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221.
222.
Emanuel Kennedy-Feitosa Rômulo Fonseca Santos Pinto Karla Maria Pereira Pires Ana Paula Teixeira Monteiro Mariana Nascimento Machado Juliana Carvalho Santos Marcelo Lima Ribeiro Walter Araújo Zin Cláudio Azevedo Canetti Bruna Romana-Souza Luís Cristóvão Porto Samuel Santos Valenca 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Pulmonary emphysema is characterized by the loss of lung architecture. Our hypothesis is that the inhibition of 5-lipoxygenase (5-LO) production may be an important strategy to reduce inflammation, oxidative stress, and metalloproteinases in lung tissue resulting from cigarette smoke (CS)-induced emphysema.Methods
5-LO knockout (129S2-Alox5tm1Fun/J) and wild-type (WT) mice (129S2/SvPas) were exposed to CS for 60 days. Mice exposed to ambient air were used as Controls. Oxidative, inflammatory, and proteolytic markers were analyzed.Results
The alveolar diameter was decreased in CS 5-LO−/− mice when compared with the WT CS group. The CS exposure resulted in less pronounced pulmonary inflammation in the CS 5-LO−/− group. The CS 5-LO−/− group showed leukotriene B4 values comparable to those of the Control group. The expression of MMP-9 was decreased in the CS 5-LO−/− group when compared with the CS WT group. The expression of superoxide dismutase, catalase, and glutathione peroxidase were decreased in the CS 5-LO−/− group when compared with the Control group. The protein expression of nuclear factor (erythroid-derived 2)-like 2 was reduced in the CS 5-LO−/− group when compared to the CS WT group.Conclusion
In conclusion, we show for the first time that 5-LO deficiency protects 129S2 mice against emphysema caused by CS. We suggest that the main mechanism of pathogenesis in this model involves the imbalance between proteases and antiproteases, particularly the association between MMP-9 and TIMP-1.General significanceThis study demonstrates the influence of 5-LO mediated oxidative stress, inflammation, and proteolytic markers in CS exposed mice. 相似文献223.
Leonardo C. Mon??o-Ribeiro Débora S. Faffe Patrícia T. Santana Flávia S. Vieira Carolyne Lalucha A. L. da Gra?a Camila Marques-da-Silva Mariana N. Machado Celso Caruso-Neves Walter A. Zin Radovan Borojevic Christina M. Takiya Robson Coutinho-Silva 《PloS one》2014,9(10)
Silicosis is an occupational lung disease, characterized by irreversible and progressive fibrosis. Silica exposure leads to intense lung inflammation, reactive oxygen production, and extracellular ATP (eATP) release by macrophages. The P2X7 purinergic receptor is thought to be an important immunomodulator that responds to eATP in sites of inflammation and tissue damage. The present study investigates the role of P2X7 receptor in a murine model of silicosis. To that end wild-type (C57BL/6) and P2X7 receptor knockout mice received intratracheal injection of saline or silica particles. After 14 days, changes in lung mechanics were determined by the end-inflation occlusion method. Bronchoalveolar lavage and flow cytometry analyzes were performed. Lungs were harvested for histological and immunochemistry analysis of fibers content, inflammatory infiltration, apoptosis, as well as cytokine and oxidative stress expression. Silica particle effects on lung alveolar macrophages and fibroblasts were also evaluated in cell line cultures. Phagocytosis assay was performed in peritoneal macrophages. Silica exposure increased lung mechanical parameters in wild-type but not in P2X7 knockout mice. Inflammatory cell infiltration and collagen deposition in lung parenchyma, apoptosis, TGF-β and NF-κB activation, as well as nitric oxide, reactive oxygen species (ROS) and IL-1β secretion were higher in wild-type than knockout silica-exposed mice. In vitro studies suggested that P2X7 receptor participates in silica particle phagocytosis, IL-1β secretion, as well as reactive oxygen species and nitric oxide production. In conclusion, our data showed a significant role for P2X7 receptor in silica-induced lung changes, modulating lung inflammatory, fibrotic, and functional changes. 相似文献
224.
Maria Angelica Machado Arroyo Paulo Ramos da Silva Santos Moacir Franco de Oliveira Antnio Chaves de Assis Neto 《Animal Reproduction》2021,18(2)
Letrozole is used as a therapeutic agent in reproductive disorders caused by high estrogen levels. Letrozole inhibits cytochrome P450 aromatase and reduces estrogen levels. However, the effects of long-term use on reproductive traits are unknown. The aim of this study was to evaluate the prolonged use of letrozole in the gonads of rodents (Spix''s yellow-toothed cavy; Galea spixii). Forty-eight rodents (24 males and 24 females) were randomly divided into the treated and control groups. Letrozole administration started at 15 days of age and continued weekly until 30, 45, 90, and 120 days of age. The body, testis, and ovary weights were analyzed, as well as the morphological progression of spermatogenesis and folliculogenesis. Macroscopically, body weight gain and gonads weight were increased in the letrozole group. Microscopically, the ovaries of treated females showed stratified epithelium and a cellular disorder of the tunica albuginea. In the testes of treated males, the development of seminiferous tubules was delayed and sperm was absent. The collective findings indicate that the prolonged use of letrozole alters secondary sexual characteristics, and causes weight gain, reproductive changes, and male infertility. 相似文献
225.
Liberato MV Nascimento AS Ayers SD Lin JZ Cvoro A Silveira RL Martínez L Souza PC Saidemberg D Deng T Amato AA Togashi M Hsueh WA Phillips K Palma MS Neves FA Skaf MS Webb P Polikarpov I 《PloS one》2012,7(5):e36297
Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8-C10) bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD) simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H) 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H) 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products. 相似文献
226.
Sulfur stable isotope signature identifies the source of reduced sulfur in benthic communities in macrophyte zones of Lake Biwa, Japan 总被引:1,自引:0,他引:1
Carbon, nitrogen and sulfur stable isotope ratios (δ13C, δ15N and δ34S) were measured from water column sulfate, sediments, particulate organic matter (POM), macrophytes, periphyton, macroinvertebrates and fish, sampled from the littoral, open water and macrophyte zones of Lake Biwa. In most of the littoral zones, the δ13C and δ15N values of organisms indicated that POM and periphyton support the consumers. However, in the dysoxic interior macrophyte (IM) zone, the δ13C values of Sinotaia quadrata histrica, Propsilocerus akamusi and Anodonta woodiana were lower than that of all resources. The δ15N values of S. quadrata histrica were lower than those of P. akamusi and A. woodiana. δ13C and δ15N values thus failed to distinguish the foods of these consumers. The δ34S values of sediment and S. quadrata histrica were lower than those of water column sulfate, suggesting that this consumer incorporated reduced sulfur derived from sulfate reduction in the sediment by ingesting detritus. In contrast, the δ34S values of P. akamusi and A. woodiana were higher than that of S. quadrata histrica, suggesting that they incorporated sulfur derived from water column sulfate by ingesting POM. Consequently, δ13C, δ15N and δ34S signatures provide complementary estimates of foods for consumers in this freshwater lake. 相似文献
227.
Pihl L Persson P Fasching A Hansell P DiBona GF Palm F 《American journal of physiology. Regulatory, integrative and comparative physiology》2012,303(1):R39-R47
Glomerular filtration rate (GFR) and renal blood flow (RBF) are normally kept constant via renal autoregulation. However, early diabetes results in increased GFR and the potential mechanisms are debated. Tubuloglomerular feedback (TGF) inactivation, with concomitantly increased RBF, is proposed but challenged by the finding of glomerular hyperfiltration in diabetic adenosine A(1) receptor-deficient mice, which lack TGF. Furthermore, we consistently find elevated GFR in diabetes with only minor changes in RBF. This may relate to the use of a lower streptozotocin dose, which produces a degree of hyperglycemia, which is manageable without supplemental suboptimal insulin administration, as has been used by other investigators. Therefore, we examined the relationship between RBF and GFR in diabetic rats with (diabetes + insulin) and without suboptimal insulin administration (untreated diabetes). As insulin can affect nitric oxide (NO) release, the role of NO was also investigated. GFR, RBF, and glomerular filtration pressures were measured. Dynamic RBF autoregulation was examined by transfer function analysis between arterial pressure and RBF. Both diabetic groups had increased GFR (+60-67%) and RBF (+20-23%) compared with controls. However, only the diabetes + insulin group displayed a correlation between GFR and RBF (R(2) = 0.81, P < 0.0001). Net filtration pressure was increased in untreated diabetes compared with both other groups. The difference between untreated and insulin-treated diabetic rats disappeared after administering N(ω)-nitro-l-arginine methyl ester to inhibit NO synthase and subsequent NO release. In conclusion, mechanisms causing diabetes-induced glomerular hyperfiltration are animal model-dependent. Supplemental insulin administration results in a RBF-dependent mechanism, whereas elevated GFR in untreated diabetes is mediated primarily by a tubular event. Insulin-induced NO release partially contributes to these differences. 相似文献
228.
Matsuura C Brunini TM Mury WV Garcia-Pinto AB Carvalho JJ Mendes-Ribeiro AC 《Canadian journal of physiology and pharmacology》2012,90(4):501-505
We investigated whether physical exercise can affect platelet L-arginine?- nitric oxide pathway in spontaneously hypertensive rats (SHR). Sixteen male SHR and 16 Wistar Kyoto rats (WKY) were divided among exercise (EX) and sedentary (SED) groups. After 20?weeks of treadmill training, systolic blood pressure (mm?Hg) was significantly lower in exercised spontaneously hypertensive rats (SHR/EX; 138?± 8) than in sedentary spontaneously hypertensive rats (SHR/SED; 214?± 9). Exercise significantly increased platelet L-arginine transport (pmol L-arginine·(10(9) cells)(-1)·min(-1)), assessed by incubation with L-[(3)H]-arginine, in both WKY (SED, 0.196?± 0.054 compared with EX, 0.531?± 0.052) and SHR (SED, 0.346?± 0.076 compared with EX, 0.600?± 0.049). Nitric oxide synthase (NOS) activity (pmol L-citrulline·(10(8) cells)(-1)), measured by the conversion of L-[(3)H]-arginine to L-[(3)H]-citrulline, was significantly increased in SHR/EX (0.072?± 0.007) compared with SHR/SED (0.038?± 0.007), but no changes were observed in WKY. The iNOS and eNOS protein levels assessed by Western blot were not affected by exercise. This upregulation of the platelet L-arginine-NO pathway may attenuate the risk of thromboembolic events, supporting the role of exercise in hypertension management. 相似文献
229.
230.
Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia 总被引:1,自引:0,他引:1
Doege H Grimm D Falcon A Tsang B Storm TA Xu H Ortegon AM Kazantzis M Kay MA Stahl A 《The Journal of biological chemistry》2008,283(32):22186-22192
Non-alcoholic fatty liver disease is a serious health problem linked to obesity and type 2 diabetes. To investigate the biological outcome and therapeutic potential of hepatic fatty acid uptake inhibition, we utilized an adeno-associated virus-mediated RNA interference technique to knock down the expression of hepatic fatty acid transport protein 5 in vivo prior to or after establishing non-alcoholic fatty liver disease in mice. Using this approach, we demonstrate here the ability to achieve specific, non-toxic, and persistent knockdown of fatty acid transport protein 5 in mouse livers from a single adeno-associated virus injection, resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced caloric uptake, and concomitant protection from diet-induced non-alcoholic fatty liver disease. Importantly, knockdown of fatty acid transport protein 5 was also able to reverse already established non-alcoholic fatty liver disease, resulting in significantly improved whole-body glucose homeostasis. Thus, continued activity of hepatic fatty acid transport protein 5 is required to sustain caloric uptake and fatty acid flux into the liver during high fat feeding and may present a novel avenue for the treatment of non-alcoholic fatty liver disease. 相似文献