Superoxide anion production by NADPH oxidase plays a major role in erectile dysfunction in middle-aged rats: prevention by antioxidant therapy

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOPrevalence of erectile dysfunction (ED) increases progressively with aging, but the ED pathophysiology at its early stages is still poorly investigated. Aim. This study aimed to evaluate the functional and molecular alterations of erectile function at middle age, focusing on the contribution of oxidative stress in erectile tissue for the ED. Methods. Young (3.5-month) and middle-aged (10-month) male Wistar rats were used. Rat corpus cavernosum (RCC) was dissected free and mounted in 10-mL organ baths containing Krebs solution. Intracavernosal pressure (ICP) in anesthetized rats was evaluated. Main Outcome Measures. Concentrationresponse curves to endothelium-dependent and endothelium-independent agents, as well as to electrical field stimulation (EFS), were obtained in RCC strips. Measurement of cyclic guanosine monophosphate (cGMP) and expressions of neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS), gp91phox and superoxide dismutase-1 (SOD-1) expressions in RCC were evaluated. Results. ICP was significantly reduced in middle-aged compared with young rats. RCC relaxations to acetylcholine (108 to 102M), sodium nitroprusside (108 to 102M), sildenafil (109 to 105M), BAY 41-2272 (109 to 105M), and EFS (432Hz) were decreased in middle-aged group, which were nearly normalized by apocynin (NADPH oxidase inhibitor; 104M) or SOD (75U/mL). Prolonged treatment with apocynin (85mg/rat/day, 4 weeks) also restored the impaired relaxations in middle-aged rats. Relaxations to 8-bromoguanosine 3,5-cyclic monophosphate sodium salt (8-Br-cGMP; 108 to 3x104M) remained unchanged between groups. Basal and stimulated cGMP production were lower in middle-aged group, an effect fully restored by apocynin and SOD. Protein expression of nNOS and phosphorylated eNOS (p-eNOS) (Ser-1177) reduced, whereas gp91phox mRNA expression increased in RCC from middle-aged rats. Conclusions. ED in middle-aged rats is associated with decreased NO bioavailability in erectile tissue due to upregulation of NADPH oxidase subunit gp91phox and downregulation of nNOS/p-eNOS. Antioxidant therapies may be a good pharmacological approach to prevent ED at its early stages. Silva FH, Monica FZ, Bau FR, Brugnerotto AF, Priviero FBM, Toque HA, and Antunes E. Superoxide anion production by NADPH oxidase plays a major role in erectile dysfunction in middle-aged rats: Prevention by antioxidant therapy104960971FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçã

Gene Expression Analysis Of The Brazilian Type Of Hereditary Persistence Of Fetal Hemoglobin: Identification Of Genes That Could Be Related To γ-globin Activation

Increased γ-globin production and consequent fetal hemoglobin (Hb F, α2γ2) formation is an important modulator of the clinical and hematological features of hemolytic anemias, such as sickle cell disease and β-thalassemia (β-thal). Hb F genes are genetically regulated, but despite numerous studies, the molecular basis of hemoglobin (Hb) switching is not completely understood. Hereditary persistence of fetal Hb (HPFH) is a consequence of impaired switching in adult life, which results in the continued expression of the γ-globin gene. This study was undertaken to identify genes that could be involved in Hb switching and/or maintenance of elevated Hb F levels. Two libraries were constructed using reticulocytes from normal donors and from Brazilian HPFH subjects. Results suggest that the maintenance of Hb F levels could be associated with some gene/protein expression modifications, such as low expression of KLF1, a transcription factor known to contribute to the regulation and modulation of Hb switching, decreased expression of MIER1, known for the recruitment of chromatin remodeling enzymes, and decreased expression of HOOK3. 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High Levels Of Human γ-globin Are Expressed In Adult Mice Carrying A Transgene Of The Brazilian Type Of Hereditary Persistence Of Fetal Hemoglobin (aγ -195)

Hereditary persistence of fetal hemoglobin (HPFH) is characterized by increased levels of Hb F during adult life. Nondeletional forms of HPFH are characterized by single base mutations in the Aγ and Gγ promoters, resulting in an increase of Hb F ranging from 3 to 20 in heterozygotes. Many point mutations in this region have been described, including the Aγ -195 (C>G) mutation that causes the Brazilian type of HPFH (HPFH-B). To better understand this mechanism, we have developed HPFH-B transgenic mice. mRNA levels of human γ-globin of -195 transgenic mice were clearly higher when compared with control transgenic mice bearing a wild type sequence of the γ promoter. Thus, our data indicate that the -195 mutation is the unique cause of elevation of Hb F in Brazilian HPFH. These results could provide us with an opportunity to study the modifying effects of the Hb F in the phenotype of sickle cell disease and β-thalassemia (β-thal). © Informa UK Ltd.336439447Olave, I.A., Doneanu, C., Fang, X., Stamatoyannopoulos, G., Li, Q., Purification and identification of proteins that bind to the hereditary persistence of fetal hemoglobin -198 mutation in the g-globin gene promoter (2007) J Biol Chem., 282 (2), pp. 853-862Stamatoyannopoulos, G., Grosveld, F.G., (2001) Hemoglobin Switching, 2. , 3rd ed. Philadelphia: W.B. Saunders CompanyTakahashi, T., Schreiber, R., Krieger, J.E., Saad, S.T., Costa, F.F., Analysis of the mechanism of action of the Brazilian type (Ag ?195 C G) of hereditary persistence of fetal hemoglobin (2003) Eur J Haematol., 71 (6), pp. 418-424Katsantoni, E.Z., Langeveld, A., Wai, A.W., Persistent g-globin expression in adult transgenic mice is mediated by HPFH-2 HPFH-3 and HPFH-6 breakpoint sequences (2003) Blood, 102 (9), pp. 3412-3419Forget, B.G., Molecular basis of hereditary persistence of fetal hemoglobin (1998) Ann NY Acad Sci., 850, pp. 38-44Keys, J.R., Tallack, M.R., Zhan, Y., A mechanism for Ikaros regulation of human globin gene switching (2008) Br J Haematol., 141 (3), pp. 398-406Tasiopoulou, M., Boussiou, M., Sinopoulou, K., Moraitis, G., Loutradi-Anagnostou, A., Karababa, P., Gg -196 CT Ag ?201 CT: Two novel mutations in the promoter region of the g-globin genes associated with nondeletional hereditary persistence of fetal hemoglobin in Greece (2008) Blood Cells Mol Dis., 40 (3), pp. 320-322Costa, F.F., Zago, M.A., Cheng, G., Nechtman, J.F., Stoming, T.A., Huisman, T.H.J., The Brazilian type of nondeletional Ag-HPFH has a C?G substitution at nucleotide ?195 of the Ag-globin gene (1990) Blood, 76 (9), pp. 1896-1990Schreiber, R., Goncalves, M.S., Junqueira, M.L., Saad, S.T., Krieger, J.E., Costa, F.F., The Ag -195 (CG) mutation in hereditary persistence of fetal hemoglobin is not associated with activation of a reporter gene in vitro (2001) Braz J Med Biol Res., 34 (4), pp. 489-492Enver, T., Raich, N., Ebens, A.J., Papayannopoulou, T., Costantini, F., Stamatoyannopoulos, G., Developmental regulation of human fetal-to-adult globin gene switching in transgenic mice (1990) Nature, 344 (6264), pp. 309-313Sabatino, D., Cline, A., Gallagher, P., Substitution of the human b-spectrin promoter for the human Ag-globin promoter prevents silencing of a linked human b-globin gene in transgenic mice (1998) Mol Cell Biol., 18 (11), pp. 6634-6640Zoueva, O., Garrett, L., Bodine, D., Rodgers, G., BP1 motif in the human b-globin promoter affects b-globin expression during embryonic/fetal erythropoiesis in transgenic mice bearing the human b-globin gene (2008) Blood Cells Mol Dis., 41 (3), pp. 244-251Gallagher, P., Sabatino, D., Basseres, D., Erythrocyte ankyrin promoter mutations associated with recessive hereditary spherocytosis cause significant abnormalities in ankyrin expression (2001) J Biol Chem., 276 (45), pp. 41683-41689Liu, L.R., Du, Z.W., Zhao, H.L., T to C substitution at -175 or -173 of the g-globin promoter affects GATA-1 and Oct-1 binding in vitro differently but can independently reproduce the hereditary persistence of fetal hemoglobin phenotype in transgenic mice (2005) J Biol Chem., 280 (9), pp. 7452-7459Gumucio, D.L., Rood, K.L., Blanchard-Mcquate, K.L., Gray, T.A., Saulino, A., Collins, F.S., Interaction of Sp1 with the human g globin promoter: Binding and transactivation of normal and mutant promoters (1991) Blood, 78 (7), pp. 1853-1863Berry, M., Grosveld, F., Dillon, N., A single point mutation is the cause of the Greek form of hereditary persistence of fetal haemoglobin (1992) Nature, 358 (6386), pp. 499-502Peterson, K.R., Li, Q.L., Clegg, C.H., Use of yeast artificial chromosomes (YACs) in studies of mammalian development: Production of b-globin locus YAC mice carrying human globin developmental mutants (1995) Proc Natl Acad Sci USA., 92 (12), pp. 5655-5659Li, Q., Duan, Z.J., Stamatoyannopoulos, G., Analysis of the mechanism of action of non-deletion hereditary persistence of fetal hemoglobin mutants in transgenic mice (2001) EMBO J., 20 (1-2), pp. 157-16

Identification Of Target Genes Using Gene Expression Profile Of Granulocytes From Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors

Differential gene expression analysis by suppression subtractive hybridization with correlation to the metabolic pathways involved in chronic myeloid leukemia (CML) may provide a new insight into the pathogenesis of CML. Among the overexpressed genes found in CML at diagnosis are SEPT5, RUNX1, MIER1, KPNA6 and FLT3, while PAN3, TOB1 and ITCH were decreased when compared to healthy volunteers. Some genes were identified and involved in CML for the first time, including TOB1, which showed a low expression in patients with CML during tyrosine kinase inhibitor treatment with no complete cytogenetic response. In agreement, reduced expression of TOB1 was also observed in resistant patients with CML compared to responsive patients. This might be related to the deregulation of apoptosis and the signaling pathway leading to resistance. Most of the identified genes were related to the regulation of nuclear factor κB (NF-κB), AKT, interferon and interleukin-4 (IL-4) in healthy cells. 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