrb, Dio2, Slc16a10 and Slc16a2 (encodes MCT 10 and 8), in the diaphragm. T4 plasma levels were measured by radioimmunoassay. Damage to diaphragm mitochondria was assessed by electron microscopy and qPCR, and function with oxygraphy. The diaphragm anti-oxidative defense system was examined by qPCR, analyzing Sod1, Sod2, Sod3, Gpx1 and Cat expression. The effect of TH replacement was tested by treating the mice with T4 and tri-iodothyronine (T3) (CLP+TH) after surgery. RESULTS CLP mice presented reduced total plasma T4 concentrations, as well as downregulated Dio1 and upregulated Il1b mRNA expression in the liver. CLP mice also displayed downregulated Thra, Thrb, Slc16a10 and Slc16a2 expression in the diaphragm, suggesting that TH signaling was compromised. The expression of Ppargc1a (encodes PGC1a) was downregulated, which correlated with the decrease in the number of total mitochondria, increase in the percentage of injured mitochondria, downregulation of respiratory chain complex 2 and 3 mRNA expression and reduced maximal respiration. Additionally, septic animals presented a 3-fold increase in Ucp3 and G6pdh expression, downregulated Sod3, Gpx1 and Cat expression; and upregulated Sod2 expression, potentially due to elevated ROS levels. The mitochondrial number and the percentage of injured mitochondrial were similar between sham and CLP+TH mice. CONCLUSIONS Sepsis induced responses consistent with NTIS, resulted in mitochondrial damage and functional impairment, and modulated the expression of key antioxidant enzymes in the diaphragm. Thus, impaired diaphragm function during sepsis seems to involve altered local TH signaling, mitochondrial dysfunction and oxidative stress defense.

  • Comparative study of calcium and calcium-related enzymes with differentiation markers in different ages and muscle types in mdx mice
    Rhayanna B Gaglianone, F. Bloise, T. Ortiga-Carvalho, T. Quirico-Santos, M. Costa and C. Mermelstein

    Sarcolemma instability and increased calcium influx in muscle fibers are characteristics of the Duchenne muscular dystrophy. Excessive calcium activates calcium-dependent enzymes, such as calpains (CAPN) and matrix metalloproteases (MMP). Here, we analyzed calcium deposits, the activity of CAPN and MMP and the expression of Myh, SERCA and myogenic regulatory factors in different skeletal muscles during myonecrosis (4-weeks) and regeneration (12-weeks) phases of the mdx muscular pathology. Alizarin red staining was used to assess calcium deposits, casein and gelatin zymography were performed to evaluate CAPN and MMP activity, and qPCR was used to evaluate the expression of Myh, Capn, Atp2a1 and Atp2a2, Myod1 and Myog. We observed the following characteristics in mdx muscles: (i) calcium deposits almost exclusively in mdx muscles, (ii) lower CAPN1 activity in mdx muscles, (iii) higher CAPN2 activity in mdx muscles (only at 12 wks), (iv) autolyzed CAPN activity exclusively in mdx muscles, (v) lower expression of Capn1 and higher expression of Capn2 in mdx muscles; (vi) lower expression of Atp2a1 and Atp2a2 in mdx muscles, (vii) higher MMP (pre pro MMP2, pro MMP2, MMP2 and MMP9) activity in mdx muscles, (viii) MMP2 activity exclusively in mdx muscles at 12 wks, (ix) MMP9 activity exclusively in mdx muscles, (x) higher expression of Myog in mdx muscles at 12 wks, and (xi) lower expression of Myh (Myh7, Myh2, Myh1, Myh4) in mdx muscles, particularly Myh7 and Myh2. The collection of our results provides valuable information for a better characterization of mdx pathology phenotype.

  • Dysregulation of placental ABC transporters in a murine model of malaria-induced preterm labor
    K. N. Fontes, M. W. Reginatto, N. L. Silva, C. B. V. Andrade, F. F. Bloise, V. R. S. Monteiro, J. L. Silva-Filho, G. E. Imperio, P. M. Pimentel-Coelho, A. A. S. Pinheiro,et al.

    Springer Science and Business Media LLC

  • Reduced mitochondrial respiration and increased calcium deposits in the EDL muscle, but not in soleus, from 12-week-old dystrophic mdx mice
    Rhayanna B. Gaglianone, Anderson Teixeira Santos, Flavia Fonseca Bloise, Tania Maria Ortiga-Carvalho, Manoel Luis Costa, Thereza Quirico-Santos, Wagner Seixas da Silva, and Claudia Mermelstein

    Springer Science and Business Media LLC

  • Breast cancer resistance protein (Bcrp/abcg2) inhibits extra villous trophoblast migration: The impact of bacterial and viral infection
    Phetcharawan Lye, Enrrico Bloise, Lubna Nadeem, Chun Peng, William Gibb, Tania M. Ortiga-Carvalho, Stephen J. Lye, and Stephen G. Matthews

    Extravillous trophoblasts (EVT) migration into the decidua is critical for establishing placental perfusion and when dysregulated, may lead to pre-eclampsia (PE) and intrauterine growth restriction (IUGR). The breast cancer resistance protein (BCRP; encoded by ABCG2) regulates the fusion of cytotrophoblasts into syncytiotrophoblasts and protects the fetus from maternally derived xenobiotics. Information about BCRP function in EVTs is limited, however placental exposure to bacterial/viral infection leads to BCRP downregulation in syncitiotrophoblasts. We hypothesized that BCRP is involved in the regulation of EVT function and is modulated by infection/inflammation. We report that besides syncitiotrophoblasts and cytotrophoblasts, BCRP is also expressed in EVTs. BCRP inhibits EVT cell migration in HTR8/SVneo (human EVT-like) cells and in human EVT explant cultures, while not affecting cell proliferation. We have also shown that bacterial—lipopolysaccharide (LPS)—and viral antigens—single stranded RNA (ssRNA)—have a profound effect in downregulating ABCG2 and BCRP levels, whilst simultaneously increasing the migration potential of EVT-like cells. Our study reports a novel function of BCRP in early placentation and suggests that exposure of EVTs to maternal infection/inflammation could disrupt their migration potential via the downregulation of BCRP. This could negatively influence placental development/function, contribute to existing obstetric pathologies, and negatively impact pregnancy outcomes and maternal/neonatal health.

  • Thyroid function disruptors: From nature to chemicals
    Karen Jesus Oliveira, Maria Isabel Chiamolera, Gisele Giannocco, Carmen Cabanelas Pazos-Moura, and Tania Maria Ortiga-Carvalho

    The modern concept of thyroid disruptors includes synthetic chemicals and bioactive compounds from food that interfere with any aspect of the hypothalamus–pituitary–thyroid axis, thyroid hormone biosynthesis and secretion, blood and transmembrane transport, metabolism and local actions of thyroid hormones. This review highlights relevant disruptors that affect populations through their diet: directly from food itself (fish oil and polyunsaturated fatty acids, pepper, coffee, cinnamon and resveratrol/grapes), through vegetable cultivation (pesticides) and from containers for food storage and cooking (bisphenol A, phthalates and polybrominated diphenyl ethers). Due to the vital role of thyroid hormones during every stage of life, we review effects from the gestational period to adulthood, including evidence fromin vitrostudies, rodent models, human trials and epidemiological studies.

  • Gestational age-dependent gene expression profiling of ATP-binding cassette transporters in the healthy human placenta
    Guinever E. Imperio, Mohsen Javam, Phetcharawan Lye, Andrea Constantinof, Caroline E. Dunk, Fernando M. Reis, Stephen J. Lye, William Gibb, Stephen G. Matthews, Tania Maria Ortiga-Carvalho,et al.

    The ATP‐binding cassette (ABC) transporters control placental transfer of several nutrients, steroids, immunological factors, chemicals, and drugs at the maternal‐fetal interface. We and others have demonstrated a gestational age‐dependent expression pattern of two ABC transporters, P‐glycoprotein and breast cancer resistance protein throughout pregnancy. However, no reports have comprehensively elucidated the expression pattern of all 50 ABC proteins, comparing first trimester and term human placentae. We hypothesized that placental ABC transporters are expressed in a gestational‐age dependent manner in normal human pregnancy. Using the TaqMan® Human ABC Transporter Array, we assessed the mRNA expression of all 50 ABC transporters in first (first trimester, n = 8) and third trimester (term, n = 12) human placentae and validated the resulting expression of selected ABC transporters using qPCR, Western blot and immunohistochemistry. A distinct gene expression profile of 30 ABC transporters was observed comparing first trimester vs. term placentae. Using individual qPCR in selected genes, we validated the increased expression of ABCA1 (P < 0.01), ABCA6 (P < 0.001), ABCA9 (P < 0.001) and ABCC3 (P < 0.001), as well as the decreased expression of ABCB11 (P < 0.001) and ABCG4 (P < 0.01) with advancing gestation. One important lipid transporter, ABCA6, was selected to correlate protein abundance and characterize tissue localization. ABCA6 exhibited increased protein expression towards term and was predominantly localized to syncytiotrophoblast cells. In conclusion, expression patterns of placental ABC transporters change as a function of gestational age. These changes are likely fundamental to a healthy pregnancy given the critical role that these transporters play in the regulation of steroidogenesis, immunological responses, and placental barrier function and integrity.

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