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Biol. Res ; 53: 25, 2020. tab, graf
Article in English | LILACS | ID: biblio-1124210


BACKGROUND: Hypoxia inducible factor-1 (HIF-1) is considered as the most activated transcriptional factor in response to low oxygen level or hypoxia. HIF-1 binds the hypoxia response element (HRE) sequence in the promoter of different genes, mainly through the bHLH domain and activates the transcription of genes, especially those involved in angiogenesis and EMT. Considering the critical role of bHLH in binding HIF-1 to the HRE sequence, we hypothesized that bHLH could be a promising candidate to be targeted in hypoxia condition. METHODS: We inserted an inhibitory bHLH (ibHLH) domain in a pIRES2-EGFP vector and transfected HEK293T cells with either the control vector or the designed construct. The ibHLH domain consisted of bHLH domains of both HIF-1a and Arnt, capable of competing with HIF-1 in binding to HRE sequences. The transfected cells were then treated with 200 µM of cobalt chloride (CoCl2) for 48 h to induce hypoxia. Real-time PCR and western blot were performed to evaluate the effect of ibHLH on the genes and proteins involved in angiogenesis and EMT. RESULTS: Hypoxia was successfully induced in the HEK293T cell line as the gene expression of VEGF, vimentin, and ß-catenin were significantly increased after treatment of untransfected HEK293T cells with 200 µM CoCl2. The gene expression of VEGF, vimentin, and ß-catenin and protein level of ß-catenin were significantly decreased in the cells transfected with either control or ibHLH vectors in hypoxia. However, ibHLH failed to be effective on these genes and the protein level of ß-catenin, when compared to the control vector. We also observed that overexpression of ibHLH had more inhibitory effect on gene and protein expression of N-cadherin compared to the control vector. However, it was not statistically significant. CONCLUSION: bHLH has been reported to be an important domain involved in the DNA binding activity of HIF. However, we found that targeting this domain is not sufficient to inhibit the endogenous HIF-1 transcriptional activity. Further studies about the function of critical domains of HIF-1 are necessary for developing a specific HIF-1 inhibitor.

Humans , Basic Helix-Loop-Helix Transcription Factors/metabolism , Hypoxia-Inducible Factor 1/metabolism , Hypoxia/metabolism , Gene Expression , Transcriptional Activation/genetics , Blotting, Western , Basic Helix-Loop-Helix Transcription Factors/genetics , Hypoxia-Inducible Factor 1/genetics , HEK293 Cells , Real-Time Polymerase Chain Reaction , Hypoxia/genetics
Acta cir. bras ; 34(8): e201900802, 2019. tab, graf
Article in English | LILACS | ID: biblio-1038128


Abstract Purpose To reveal the function of miR-134 in myocardial ischemia. Methods Real-time PCR and western blotting were performed to measure the expression of miR-134, nitric oxide synthase 3 (NOS3) and apoptotic-associated proteins. Lactic dehydrogenase (LDH) assay, cell counting kit-8 (CCK-8), Hoechst 33342/PI double staining and flow cytometry assay were implemented in H9c2 cells, respectively. MiR-134 mimic/inhibitor was used to regulate miR-134 expression. Bioinformatic analysis and luciferase reporter assay were utilized to identify the interrelation between miR-134 and NOS3. Rescue experiments exhibited the role of NOS3. The involvement of PI3K/AKT was assessed by western blot analysis. Results MiR-134 was high regulated in the myocardial ischemia model, and miR-134 mimic/inhibitor transfection accelerated/impaired the speed of cell apoptosis and attenuated/exerted the cell proliferative prosperity induced by H/R regulating active status of PI3K/AKT signaling. LDH activity was also changed due to the different treatments. Moreover, miR-134 could target NOS3 directly and simultaneously attenuated the expression of NOS3. Co-transfection miR-134 inhibitor and pcDNA3.1-NOS3 highlighted the inhibitory effects of miR-134 on myocardial H/R injury. Conclusion This present work puts insights into the crucial effects of the miR-134/NOS3 axis in myocardial H/R injury, delivering a potential therapeutic technology in future.

Animals , Rats , Myocardial Reperfusion Injury/metabolism , MicroRNAs/metabolism , Nitric Oxide Synthase Type III/metabolism , Hypoxia/metabolism , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/drug therapy , Signal Transduction/drug effects , Apoptosis/drug effects , Apoptosis/physiology , Phosphatidylinositol 3-Kinases/metabolism , MicroRNAs/genetics , MicroRNAs/therapeutic use , Cell Proliferation/drug effects , Nitric Oxide Synthase Type III/genetics , Nitric Oxide Synthase Type III/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism
Acta cir. bras ; 34(4): e201900407, 2019. graf
Article in English | LILACS | ID: biblio-1001083


Abstract Purpose: To evaluate the functional and structural response of tadalafil effects in the intestinal mucosa, using an experimental model of hypoxia and reoxygenation injury in rats. Methods: The animals were divided into 4 groups: CTL, H/R, H/R+Td and M+Td. The newborn rats allocated in groups H/R, H/R+Td and M+Td were submitted twice a day, to a gas chamber with CO2 at 100% for 10 minutes and afterward reoxygenation with O2 at 98% for 10 minutes, in the three first days of life. Tadalafil dose was given to newborn of group H/R+Td and to the pregnant rat of group M+Td. Histological analysis was made with hematoxylin-eosin technique and oxidative stress through nitrite and nitrate levels and lipid peroxidation. Results: The histological analysis showed a reduction of mucosa alterations in the groups that received tadalafil. In the oxidative stress evaluation, occurred an increase of NO levels and less lipidic peroxidation in the ileum segments that received tadalafil. Conclusion: Tadalafil provides tissue protection when administered independently to both, pregnant or newborns.

Humans , Animals , Female , Pregnancy , Oxygen/metabolism , Oxidative Stress/drug effects , Phosphodiesterase 5 Inhibitors/pharmacology , Tadalafil/pharmacology , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Hypoxia/metabolism , Time Factors , Lipid Peroxidation , Random Allocation , Reproducibility of Results , Rats, Wistar , Intestinal Mucosa/pathology , Animals, Newborn , Malondialdehyde/analysis , Nitrates/analysis , Nitrites/analysis
Biol. Res ; 52: 32, 2019. graf
Article in English | LILACS | ID: biblio-1038783


BACKGROUND: Long non-coding RNA H19 (H19) plays an important role by regulating protein expression in different tissues and organs of the body. However, whether H19 induces hypoxia/reoxygenation (h/R) injury via increase of autophagy in the hepatoma carcinoma cells is unknown. RESULTS: H19 was expressed in the hepatoma carcinoma cells (Hep G2 and HCCLM3 cells) and its expression was most in 8 h/24R. The knockdown of H19 and 3-MA (an autophagy inhibitor) protected against h/R-induced apoptosis, cell damage, the expression of cleaved caspase-3 and cleaved caspase-9, the release of cytochrome c (Cyt c). The knockdown of H19 and 3-MA also decreased the autophagic vesicles (AVs) and the expression of Beclin-1 and the ration of LC3-II/LC3-I, and increased cell viability, the expression of Bcl-2 and P62 and the phosphorylation of PI3K, Akt and mTOR. In addition, chloroquine (CQ, an inhibitor of autophagy flux) markedly decreased formation of autophagy flux (the ration of LC3-II/LC3-I). The results of the knockdown of H19 group were similar to those of the 3-MA (or CQ) group. Rapamycin (a mTOR inhibitor, an autophagy activator) further down-regulated h/R-induced decrease of the phosphorylated PI3K, Akt and mTOR. The knockdown of H19 cancelled the effect of rapamycin. The overexpression of H19 further expanded h/R-induced increase of the ration of LC3-II/LC3-I and decrease of the phosphorylated PI3K, Akt and mTOR. CONCLUSIONS: Our results suggest that the long non-coding RNA H19 induces h/R injury by up-regulation of autophagy via activation of PI3K-Akt-mTOR pathway in the hepatoma carcinoma cells.

Humans , Reperfusion Injury/metabolism , Carcinoma, Hepatocellular/metabolism , RNA, Long Noncoding/metabolism , Liver Neoplasms/metabolism , Hypoxia/metabolism , Oxygen/metabolism , Autophagy/drug effects , Up-Regulation/physiology , Brain Ischemia/metabolism , Apoptosis/physiology , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology
Braz. j. med. biol. res ; 50(5): e5742, 2017. tab, graf
Article in English | LILACS | ID: biblio-839290


Cardiac remodeling is defined as changes in shape and function of the heart in response to aggression (pressure overload). The sarcoplasmic reticulum calcium ATPase cardiac isoform 2a (SERCA2a) is a known factor that influences function. A wide spectrum of studies report a decrease in SERCA2a in heart failure, but none evaluate it's the role in early isolated diastolic dysfunction in supravalvular aortic stenosis (AoS). Our hypothesis was that SERCA2a participates in such dysfunction. Thirty-day-old male Wistar rats (60-80 g) were divided into AoS and Sham groups, which were submitted to surgery with or without aorta clipping, respectively. After 6 weeks, the animals were submitted to echocardiogram and functional analysis by isolated papillary muscle (IPM) in basal condition, hypoxia, and SERCA2a blockage with cyclopiazonic acid at calcium concentrations of 0.5, 1.5, and 2.5 mM. Western-blot analyses were used for SERCA2a and phospholamban detection. Data analysis was carried out with Student's t-test and ANOVA. AoS enhanced left atrium and E and A wave ratio, with preserved ejection fraction. Basal condition in IPM showed similar increases in developed tension (DT) and resting tension (RT) in AoS, and hypoxia was similar between groups. After cyclopiazonic acid blockage, final DT was equally decreased and RT was similar between groups, but the speed of relaxation was decreased in the AoS group. Western-blot was uniform in all evaluations. The hypothesis was confirmed, since functional parameters regarding SERCA2a were changed in the AoS group.

Animals , Male , Aortic Stenosis, Supravalvular/complications , Hypertrophy, Left Ventricular/physiopathology , Sarcoplasmic Reticulum Calcium-Transporting ATPases/physiology , Ventricular Dysfunction, Left/physiopathology , Aortic Stenosis, Supravalvular/metabolism , Calcium-Binding Proteins/analysis , Collagen/analysis , Diastole/physiology , Disease Models, Animal , Echocardiography , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Hypertrophy, Left Ventricular/etiology , Hypertrophy, Left Ventricular/metabolism , Hypoxia/metabolism , Hypoxia/physiopathology , Indoles , Myocardial Contraction/physiology , Rats, Wistar , Sarcoplasmic Reticulum Calcium-Transporting ATPases/analysis , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Time Factors , Ventricular Dysfunction, Left/etiology , Ventricular Dysfunction, Left/metabolism , Ventricular Remodeling/physiology
Braz. j. med. biol. res ; 49(10): e5526, 2016. graf
Article in English | LILACS | ID: lil-792523


Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling.

Animals , Male , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/prevention & control , Hypoxia/metabolism , Myocytes, Smooth Muscle/physiology , Pseudomonas aeruginosa/physiology , Smad Proteins/metabolism , Transforming Growth Factor beta1/metabolism , Actins/analysis , Actins/metabolism , Blotting, Western , Cell Proliferation/physiology , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Hypertension, Pulmonary/etiology , Hypoxia/complications , Immunohistochemistry , Rats, Sprague-Dawley , Reproducibility of Results , Signal Transduction/physiology , Smad Proteins/analysis , Transforming Growth Factor beta1/analysis
Rev. panam. salud pública ; 38(6): 450-456, nov.-dic. 2015. ilus, tab
Article in Spanish | LILACS | ID: lil-788102


OBJETIVO:Investigar el patrón de distribución espacial de la tasa de homicidios y su relación con las características sociodemográficas en las delegaciones de Benito Juárez, Coyoacán y Cuauhtémoc de la Ciudad de México en el año 2010. MÉTODOS: Estudio inferencial de corte transversal que usa métodos de análisis espacial para estudiar la asociación espacial de la tasa de homicidios y las características demográficas. La asociación espacial fue determinada a través del cociente de localización, análisis de regresión múltiple y el uso de la regresión geográficamente ponderada. RESULTADOS: Los homicidios muestran un patrón de localización heterogéneo con altas tasas en zonas con uso del suelo no residencial, con baja densidad de población y baja marginación. CONCLUSIONES: El uso de herramientas de análisis espacial son instrumentos poderosos para el diseño de políticas de seguridad pública preventiva y recreativa que busquen reducir la mortalidad por causas externas como homicidios.

OBJECTIVE:Investigate the spatial distribution pattern of the homicide rate and its relation to sociodemographic features in the Benito Juárez, Coyoacán, and Cuauhtémoc districts of Mexico City in 2010. METHODS: Inferential cross-sectional study that uses spatial analysis methods to study the spatial association of the homicide rate and demographic features. Spatial association was determined through the location quotient, multiple regression analysis, and the use of geographically weighted regression. RESULTS: Homicides show a heterogeneous location pattern with high rates in areas with non-residential land use, low population density, and low marginalization. CONCLUSIONS: Spatial analysis tools are powerful instruments for the design of prevention- and recreation-focused public safety policies that aim to reduce mortality from external causes such as homicides.

Animals , Cattle , Female , Humans , Male , Rats , Hypoxia/metabolism , Cation Transport Proteins/metabolism , Hypertension, Pulmonary/metabolism , Muscle, Smooth, Vascular/metabolism , Animals, Congenic , Hypoxia/genetics , Arterioles/metabolism , Cell Hypoxia , Cell Proliferation , Cells, Cultured , Chronic Disease , Cation Transport Proteins/deficiency , Cation Transport Proteins/genetics , Chromosomes, Mammalian/genetics , Gene Knockdown Techniques , Homeostasis , Hypertension, Pulmonary/genetics , Intracellular Space/metabolism , Muscle, Smooth, Vascular/cytology , Rats, Inbred WKY , Zinc/metabolism
J. bras. pneumol ; 41(2): 167-174, Mar-Apr/2015. graf
Article in English | LILACS | ID: lil-745920


Objective: To investigate the effect of intermittent hypoxia-a model of obstructive sleep apnea (OSA)-on pancreatic expression of uncoupling protein-2 (UCP2), as well as on glycemic and lipid profiles, in C57BL mice. Methods: For 8 h/day over a 35-day period, male C57BL mice were exposed to intermittent hypoxia (hypoxia group) or to a sham procedure (normoxia group). The intermittent hypoxia condition involved exposing mice to an atmosphere of 92% N and 8% CO2 for 30 s, progressively reducing the fraction of inspired oxygen to 8 ± 1%, after which they were exposed to room air for 30 s and the cycle was repeated (480 cycles over the 8-h experimental period). Pancreases were dissected to isolate the islets. Real-time PCR was performed with TaqMan assays. Results: Expression of UCP2 mRNA in pancreatic islets was 20% higher in the normoxia group than in the hypoxia group (p = 0.11). Fasting serum insulin was higher in the hypoxia group than in the normoxia group (p = 0.01). The homeostasis model assessment of insulin resistance indicated that, in comparison with the control mice, the mice exposed to intermittent hypoxia showed 15% lower insulin resistance (p = 0.09) and 21% higher pancreatic β-cell function (p = 0.01). Immunohistochemical staining of the islets showed no significant differences between the two groups in terms of the area or intensity of α- and β-cell staining for insulin and glucagon. Conclusions: To our knowledge, this is the first report of the effect of intermittent hypoxia on UCP2 expression. Our findings suggest that UCP2 regulates insulin production in OSA. Further study of the role that UCP2 plays in the glycemic control of OSA patients is warranted. .

Objetivo: Investigar o efeito da hipóxia intermitente com um modelo de apneia obstrutiva do sono (AOS) sobre a expressão de uncoupling protein-2 (UCP2), assim como sobre perfis glicêmicos e lipídicos, em camundongos C57BL. Métodos: Camundongos C57BL machos foram expostos a hipóxia intermitente ou hipóxia simulada (grupo controle) 8 h/dia durante 35 dias. A condição de hipóxia intermitente envolveu a exposição dos camundongos a uma atmosfera de 92% de N e 8% de CO2 por 30 s, com redução progressiva de fração de O2 inspirado até 8 ± 1%, seguida por exposição a ar ambiente por 30 s e repetições do ciclo (480 ciclos no período experimental de 8 h). Os pâncreas foram dissecados para isolar as ilhotas. Foi realizada PCR em tempo real utilizando o método TaqMan. Resultados: A expressão do mRNA da UCP2 nas ilhotas pancreáticas foi 20% maior no grupo controle que no grupo hipóxia (p = 0,11). A insulina sérica de jejum foi maior no grupo hipóxia do que no grupo controle (p = 0,01). O modelo de avaliação da homeostase de resistência à insulina indicou que, em comparação com os camundongos controle, aqueles expostos à hipóxia intermitente apresentaram 15% menor resistência à insulina (p = 0,09) e 21% maior função das células beta (p = 0,01). A coloração das ilhotas pancreáticas por imuno-histoquímica não mostrou diferenças significativas entre os grupos em termos da área ou da intensidade das células alfa e beta, marcadas por insulina e glucagon. Conclusões: Segundo nosso conhecimento, esta é a primeira descrição do efeito da hipóxia intermitente sobre a expressão da UCP2. Nossos achados sugerem que UCP2 regula a produção de insulina na AOS. Futuras investigações sobre o papel da UCP2 no controle glicêmico em pacientes com AOS são justificadas. .

Animals , Male , Mice , Hypoxia/metabolism , Ion Channels/metabolism , Islets of Langerhans/metabolism , Mitochondrial Proteins/metabolism , RNA, Messenger/metabolism , Sleep Apnea, Obstructive/metabolism , Hypoxia/physiopathology , Disease Models, Animal , Insulin Resistance , Ion Channels/genetics , Mitochondrial Proteins/genetics , Sleep Apnea, Obstructive/physiopathology
ABCD arq. bras. cir. dig ; 28(1): 28-31, 2015. graf
Article in English | LILACS | ID: lil-742748


BACKGROUND: The surgical treatment of advanced megaesophagus has no consensus, being esophagectomy the more commonly used method. Since it has high morbimortality - inconvenient for benign disease -, in recent years an alternative has been introduced: the esophageal mucosal resection. AIM: To compare early and late results of the two techniques evaluating the operative time, length of ICU stay; postoperative hospitalization; total hospitalization; intra- and postoperative complication rates; mortality; and long-term results. METHODS: Were evaluated retrospectively 40 charts, 23 esophagectomies and 17 mucosectomies. In assessing postoperative results, interviews were conducted by using a specific questionnaire. RESULTS: Comparing the means of esophagectomy and mucosal resection, respectively, the data were: 1) surgical time - 310.2 min and 279.7 min (p> 0.05); 2) length of stay in ICU - 5 days and 2.53 days (p <0.05); 3) total time of hospitalization - 24.25 days and 20.76 days (p> 0.05); 4) length of hospital stay after surgery - 19.05 days and 14.94 days (p> 0.05); 5) presence of intraoperative complications - 65% and 18% (p <0.05); 6) the presence of postoperative complications - 65% and 35% (p> 0.05). In the assessment of late postoperative score (range 0-10) esophagectomy (n = 5) obtained 8.8 points and 8.8 points also got mucosal resection (n = 5). CONCLUSIONS: Esophageal mucosal resection proved to be good alternative for surgical treatment of megaesophagus. It was advantageous in the immediate postoperative period by presenting a lower average time in operation, the total hospitalization, ICU staying and complications rate. In the late postoperative period, the result was excellent and good in both operations. .

RACIONAL: O tratamento cirúrgico do megaesôfago avançado não é consensual sendo mais comumente usada a esofagectomia. Por tratar-se de técnica que apresenta maior morbimortalidade e empregada em doença benigna, foi introduzida nos últimos anos, como alternativa, a mucosectomia esofágica. OBJETIVO: Comparar os resultados imediatos e tardios das duas técnicas avaliando-se os tempos operatório, de internação em UTI, de internação do pós-operatório, de internação total; taxas de complicações intra-operatórias e pós-operatórias; taxa de mortalidade; e resultados a longo prazo. MÉTODOS: Foram avaliados 40 prontuários, retrospectivamente, sendo 23 esofagectomias e 17 mucosectomias. Na avaliação dos resultados pós-operatórios, foram realizadas entrevistas, mediante uso de questionário específico. RESULTADOS: Comparando-se as médias da esofagectomia e mucosectomia, respectivamente, os dados foram: 1) tempo cirúrgico - 310,2 min e 279,7 min (p>0,05); 2) tempo de internação em UTI - 5 dias e 2,53 dias (p<0,05); 3) tempo de internação total - 24,25 dias e 20,76 dias (p>0,05); 4) tempo de internação após a operação - 19,05 dias e 14,94 dias (p>0,05); 5) presença de complicações intra-operatórias - 65% e 18% (p<0,05); 6) presença de complicações pós-operatórias imediatas - 65% e 35% (p>0,05). Na avaliação do escore pós-operatório tardio (escala 0-10) a esofagectomia (n=5) obteve 8,8 pontos e também 8,8 pontos obteve a mucosectomia (n=5). CONCLUSÕES: A mucosectomia esofágica mostrou-se boa alternativa no tratamento cirúrgico do megaesôfago avançado. Foi vantajosa no pós-operatório imediato por apresentar menor média de tempo na operação, na internação total, na UTI e no índice de complicações. No pós-operatório tardio, o resultado foi excelente e bom nas duas operações. .

Animals , Male , Mice , Energy Metabolism , /metabolism , Insulin/metabolism , Myocardial Contraction/physiology , Myocytes, Cardiac/metabolism , Signal Transduction/physiology , Hypoxia/metabolism , Cells, Cultured , Clathrin/metabolism , /genetics , Mice, Transgenic , Myocytes, Cardiac/cytology , Protein Transport/physiology , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Sarcolemma/metabolism , Sarcolemma/ultrastructure
Yonsei Medical Journal ; : 1678-1685, 2015.
Article in English | WPRIM | ID: wpr-70402


PURPOSE: To investigate the effects of resveratrol on the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in human adult retinal pigment epithelial (ARPE-19) cells, and on experimental choroidal neovascularization (CNV) in mice. MATERIALS AND METHODS: ARPE-19 cells were treated with different concentrations of resveratrol and then incubated under hypoxic conditions with subsequent evaluation of cell viability, expression of HIF-1alpha, and expression of VEGF. The effects of resveratrol on the synthesis and degradation of hypoxia-induced HIF-1alpha were evaluated using inhibitors of the PI3K/Akt/mTOR and the ubiquitin proteasome pathways. In animal studies, CNV lesions were induced in C57BL/6 mice by laser photocoagulation. After 7 days of oral administration of resveratrol or vehicle, which began one day after CNV induction, image analysis was used to measure CNV areas on choroidal flat mounts stained with isolectin IB4. RESULTS: In ARPE-19 cells, resveratrol significantly inhibited HIF-1alpha and VEGF in a dose-dependent manner, by blocking the PI3K/Akt/mTOR signaling pathway and by promoting proteasomal HIF-1alpha degradation. In mice experiments, orally administered resveratrol significantly inhibited CNV growth in a dose-dependent manner. CONCLUSION: Resveratrol may have therapeutic value in the management of diseases involving pathological neovascularization.

Adult , Animals , Hypoxia/metabolism , Cell Survival/drug effects , Choroidal Neovascularization/metabolism , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/drug effects , Mice , Mice, Inbred C57BL , Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Proteasome Endopeptidase Complex , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Retinal Pigment Epithelium/drug effects , Signal Transduction , Stilbenes/administration & dosage , TOR Serine-Threonine Kinases/antagonists & inhibitors , Ubiquitin , Vascular Endothelial Growth Factor A/drug effects
Indian J Exp Biol ; 2014 Nov; 52(11): 1098-1105
Article in English | IMSEAR | ID: sea-153796


At high altitude (HA) hypobaric hypoxic environment manifested several pathophysiological consequences of which gastrointestinal (GI) disorder are very common phenomena. To explore the most possible clue behind this disorder intestinal flora, the major player of the GI functions, were subjected following simulated hypobaric hypoxic treatment in model animal. For this, male albino rats were exposed to 55 kPa (~ 4872.9 m) air pressure consecutively for 30 days for 8 h/day and its small intestinal microflora, their secreted digestive enzymes and stress induced marker protein were investigated of the luminal epithelia. It was observed that population density of total aerobes significantly decreased, but the quantity of total anaerobes and Escherichia coli increased significantly after 30 days of hypoxic stress. The population density of strict anaerobes like Bifidobacterium sp., Bacteroides sp. and Lactobacillus sp. and obligate anaerobes like Clostridium perfringens and Peptostreptococcus sp. were expanded along with their positive growth direction index (GDI). In relation to the huge multiplication of anaerobes the amount of gas formation as well as content of IgA and IgG increased in duration dependent manner. The activity of some luminal enzymes from microbial origin like α-amylase, gluco-amylase, proteinase, alkaline phosphatase and β-glucuronidase were also elevated in hypoxic condition. Besides, hypoxia induced in formation of malondialdehyde along with significant attenuation of catalase, glutathione peroxidase, superoxide dismutase activity and lowered GSH/GSSG pool in the intestinal epithelia. Histological study revealed disruption of intestinal epithelial barrier with higher infiltration of lymphocytes in lamina propia and atrophic structure. It can be concluded that hypoxia at HA modified GI microbial imprint and subsequently causes epithelial barrier dysfunction which may relate to the small intestinal dysfunction at HA.

Acclimatization/physiology , Altitude , Animals , Hypoxia/etiology , Hypoxia/metabolism , Hypoxia/physiopathology , Atmosphere Exposure Chambers , Atmospheric Pressure , Bacteria, Aerobic/enzymology , Bacteria, Aerobic/isolation & purification , Bacteria, Anaerobic/enzymology , Bacteria, Anaerobic/isolation & purification , Bacterial Proteins/metabolism , Catalase/analysis , Digestion/physiology , Enzymes/metabolism , Feces/physiology , Glutathione/analysis , Ileum/enzymology , Ileum/metabolism , Ileum/ultrastructure , Lipid Peroxidation , Male , Microbiota/physiology , Random Allocation , Rats , Stress, Physiological/physiology , Superoxide Dismutase/analysis
Article in English | WPRIM | ID: wpr-214933


PURPOSE: We investigated whether oxygen-induced retinopathy (OIR) results in changes in the protein expression of neuronal and inducible nitric oxide synthases (nNOS and iNOS, respectively) in rat model of OIR. In addition, we evaluated whether treatment of rats with triamcinolone acetonide (TA) prevents this response. METHODS: To promote OIR, Sprague-Dawley rats were exposed to hyperoxia from postnatal day 2 (P2) to P14. They were then returned to normoxia after P15. TA was injected into the right vitreous of P15 rats, while saline was injected into the left vitreous. At P18 the expression of nNOS and iNOS was determined using Western blotting and immunostaining techniques in retinas obtained from control rats. RESULTS: In P18 OIR rats, the abundance of nNOS and iNOS protein was significantly increased compared with controls. These increases were not observed in the retinas of rats treated with TA. The change in expression of nNOS and iNOS were specific to parvalbumin and glial fibrillary acidic protein-positive cells. Treatment with TA prevented the increased expression of nNOS and iNOS in all samples. CONCLUSIONS: Hypoxia upregulates expression of nNOS and iNOS in OIR rat retinas, which is can be prevented by treatment with TA.

Animals , Animals, Newborn , Hypoxia/metabolism , Blotting, Western , Disease Models, Animal , Female , Glucocorticoids/pharmacology , Immunohistochemistry , Neurons/metabolism , Nitric Oxide Synthase Type II/biosynthesis , Oxygen/toxicity , Pregnancy , Pregnancy, Animal , Rats , Rats, Sprague-Dawley , Retina/metabolism , Retinal Diseases/chemically induced , Triamcinolone Acetonide/pharmacology
Rev. biol. trop ; 58(4): 1467-1478, dic. 2010. ilus, graf, tab
Article in English | LILACS | ID: lil-638013


Tadpoles inhabit generally well oxygenated rivers and streams, nevertheless they were found in areas with limited oxygen availability inside the rivers. To assess this feature, I examined factors that influence centrolenid tadpole behaviour using Cochranella granulosa. The tadpoles were reared in well-oxygenated and hypoxic environments and their development, survivorship and growth were compared. The tadpoles in oxygenated water acquired a pale color, while tadpoles in hypoxic water grew faster and were bright red and more active. In the oxygenated water, the ammonium, which had its origin in the tadpoles’ urine and feces, was oxidized to nitrate. In contrast, in the hypoxic treatment, the nitrogen compounds remained mainly as ammonium. Presumably, the nitrate in oxygenated water was secondarily reduced to nitrite inside the long intestine coils, because all symptoms in the tadpoles point to methemoglobinemia, which can occur when the nitrite passes through the intestine wall into the bloodstream, transforming the hemoglobin into methemoglobin. This could be checked by a blood test where the percentage of methemoglobin was 2.3% in the blood of tadpoles reared in hypoxic condition, while there was a 19.3% level of methemoglobin in the blood of tadpoles reared in oxygenated water. Together with the elevated content of methemoglobin, the growth of the tadpoles was delayed in oxygenated water, which had high nitrate content. The study about quantitative food-uptake showed that the tadpoles benefit more from the food in hypoxic water, although they spent there more energy moving around than the tadpoles living in oxygenated but nitrate-charged water. Rev. Biol. Trop. 58 (4): 1467-1478. Epub 2010 December 01.

Los renacuajos por lo general viven en ríos y arroyos bien oxigenados, sin embargo, como han sido encontrados en áreas con disponibilidad de oxígeno limitada en los ríos, se estudió como influye este factor en su comportamiento. Renacuajos de Cochranella granulosa fueron criados en ambientes bien oxigenados y de hipoxia para comparar su desarrollo, supervivencia y crecimiento. En el agua que no fue cambiada durante al menos un mes, los renacuajos mostraron diferencias en su desarrollo cuando vivían en agua hipóxica u oxigenada. Los renacuajos en el agua aireada tenían un color pálido, mientras que en la hipóxica fueron más activos y de un color rojo brillante. En el agua hipóxica, el nitrógeno que se originó de la orina y las heces de los renacuajos se mantuvo principalmente en forma de amonio; en cambio, el amonio fue oxidado a nitrato en el agua aireada. Presumiblemente, el nitrato en el agua oxigenada se redujo secundariamente a nitrito dentro del intestino, ya que todos los síntomas en los renacuajos que vivían en esta agua apuntaron a una metahemoglobinemia, que se produce cuando el nitrito pasa a través de la pared del intestino a la corriente sanguínea transformando la hemoglobina en metahemoglobina. Esto pudo comprobarse mediante un análisis sanguíneo en donde el porcentaje de metahemoglobina fue del 2.3% en la sangre de los renacuajos criados en condición hipóxica y de un 19.3% de metahemoglobina en aquellos criados en agua aireada. En la misma forma en que la metahemoglobina aumenta en la sangre de los renacuajos que viven en agua oxigenada, su crecimiento disminuye en agua con alto contenido de nitrato. El estudio cuantitativo de la ingestión de nutrientes mostró que el crecimiento de los renacuajos se beneficia más de los alimentos en agua hipóxica, a pesar de que los renacuajos son más activos en sus movimientos que los que viven en agua oxigenada pero cargada de nitratos.

Animals , Hypoxia/metabolism , Anura/metabolism , Cyanosis/metabolism , Methemoglobinemia/metabolism , Water Pollutants, Chemical/pharmacokinetics , Anura/growth & development , Anura/physiology , Larva/growth & development , Larva/metabolism , Larva/physiology , Nitrates/pharmacokinetics , Nitrites/pharmacokinetics , Water Pollutants, Chemical/adverse effects
Braz. j. biol ; 70(2): 425-434, May 2010. graf, tab
Article in English | LILACS | ID: lil-548247


In order to verify the influence of chronic and acute ambient oxygen levels from egg to adult stage of the zebrafish, in vivo oxygen consumption (MO2), critical tensions of oxygen (Pcrit), heart rate (fH) and total body lactate concentration (Lc) were determined for Danio rerio (Hamilton, 1822) raised at 28 °C under normoxic (7.5 mgO2.L-1 or 80 mm.Hg-1) and hypoxic conditions (4.3 mgO2.L-1) and exposed to acute hypoxia during different developmental stages. Our findings confirmed that very early stages do not respond effectively to ambient acute hypoxia. However, after the stage corresponding to the age of 30 days, D. rerio was able to respond to acute hypoxia through effective physiological mechanisms involving aerobic and anaerobic metabolism. Such responses were more efficient for the fishes reared under hypoxia which showed that D. rerio survival capability increased during acclimation to mild hypoxia. Measurements of body mass and length showed that moderate hypoxia did not affect growth significantly until the fish reached the stage of 60 days. Moreover, a growth delay was verified for the hypoxic-reared animals. Also, the D. rerio eggs-to-larvae survival varied from 87.7 to 62.4 percent in animals reared under normoxia and mild hypoxia, respectively. However, the surviving animals raised under moderated hypoxia showed a better aptitude to regulate aerobic and anaerobic capacities when exposed to acute hypoxia.

A influência de diferentes níveis de oxigênio no desenvolvimento (ovos a adulto) do peixe paulistinha Danio rerio (Hamilton, 1822) foi verificada por meio de medidas experimentais de consumo de oxigênio (MO2), tensões críticas de oxigênio (Pcrit), taxa de batimentos cardíacos (fH) e concentração total de lactato nos tecidos (Lc), para os animais mantidos a 28 ºC sob níveis normóxicos de oxigênio (7.5 mgO2.L-1 ou 80 mmHg) e hipóxicos (4.3 mgO2.L-1) e submetidos a hipóxia ambiental aguda, em diferentes estágios de desenvolvimento. Os resultados obtidos indicam que os peixes em estágios iniciais do desenvolvimento não variam suas respostas fisiológicas em função das oscilações ambientais nos níveis de oxigênio, visto que tais respostas iniciaram-se somente no estágio de 30 dias de vida. A partir deste estágio D. rerio apresentou capacidade em responder à hipóxia aguda por meio de mecanismos fisiológicos efetivos envolvendo metabolismo aeróbico e anaeróbico. Tais respostas foram mais efetivas para os peixes mantidos sob hipóxia, o que mostrou que a capacidade de sobrevivência de D. rerio aumentou durante o período de aclimatação à hipóxia moderada. As medidas de massa e comprimento corpóreos mostraram que a permanência dos peixes em hipóxia durante o desenvolvimento não afetou esses parâmetro até os peixes atingirem o estágio de 60 dias. A partir deste estágio foi observado ligeiro atraso no crescimento dos espécimes mantidos sob hipóxia. A taxa de sobrevivência de D.rerio variou de 87,7 a 62,4 por cento para os animais mantidos respectivamente sob níveis normóxicos e hipóxicos. No entanto, os animais mantidos sob hipóxia moderada, que sobreviveram, mostraram maior capacidade em regular seu metabolismo aeróbico e anaeróbico quando expostos à hipóxia ambiental aguda.

Animals , Hypoxia/physiopathology , Oxygen Consumption/physiology , Zebrafish/physiology , Aerobiosis/physiology , Anaerobiosis/physiology , Hypoxia/metabolism , Body Mass Index , Heart Rate/physiology , Lactic Acid/analysis , Zebrafish/growth & development , Zebrafish/metabolism
Arq. bras. med. vet. zootec ; 61(5): 1183-1190, out. 2009. tab, ilus
Article in Portuguese | LILACS | ID: lil-532031


Avaliou-se a variação da resposta secundária ao estresse causado por hipóxia durante 18 dias, em sistema de recirculação, em uma linhagem de tilápia nilótica (Oreochromis niloticus), chitralada, refletida no perfil proteico eletroforético do peixe e avaliou-se a diferença entre sexos para essa resposta. Foram utilizados 126 peixes, sendo 60 machos e 66 fêmeas, ambos com média de peso de 800g. O estresse crônico por hipóxia alterou (P<0,05) os valores médios relativos de albumina, α+β-globulinas e de γ-globulina, provocou alteração (P<0,05) nos níveis de proteína total relativo ao aumento no grupo dos machos, diminuição significativa dos valores médios absolutos de albumina devido à diminuição nas fêmeas e à diminuição de γ-globulina nos machos. As variantes proteicas, albumina e γ-globulina tiveram influência do sexo.

This study evaluated the secundary response variation to hypoxia stress in a strain of chitralada nilotic tilapia (Oreochromis niloticus) during 18 days, in a recirculation system. The effects were measured by the proteic electrophoretic profile and the difference between the genders. One hundred twenty-six fish were used, 60 males and 66 females, both averaging 800g. The chronic hypoxia stress altered (P<0.05) the relative values of albumin, α+β-globulins, and γ-globulin; modified (P<0.05) the levels of total protein due to an increase in the male group; significantly decreased of the absolute mean values of albumin due to a decrease in the female group; and decreased the g-globulin values in males. The proteic profile, albumin, and γ-globulin were influenced by gender.

Animals , Serum Albumin/analysis , Cichlids , Globulins/analysis , Immunoglobulins/analysis , Hypoxia/metabolism , Stress, Physiological
Rev. bras. anestesiol ; 59(4): 452-460, jul.-ago. 2009. tab
Article in English, Portuguese | LILACS | ID: lil-521557


JUSTIFICATIVA E OBJETIVOS: Apesar das alterações na função pulmonar, a oxigenação materna se mantém nas anestesias regionais para obstetrícia. Mesmo assim, nessas situações, o fornecimento de oxigênio suplementar para a mãe é prática disseminada. A principal justificativa é a boa oxigenação fetal; entretanto, não há devida comprovação. Este estudo prospectivo e com distribuição randômica das pacientes teve o objetivo de testar a hipótese da existência ou não de correlação entre hiperóxia materna e elevação de parâmetros gasométricos fetais na cesariana eletiva. MÉTODO: Foram estudadas vinte pacientes grávidas, submetidas à raquianestesia, através de gasometrias arteriais, com diferentes frações inspiradas de oxigênio e correlacionadas com a gasometria fetal. RESULTADOS: O aumento da fração inspirada de oxigênio materno não se correlacionou com o aumento da pressão parcial de oxigênio fetal. CONCLUSÕES: A indução de hiperóxia materna através de oxigenoterapia suplementar não foi capaz de aumentar a pressão parcial de oxigênio no feto. Não houve modificação nos parâmetros gasométricos fetais, mesmo em caso de mudança desses parâmetros na parturiente, induzidos pela hiperóxia durante a cesariana sob raquianestesia.

BACKGROUND AND OBJECTIVES: Despite changes in pulmonary function, maternal oxygenation is maintained during obstetric regional blocks. But in those situations, the administration of supplementary oxygen to parturients is a common practice. Good fetal oxygenation is the main justification; however, this has not been proven. The objective of this randomized, prospective study was to test the hypothesis of whether maternal hyperoxia is correlated with an increase in fetal gasometric parameters in elective cesarean sections. METHODS: Arterial blood gases of 20 parturients undergoing spinal block with different inspired fractions of oxygen were evaluated and correlated with fetal arterial blood gases. RESULTS: An increase in maternal inspired fraction of oxygen did not show any correlation with an increase of fetal partial oxygen pressure. CONCLUSIONS: Induction of maternal hyperoxia by the administration of supplementary oxygen did not increase fetal partial oxygen pressure. Fetal gasometric parameters did not change even when maternal parameters changed, induced by hyperoxia, during cesarean section under spinal block.

JUSTIFICATIVA Y OBJETIVOS: A pesar de las alteraciones en la función pulmonar, la oxigenación materna se mantiene en las anestesias regionales para obstetricia. Pero incluso así, en esas situaciones, el suministro de oxígeno suplementario para la madre se practica en forma diseminada. La principal justificación es la buena oxigenación fetal, sin embargo, no existe la debida comprobación al respecto. Este estudio prospectivo y con distribución randómica de las pacientes, tuvo el objetivo de comprobar la hipótesis de la existencia o no de una correlación entre la hiperoxia materna y la elevación de los parámetros gasométricos fetales en la cesárea por elección.? MÉTODO: Se estudiaron veinte pacientes embarazadas, sometidas a la raquianestesia, a través de gasometrías arteriales, con diferentes fracciones inspiradas de oxígeno y correlacionadas con la gasometría fetal. RESULTADOS: El aumento de la fracción inspirada de oxígeno materno no se correlacionó con el aumento de la presión parcial de oxígeno fetal. CONCLUSIONES: La inducción de hiperoxia materna a través de la oxigenoterapia suplementaria, no fue capaz de aumentar la presión parcial de oxígeno en el feto. No hubo modificación en los parámetros gasométricos fetales, incluso en el caso del cambio de esos parámetros en la parturiente, inducidos por la hiperoxia durante la cesárea bajo raquianestesia.

Adult , Female , Humans , Pregnancy , Young Adult , Cesarean Section , Fetus/metabolism , Oxygen/metabolism , Hypoxia/metabolism , Blood Gas Analysis , Inhalation , Pressure , Prospective Studies , Pregnancy Complications/metabolism , Young Adult
Braz. j. biol ; 68(3): 571-575, Aug. 2008. graf, tab
Article in English | LILACS | ID: lil-493576


The aim of this study was to describe the effect of hypoxia on whole body ion fluxes and hematological parameters in two Amazonian teleosts: Serrasalmus eigenmanni and Metynnis hypsauchen. The increase of Na+ and Cl- effluxes on M. hypsauchen exposed to hypoxia may be related to an increase of gill ventilation and effective respiratory surface area, to avoid a reduction in the oxygen uptake, and/or with the decrease of pHe, that could inhibit Na+ and Cl- transporters and, therefore, reduce influx of these ions. Effluxes of Na+ and Cl- were lower in hypoxia than in normoxia for S. eigenmanni, possibly because in hypoxia this species would reduce gill ventilation and oxygen uptake, which would lead to a decrease of gill ion efflux and, consequently, reducing ion loss. The increase on hematocrit (Ht) during hypoxia in M. hypsauchen probably was caused by an increase of the red blood cell volume (MCV). For S. eigenmanni the increase on glucose possibly results from the usage of glucose reserve mobilization. Metynnis hypsauchen showed to be more sensitive to hypoxia than Serrasalmus eigenmanni, since the first presented more significant alterations on these osmoregulatory and hematological parameters. Nevertheless, the alterations observed for both species are strategies adopted by fishes to preserve oxygen supply to metabolizing tissues during exposure to hypoxia.

O objetivo deste trabalho foi descrever o efeito da hipoxia no fluxo iônico corporal e nos parâmetros hematológicos em duas espécies de teleósteos da Amazônia: Serrasalmus eigenmanni e Metynnis hypsauchen. O aumento dos efluxos de Na+ e Cl- em M. hypsauchen expostos à hipoxia pode estar relacionado ao aumento da ventilação branquial e da eficiência da área da superfície respiratória, a fim de evitar redução na captação de oxigênio; e/ou com a diminuição do pHe, que pode inibir os transportadores de Na+ e Cl- e, então, reduzir o influxo destes íons. Os efluxos de Na+ e Cl- foram menores em hipoxia do que em normoxia para a espécie S. eigenmanni, possivelmente porque esta espécie em hipoxia poderia reduzir a ventilação branquial e a captação de oxigênio, a qual levaria a uma diminuição do efluxo branquial de íons e, conseqüentemente, à redução da perda de íons. O aumento do hematócrito (Ht) durante hipoxia em M. hypsauchen provavelmente foi causado pelo aumento do volume das células vermelhas do sangue (MCV). Para a espécie S. eigenmanni, o aumento da glicose possivelmente foi resultado do uso da mobilização da reserva de glicose. A espécie Metynnis hypsauchen mostrou ser mais sensível à hipoxia do que a espécie Serrasalmus eigenmanni, uma vez que a primeira espécie apresentou mais alterações significativas em seus parâmetros osmorregulatórios e hematológicos. Contudo, as alterações observadas em ambas as espécies são estratégias adotadas pelos peixes a fim de preservar o suprimento de oxigênio para metabolização nos tecidos durante exposição à hipoxia.

Animals , Hypoxia/metabolism , Fishes/metabolism , Potassium Channels/metabolism , Sodium Channels/metabolism , Adaptation, Physiological , Hypoxia/blood , Fishes/blood , Rivers
Rev. méd. Chile ; 134(4): 491-498, abr. 2006. tab
Article in Spanish | LILACS | ID: lil-428551


Preeclampsia is the second cause of maternal death in Ecuador. The etiology of this condition is probably a placental alteration, although the details are not well known. The development of the placenta is closely related to the availability of oxygen. A defect in the differentiation of trophoblastic cells due to a faulty sensitization to changes in oxygen pressure, could be the cause of the alteration in placental development. The role of iron and local environmental conditions of a susceptible population, should be considered in the study of the etiology of preeclampsia. In the Andrean area of Ecuador, the high incidence of preeclampsia could be explained by the high prevalence of anemia and high altitude. However more studies are required to establish a close link between the environmental conditions of this area and the imperfect placental development.

Female , Humans , Pregnancy , Altitude , Anemia, Iron-Deficiency/complications , Iron/metabolism , Oxygen/metabolism , Placentation/physiology , Pre-Eclampsia/etiology , Hypoxia/metabolism , Hypoxia/physiopathology , Ecuador , Hypoxia-Inducible Factor 1/metabolism , Hypoxia-Inducible Factor 1/physiology , Oxygen Inhalation Therapy , Pre-Eclampsia/metabolism , Pre-Eclampsia/physiopathology , Pregnancy Trimesters/metabolism , Pregnancy Trimesters/physiology
Acta gastroenterol. latinoam ; 36(3): 113-124, 2006.
Article in English | LILACS | ID: lil-461597


Chronic hypobaric hypoxia is a physiological environmental stressor. While its effects on most major organsystems have been extensively studied, few works have addressed hypoxia-induced changes in intestinal transport.The effects of cyclooxygenase blockade with indomethacin on short-circuit current (Isc) and oxygen consumption(QO2) of the distal colonic epithelium ofcontrol rats and rats submitted to hypoxia for 10 days at 0.52 atm were studied. Isolated mucosae weremounted in an Ussing chamber modified for measuring QO2 while preserving transepithelial vectorial transport. Amiloride was added to the mucosal hemichamber to block a sodium component of Isc present in hypoxic rats. In this condition, basal Isc did not differ between the hypoxic and the control group, but QO2 was higher in the former. Indomethacin (30 ìmol/L)reduced Isc to the same extent in both groups, but QO2 reduction was larger in the hypoxic group. Pharmacologicalblockade of chloride secretion and a low-chloride solution abolished the indomethacin-induced reductionsof Isc in both groups, and the reduction of QO2 in controls, and attenuated but did not suppress the QO2 reduction in the hypoxic group. Linear regressionanalysis of QO2 changes versus Isc changes yielded a significant correlation for both groups, with regression lines with the same slope, but a higher position in hypoxic hypoxic animals. Results suggest that spontaneously released prostaglandins are equally important for maintaining colonic chloride secretion in hypoxic as in normoxic rats, but that, in the former, indomethacin has an additional effect on QO2 which is unrelated to ion transport.

La hipoxia hipobárica crónica es un estresante ambiental fisiológico. Aunque sus efectos se han estudiado en lamayoría de los sistemas orgánicos, hay pocos trabajos sobre su influencia en el transporte intestinal. Se estudió el efecto del bloqueo de la ciclooxigenasa con indometacina sobre la corriente de cortocircuito (Isc), el consumo de oxígeno (QO2) del epitelio del colon distal de ratas controles y fueron sometidas a hipoxia durante 10 díasa 0,52 atm. Se montaron preparados de mucosa aislada en una cámara de Ussing modificada para medir QO2 preservando el transporte vectorial transepitelial. Se añadió amilorida a la hemicámara mucosa para bloquear un componente de la Isc debido al sodio presente en ratas hipóxicas. En esta condición, la Isc basal fue similar en ambos grupos, pero el QO2 fue mayor enlos controles. La indometacina (30 mmol/L) redujo igualmente la Isc en ambos grupos; siendo la disminuciónde QO2 mayor en el hipóxico. El bloqueo de la secreció de cloruro (farmacológico y por omisión del ión) suprimió la disminución de Isc en ambos grupos y deQO2 en el control, y redujo, sin abolir, la disminución de QO2 en el hipóxico. El análisis de regresión lineal de cambios en QO2 versus cambios en Isc mostró en ambos grupos correlación significativa con líneas de regresiónde igual pendiente, pero más alta en el hipóxico. Los resultados sugieren que las prostaglandinas liberadas espontáneamente son igualmente importantes en mantener la secreción de cloruro en ratas hipóxicas y normóxicas,pero en las primeras la indometacina tiene además un efecto depresor del QO2 no relacionado con el transporte iónico.

Animals , Male , Rats , Hypoxia/metabolism , Colon/drug effects , Indomethacin/pharmacology , Oxygen Consumption/drug effects , Colon/metabolism , Disease Models, Animal , Indomethacin/metabolism , Oxygen Consumption/physiology , Rats, Wistar
Article in English | WPRIM | ID: wpr-20727


BACKGROUND: The interindividual variability for the development of collaterals in coronary artery disease is dependent on the hypoxic induction level of VEGF. To determine whether the hypoxic induction of VEGF is controlled by the transcription of HIF-1 (alpha), the VEGF and HIF-1 (alpha) m-RNA levels were correlated to hypoxia in monocytes harvested from patients with coronary artery disease. METHODS: The collateral scoring system used was modified from the TIMI system. The mononuclear cell layer of the patients' blood was cultured in hypoxia (1% O2, 5% CO2, 94%N2) and normoxia (5% CO2, 95% room air) for 17 hours. The VEGF and HIF-1 (alpha) mRNA levels were measured using a RT-PCR technique. We calculated the fold inductions of VEGF, HIF-1 (alpha) mRNA with hypoxia by dividing thehypoxic and the normoxic values. RESULTS: We found significantly higher hypoxic inductions of VEGF m-RNA in patients with collaterals compared to patients with no collaterals. However, there was no difference in the hypoxic inductions of HIF-1 (alpha) between the two groups (VEGF m-RNA mean fold inductions 3.71+/-3.30 versus 1.65+/-0.62, p=0.012, HIF-1 (alpha) mRNA 1.42+/-0.58 versus 1.20+/-0.39, p=0.165). CONCLUSIONS: We concluded that the interindividual variability in the hypoxic inductions of VEGF m-RNA in monocytes in patients is not controlled by the transcriptional levels of HIF-1 (alpha) with hypoxia. These findings suggest that a mechanism such as the post-transcriptional modification of HIF-1 (alpha) is involved in the hypoxic inductions of VEGF.

Vascular Endothelial Growth Factor A/metabolism , RNA, Messenger/metabolism , Monocytes/metabolism , Middle Aged , Male , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Humans , Female , Coronary Circulation , Coronary Artery Disease/metabolism , Collateral Circulation , Cells, Cultured , Hypoxia/metabolism