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1.
BJOG ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31715077

RESUMO

OBJECTIVE: Women with preeclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve pregnancy outcome in animals with a preeclampsia-like syndrome. We investigated the effect of pravastatin on plasma sFlt-1 levels during preeclampsia. DESIGN: Blinded (clinician and participant), proof of principle, placebo-controlled trial SETTING: 15 UK maternity units. POPULATION: We used a minimization algorithm to assign 62 women with early-onset preeclampsia (24+0 - 31+6 weeks' gestation) to receive pravastatin 40mg daily (n=30) or matched placebo (n=32), from randomization to childbirth. PRIMARY OUTCOME: Difference in mean plasma sFlt-1 levels over the first three days following randomization. RESULTS: The difference in the mean maternal plasma sFlt-1 levels over the first three days after randomisation between the pravastatin (n=27) and placebo (n=29) groups was 292pg/mL (95%CI: -1175- 592; p=0.5), and over days 1-14 was 48pg/ml (95% CI -1009 to 913; p=0.9). Women who received pravastatin had a similar length of pregnancy following randomization compared with those who received placebo (Hazard ratio 0.84; 95%CI: 0.50-1.40; p=0.6). The median time from randomization to childbirth was 9 days (IQR 5-14 days) for the pravastatin group and 7 days (IQR 4-11 days) for the placebo group. There were 3 perinatal deaths in the placebo-treated group and no deaths or serious adverse events attributable to pravastatin. CONCLUSIONS: We found no evidence that pravastatin lowered maternal plasma sFlt-1 levels once early onset preeclampsia had developed. Pravastatin appears to have no adverse perinatal effects.

2.
PLoS One ; 14(10): e0224436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31648266

RESUMO

Tuned liquid column ball damper (TLCBD) is a passive control device used for controlling the building vibrations induced from wind or earthquakes. TLCBD is a modified form of conventional tuned liquid column damper (TLCD). This paper studies the effect of TLCBD on the four-storey steel frame structure. The performance of the TLCBD is also compared with conventional TLCD. The analytical model of both TLCD and TLCBD is presented here. The effectiveness of these analytical models is examined experimentally by series of shaking table tests under different excitation levels including harmonic loadings and seismic excitations. In TLCBD, the vibration is reduced significantly as compared to TLCD by using steel ball as a moving orifice. The difference in diameter of steel ball and tube, containing the liquid column, acts as an orifice which moves with the movement of the ball. This moving orifice phenomenon enhanced the vibration reduction effect by resisting the water motion in the TLCBD. Root mean square (RMS) and peak values of acceleration were calculated for each loading and each storey of uncontrolled and controlled structures. Comparison of the time histories of controlled and uncontrolled structures for different loadings is also reported. Results indicate that the TLCBD is more effective in the earthquake scenarios as compared to the harmonic excitations. The TLCBD controls the vibration of the primary structure significantly in vibration reduction.

3.
Nat Cell Biol ; 21(6): 687-699, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160711

RESUMO

We recently derived mouse expanded potential stem cells (EPSCs) from individual blastomeres by inhibiting the critical molecular pathways that predispose their differentiation. EPSCs had enriched molecular signatures of blastomeres and possessed developmental potency for all embryonic and extra-embryonic cell lineages. Here, we report the derivation of porcine EPSCs, which express key pluripotency genes, are genetically stable, permit genome editing, differentiate to derivatives of the three germ layers in chimeras and produce primordial germ cell-like cells in vitro. Under similar conditions, human embryonic stem cells and induced pluripotent stem cells can be converted, or somatic cells directly reprogrammed, to EPSCs that display the molecular and functional attributes reminiscent of porcine EPSCs. Importantly, trophoblast stem-cell-like cells can be generated from both human and porcine EPSCs. Our pathway-inhibition paradigm thus opens an avenue for generating mammalian pluripotent stem cells, and EPSCs present a unique cellular platform for translational research in biotechnology and regenerative medicine.


Assuntos
Diferenciação Celular/genética , Reprogramação Celular/genética , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes/citologia , Animais , Blastômeros/citologia , Blastômeros/metabolismo , Linhagem da Célula/genética , Células-Tronco Embrionárias/citologia , Camadas Germinativas/crescimento & desenvolvimento , Camadas Germinativas/metabolismo , Humanos , Camundongos , Medicina Regenerativa , Transdução de Sinais/genética , Suínos , Trofoblastos/citologia , Trofoblastos/metabolismo
4.
Free Radic Biol Med ; 137: 87-98, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31022448

RESUMO

α-Terthienyl (α-T) is a photosensitizer that produces many reactive oxygen species (ROS) under ultraviolet light. Here, we aimed to evaluate the oxidation mechanism of the 25%, 50%, and 75% lethal concentrations in Aedes aegypti larvae; the lethal concentration of α-T was used as the test value. The effects on mitochondria, oxidative stress, and cell death patterns caused by ROS were evaluated. The results showed that α-T mainly produced large amounts of ROS in the midgut of larvae. Moreover, mitochondrial ROS were increased in midgut cells, and the production of ROS sites, such as complex enzymes, was inhibited, resulting in enhanced production of ROS. Ultrastructural analysis of mitochondria revealed significant vacuolation, decreased activity of tricarboxylic acid cycle enzymes, and reduced ATP content and mitochondrial membrane potential in the high concentration group compared with those in the control group. Additionally, mitochondrial biosynthesis was blocked in the high concentration group. Thus, exposure to α-T disrupted mitochondrial function, although the mitochondrial DNA content may have increased because of mitochondrial self-protection mechanisms against oxidative stress. Furthermore, high concentrations of α-T aggravated oxidative stress and increased the number of intracellular oxidative damage products. Reverse transcription polymerase chain reaction and fluorescence staining showed that ROS induced by low α-T concentrations upregulated apoptotic genes, including Dronc (P < 0.05), thereby promoting apoptosis. Moderate concentrations of α-T promoted autophagy through induction of ROS, inhibited apoptosis, and induced necrosis. In contrast, high α-T concentrations induced high levels of ROS, which caused mitochondrial dysfunction and increased cytoplasmic Ca2+ concentration, directly inducing cell necrosis. We also found that α-T may disrupt the permeability of the peritrophic membrane, leading to intestinal barrier dysfunction. These results provided insights into the mode of action of α-T in Aedes aegypti.

5.
Int J Mol Sci ; 19(12)2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30563093

RESUMO

Kupffer cells are professional phagocytes of the liver clearing bacteria from portal blood. Their clearance capacity, however, can be overwhelmed, transforming them into critical mediators of hepatic-injury. We investigated the consequences of selective Kupffer cell-overload by intraperitoneally administering pyrogen-free gadolinium chloride (GdCl3) or Zymosan into rats and into endotoxin-resistant mice (C3H/HeJ). The number of myeloperoxidase-positive (MPO⁺) cells increased at 3 h mainly around the portal vessel after both GdCl3 and Zymosan treatment. Simultaneously, GdCl3 administration reduced detectability of ED-1⁺ (but not ED-2) cells near the portal vessel. Serum chemokine (C-X-C motif) ligand 1 (CXCL-1), CXCL-2 and chemokine (C-C motif) ligand 2 (CCL-2) showed a peak at 3 h after both treatment regimens although at a higher extent after Zymosan administration. Accordingly, CXCL-1, CXCL-5 and CCL-2 gene expression in the liver was up-regulated after GdCl3 treatment at 3 h. After Zymosan administration a significant up-regulation of CXCL-1, CXCL-2, CXCL-10, CCL-2, CCL-3 and CCL-20 gene expression in liver at 3 h was observed. After Zymosan administration intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) gene expression was up-regulated in rat liver tissue. In C3H/HeJ mice both treatment regimens up-regulated CCL-2 and ICAM-1 gene expression after 3 h and down-regulated platelet endothelial cell adhesion molecule 1 (PECAM-1) gene expression. In conclusion, phagocytosis overload of Kupffer cells causes induction of several CXC, CC-chemokines, upregulation of "positive" adhesion molecule gene expression, down-regulation of the "negative" adhesion molecule PECAM-1 and a recruitment of neutrophil granulocytes in the portal area of the liver of treated rats and mice mainly in close contact to the liver macrophages.


Assuntos
Moléculas de Adesão Celular/biossíntese , Quimiocinas/biossíntese , Gadolínio/farmacologia , Fígado/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Zimosan/farmacologia , Animais , Macrófagos do Fígado/metabolismo , Macrófagos do Fígado/patologia , Fígado/patologia , Masculino , Camundongos , Neutrófilos/patologia , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacos
6.
ESC Heart Fail ; 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30378291

RESUMO

AIMS: In hypertrophy and heart failure, the proarrhythmic persistent Na+ current (INaL ) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel NaV 1.8 in human hypertrophied myocardium. METHODS AND RESULTS: Myocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload-induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real-time PCR and western blot and detected a significant up-regulation of NaV 1.8 mRNA (2.34-fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, NaV 1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent INaL was significantly reduced after addition of novel NaV 1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 µM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of NaV 1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)-Ca2+ leak and SR-Ca2+ spark frequency after exposure to both NaV 1.8 inhibitors. CONCLUSIONS: We show for the first time that the neuronal sodium channel NaV 1.8 is up-regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of NaV 1.8 reduced augmented INaL , abbreviated the action potential duration, and decreased the SR-Ca2+ leak. The findings of our study suggest that NaV 1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.

7.
Sci Rep ; 8(1): 11488, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30065265

RESUMO

S100P has been shown to be a marker for carcinogenesis where its expression in solid tumours correlates with metastasis and a poor patient prognosis. This protein's role in any physiological process is, however, unknown. Here we first show that S100P is expressed both in trophoblasts in vivo as well as in some corresponding cell lines in culture. We demonstrate that S100P is predominantly expressed during the early stage of placental formation with its highest expression levels occurring during the first trimester of gestation, particularly in the invading columns and anchoring villi. Using gain or loss of function studies through overexpression or knockdown of S100P expression respectively, our work shows that S100P stimulates both cell motility and cellular invasion in different trophoblastic and first trimester EVT cell lines. Interestingly, cell invasion was seen to be more dramatically affected than cell migration. Our results suggest that S100P may be acting as an important regulator of trophoblast invasion during placentation. This finding sheds new light on a hitherto uncharacterized molecular mechanism which may, in turn, lead to the identification of novel targets that may explain why significant numbers of confirmed human pregnancies suffer complications through poor placental implantation.

8.
Cardiovasc Res ; 114(13): 1728-1737, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931291

RESUMO

Aims: In heart failure (HF), enhanced persistent Na+ current (INaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. However, the underlying regulatory mechanisms remain unclear. Our aim was to potentially investigate the regulation and electrophysiological contribution of neuronal sodium channel NaV1.8 in failing human heart and eventually to reveal a novel anti-arrhythmic therapy. Methods and results: By western blot, we found that NaV1.8 protein expression is significantly up-regulated, while of the predominant cardiac isoform NaV1.5 is inversely reduced in human HF. Furthermore, to investigate the relation of NaV1.8 regulation with the cellular proarrhythmic events, we performed comprehensive electrophysiology recordings and explore the effect of NaV1.8 on INaL, action potential duration (APD), Ca2+ spark frequency, and arrhythmia induction in human failing cardiomyocytes. NaV1.8 inhibition with the specific blockers A-803467 and PF-01247324 decreased INaL, abbreviated APD and reduced cellular-spontaneous Ca2+-release and proarrhythmic events in human failing cardiomyocytes. Consistently, in mouse cardiomyocytes stressed with isoproterenol, pharmacologic inhibition and genetically knockout of NaV1.8 (SCN10A-/-), were associated with reduced INaL and abbreviated APD. Conclusion: We provide first evidence of differential regulation of NaV1.8 and NaV1.5 in the failing human myocardium and their contribution to arrhythmogenesis due to generation of INaL. We propose inhibition of NaV1.8 thus constitutes a promising novel approach for selective anti-arrhythmic therapy in HF.

9.
J Patient Saf ; 2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-29668574

RESUMO

OBJECTIVES: Primary Health Care Corporation (PHCC) is the public primary health care provider in Qatar. Having a patient safety culture (PSC) is the keystone to enabling a continuous process to improve the quality of services and to reduce errors. The objective of this study was to assess the impact of accreditation, quality improvement trainings, and patient safety (PS) trainings on the improvement of the PSC at the PHCC in Qatar. METHODS: The Medical Office Survey on Patient Safety Culture from the Agency for Healthcare Research and Quality was used in 2012 and 2015 to assess the culture of PS and health care quality in the 21 health centers. The results of the two surveys were compared using the χ test. A P value of less than 0.05 was considered significant. RESULTS: Out of 2689 staff working in the 21 health centers, 1810 (67.3%) completed the survey in 2012, and 2616 (70.0%) of 3735 completed the survey in 2015. The comparison between 2012 and 2015 survey's results showed a statistically significant improvement for all the 10 dimensions (P < 0.05). Although a statistically significant difference was observed between 2012 and 2015 results for work pressure and pace, three of the four questions of the work pressure and pace dimension presented nonsignificant differences. CONCLUSIONS: The survey was a good tool to raise awareness on PS and quality issues at PHCC. There is evidence that the implementation of accreditation program, the quality improvement trainings, and PS trainings helped the organization improve its PS culture.

10.
J Am Heart Assoc ; 6(9)2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28887315

RESUMO

BACKGROUND: In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina. METHODS AND RESULTS: Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, P=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, P=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] µmol/L, P<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, P=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation. CONCLUSIONS: Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02078921. EudraCT number: 2012-000196-17.


Assuntos
Angina Estável/tratamento farmacológico , Fármacos Cardiovasculares/administração & dosagem , Tolerância ao Exercício/efeitos dos fármacos , Nitratos/administração & dosagem , Administração Oral , Idoso , Angina Estável/sangue , Angina Estável/diagnóstico , Angina Estável/fisiopatologia , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/sangue , Estudos Cross-Over , Método Duplo-Cego , Quimioterapia Combinada , Ecocardiografia sob Estresse , Eletrocardiografia , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitratos/efeitos adversos , Nitratos/sangue , Nitritos/sangue , Escócia , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento
11.
Curr Heart Fail Rep ; 14(3): 179-186, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28455610

RESUMO

PURPOSE OF REVIEW: Over the last years, evidence is accumulating that enhanced late sodium current (INaL) in cardiac pathologies has fundamental consequences for cellular electrophysiology. This review discusses the underlying mechanisms of INaL-induced arrhythmias and the significance of INaL-inhibition as a possible therapeutic approach. RECENT FINDINGS: Inhibition of enhanced INaL, e.g., by ranolazine, was shown to reverse these effects in different myocardial diseases including heart failure. The antianginal drug ranolazine has already been examined in larger clinical trials with promising antiarrhythmic actions. Enhanced INaL was found to be present in several cardiac pathologies like ischemia, long QT syndromes, hypertrophic cardiomyopathy, and heart failure. In settings of enhanced INaL, a sodium-dependent calcium overload leads to severe impairment of excitation-contraction coupling and therefore has a high proarrhythmogenic potential. Experimental data showed that inhibition of INaL has a high antiarrhythmic potential which could be confirmed in further clinical trials.


Assuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Ranolazina/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Canais de Sódio/efeitos dos fármacos , Arritmias Cardíacas/etiologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Humanos , Síndrome do QT Longo/metabolismo , Canais de Sódio/fisiologia
12.
Cardiovasc Res ; 113(1): 81-89, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28069704

RESUMO

AIMS: Atherosclerosis is a chronic inflammatory disease occurring within the artery wall. A crucial step in atherogenesis is the infiltration and retention of monocytes into the subendothelial space of large arteries induced by chemokines and growth factors. Angiopoietin-1 (Ang-1) regulates angiogenesis and reduces vascular permeability and has also been reported to promote monocyte migration in vitro. We investigated the role of Ang-1 in atherosclerosis-prone apolipoprotein-E (Apo-E) knockout mouse. METHODS AND RESULTS: Apo-E knockout (Apo-E-/-) mice fed a western or normal chow diet received a single iv injection of adenovirus encoding Ang-1 or control vector. Adenovirus-mediated systemic expression of Ang-1 induced a significant increase in early atherosclerotic lesion size and monocyte/macrophage accumulation compared with control animals receiving empty vector. Ang-1 significantly increased plasma MCP-1 and VEGF levels as measured by ELISA. FACS analysis showed that Ang-1 selectively increased inflammatory Gr1+ monocytes in the circulation, while the cell-surface expression of CD11b, which mediates monocyte emigration, was significantly reduced. CONCLUSIONS: Ang-1 specifically increases circulating Gr1+ inflammatory monocytes and increases monocyte/macrophage retention in atherosclerotic plaques, thereby contributing to development of atherosclerosis.


Assuntos
Angiopoietina-1/biossíntese , Antígenos Ly/metabolismo , Aorta Torácica/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Monócitos/metabolismo , Placa Aterosclerótica , Adenoviridae/genética , Angiopoietina-1/genética , Animais , Aorta Torácica/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/patologia , Antígeno CD11b/sangue , Quimiocina CCL2/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Predisposição Genética para Doença , Vetores Genéticos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/patologia , Fenótipo , Transdução de Sinais , Técnicas de Cultura de Tecidos , Fator A de Crescimento do Endotélio Vascular/sangue
13.
Future Cardiol ; 12(6): 617-626, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27730819

RESUMO

In an aging western population, a significant number of patients continue to suffer from angina once all revascularization and optimal medical treatment options are exhausted. Under experimental conditions, oral supplementation with inorganic nitrate was shown to exhibit a blood pressure-lowering effect, and has also been shown to promote angiogenesis, improve endothelial dysfunction and mitochondrial efficiency in skeletal muscle. It is unknown whether similar changes occur in cardiac muscle. In the current study, we investigate whether oral sodium nitrate treatment will improve myocardial ischemia in patients with stable angina.


Assuntos
Angina Estável/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Nitratos/administração & dosagem , Administração Oral , Idoso , Estudos Cross-Over , Método Duplo-Cego , Teste de Esforço , Humanos
14.
Int J Mol Sci ; 17(5)2016 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-27136530

RESUMO

Previously, we showed that lipocalin2 (LCN2) serum levels increased after liver irradiation and during acute-phase conditions. Here, we evaluate LCN2 expression and serum levels after single-dose lung irradiation with 25 Gy, percutaneously administered to the lung of randomly-paired male Wistar rats. Due to the concave anatomy of the lung recesses, the irradiation field included the upper part of the liver. No rat died due to irradiation. In control tissue, lung immunohistochemistry showed a high constitutive expression of LCN2+ granulocytes. LCN2 mRNA levels in lung tissue increased up to 24 h (9 ± 2.3-fold) after irradiation. However, serum LCN2 levels remained undetectable after lung irradiation. LCN2 expression in the upper part of the liver increased up to 4.2-fold after lung irradiation, but the lower liver showed an early decrease. Acute-phase cytokines (IL-1ß and TNF-α) showed a significant increase on transcript level in both lung and upper liver, whilst the lower liver did not show any considerable increase. In conclusion, constitutive expression of LCN2 in local immune cells demonstrates its local role during stress conditions in the lung. The absence of LCN2 in the serum strengthens our previous findings that the liver is the key player in secreting LCN2 during stress conditions with liver involvement.


Assuntos
Raios gama , Lipocalina-2/sangue , Pulmão/efeitos da radiação , Animais , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Lipocalina-2/genética , Lipocalina-2/metabolismo , Fígado/metabolismo , Fígado/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Microscopia de Fluorescência , Modelos Animais , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Fator de Necrose Tumoral alfa/metabolismo
15.
J Biomed Opt ; 20(5): 56012, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26021717

RESUMO

Mueller matrix polarimetry along with polar decomposition algorithm was employed for the characterization of ex vivo normal and adenocarcinoma human colon tissues by polarized light in the visible spectral range (425-725 nm). Six derived polarization metrics [total diattenuation (DT ), retardance (RT ), depolarization(ΔT ), linear diattenuation (DL), retardance (δ), and depolarization (ΔL)] were compared for normal and adenocarcinoma colon tissue samples. The results show that all six polarimetric properties for adenocarcinoma samples were significantly higher as compared to the normal samples for all wavelengths. The Wilcoxon rank sum test illustrated that total retardance is a good candidate for the discrimination of normal and adenocarcinoma colon samples. Support vector machine classification for normal and adenocarcinoma based on the four polarization properties spectra (ΔT , ΔL, RT ,and δ) yielded 100% accuracy, sensitivity, and specificity, while both DTa nd DL showed 66.6%, 33.3%, and 83.3% accuracy, sensitivity, and specificity, respectively. The combination of polarization analysis and given classification methods provides a framework to distinguish the normal and cancerous tissues.


Assuntos
Adenocarcinoma/patologia , Algoritmos , Colo/patologia , Neoplasias do Colo/patologia , Interpretação de Imagem Assistida por Computador/métodos , Microscopia de Polarização/métodos , Diagnóstico Diferencial , Desenho de Equipamento , Análise de Falha de Equipamento , Humanos , Aumento da Imagem/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Máquina de Vetores de Suporte , Células Tumorais Cultivadas
16.
Thromb Haemost ; 113(2): 329-37, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25354586

RESUMO

Carbon monoxide (CO) is a gaseous autacoid known to positively regulate vascular tone; however, its role in angiogenesis is unknown. The aim of this study was to investigate the effect of CO on angiogenesis and vascular endothelial growth factor (VEGF) receptor-2 phosphorylation. Human umbilical vein endothelial cells (HUVECs) were cultured on growth factor-reduced Matrigel and treated with a CO-releasing molecule (CORM-2) or exposed to CO gas (250 ppm). Here, we report the surprising finding that exposure to CO inhibits vascular endothelial growth factor (VEGF)-induced endothelial cell actin reorganisation, cell proliferation, migration and capillary-like tube formation. Similarly, CO suppressed VEGF-mediated phosphorylation of VEGFR-2 at tyrosine residue 1175 and 1214 and basic fibroblast growth factor- (FGF-2) and VEGF-mediated Akt phosphorylation. Consistent with these data, mice exposed to 250 ppm CO (1h/day for 14 days) exhibited a marked decrease in FGF-2-induced Matrigel plug angiogenesis (p<0.05). These data establish a new biological function for CO in angiogenesis and point to a potential therapeutic use for CO as an anti-angiogenic agent in tumour suppression.


Assuntos
Monóxido de Carbono/química , Neovascularização Patológica , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Movimento Celular , Proliferação de Células , Colágeno/química , Combinação de Medicamentos , Células Endoteliais/citologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunoprecipitação , Laminina/química , Camundongos Endogâmicos C57BL , Compostos Organometálicos/química , Fosforilação , Proteoglicanas/química , Proteínas Recombinantes/química , Tirosina/química
17.
Artigo em Inglês | MEDLINE | ID: mdl-25352830

RESUMO

Progression and severity of type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic ß-cell damage. Glucocorticoids (GCs) are highly effective anti-inflammatory agents but have been precluded in type 1 diabetes and in islet transplantation protocols because they exacerbated insulin resistance and suppressed ß-cell insulin secretion at the high-doses employed clinically. In contrast, physiological-range elevation of GC action within ß-cells ameliorated lipotoxic ß-cell failure in transgenic mice overexpressing the intracellular enzyme 11ß-hydroxysteroid dehydrogenase type 1 (MIP-HSD1(tg/+) mice). Here, we tested the hypothesis that elevated ß-cell 11beta-HSD1 protects against the ß-cell destruction elicited by streptozotocin (STZ), a toxin that dose-dependently mimics aspects of inflammatory and autoimmune ß-cell destruction. MIP-HSD1(tg/+) mice exhibited an episodic protection from the severe hyperglycemia caused by a single high dose of STZ associated with higher and sustained ß-cell survival, maintained ß-cell replicative potential, higher plasma and islet insulin levels, reduced inflammatory macrophage infiltration and increased anti-inflammatory T regulatory cell content. MIP-HSD1(tg/+) mice also completely resisted mild hyperglycemia and insulitis induced by multiple low-dose STZ administration. In vitro, MIP-HSD1(tg/+) islets exhibited attenuated STZ-induced nitric oxide production, an effect reversed with a specific 11beta-HSD1 inhibitor. GC regeneration selectively within ß-cells protects against inflammatory ß-cell destruction, suggesting therapeutic targeting of 11beta-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation.

19.
World J Gastroenterol ; 20(7): 1807-21, 2014 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-24587658

RESUMO

AIM: To explore lipocalin-2 (LCN-2) expression and its possible role and mechanism(s) of production in rat models of diet-inducible fatty liver. METHODS: Fatty liver was triggered in male Sprague-Dawley rats fed either with liquid Lieber-DeCarli (LDC) or LDC + 70% cal fructose (L-HFr) diet for 4 or 8 wk. Chow-nourished animals served as controls. Hepatic expression of LCN-2 and other metabolic and inflammatory mediators was assessed by quantitative reverse transcription polymerase chain reaction and Western blotting. Serum LCN-2, fasting leptin, and lipid profile were evaluated via Enzyme-Linked Immunosorbent Assay, Radioimmunoassay, and colorimetric assays, respectively. The localization of LCN-2 in the liver was detected by using immunofluorescence staining. Furthermore, HE stain was used to evaluate hepatic fat degeneration and inflammation. RESULTS: Both LDC-fed and L-HFr-fed rat histologically featured fatty liver. In the liver, mRNA transcriptions of Mcp-1, a2-m, Il-8 and Glut5 were increased in the L-HFr group at both time points (P < 0.001), while the transcription of Tlr4, Inos, and Tnf-α was significantly up-regulated at week 4. Interestingly, hepatic Lcn-2 expression was 90-fold at week 4 and 507-fold at week 8 higher in L-HFr-subjected rats vs control (P < 0.001). In contrast to HDL-cholesterol, systemic levels of LCN-2, fasting leptin and triglycerides were elevated in the L-HFr regimen (P < 0.001). Moreover, protein expression of hepatic LCN-2, CD14, phospho-MAPK, caspase-9, cytochrome c and 4-hydroxynonenal was increased in the L-HFr group. Conversely, the hepatic expression of PGC-1α (a mitochondrial-biogenic protein) was reduced in the L-HFr category at week 8. The localization of LCN-2 in the liver was predominantly restricted to MPO⁺ granulocytes. CONCLUSION: Fructose diet up-regulates hepatic LCN-2 expression, which correlates with the increased indicators of oxidative stress and mitochondrial dysfunction. The LCN-2 may be involved in liver protection.


Assuntos
Ração Animal , Fígado Gorduroso/metabolismo , Frutose/metabolismo , Lipocalinas/metabolismo , Animais , Apoptose , Quimiocina CCL2/metabolismo , Colorimetria , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica , Transportador de Glucose Tipo 5/metabolismo , Inflamação , Interleucina-8/metabolismo , Leptina/metabolismo , Peroxidação de Lipídeos , Lipocalina-2 , Fígado/metabolismo , Masculino , Estresse Oxidativo , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo
20.
Dig Liver Dis ; 46(4): 369-75, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24433995

RESUMO

BACKGROUND: Carbon monoxide, the gaseous product of heme oxygenase, is a signalling molecule with a broad spectrum of biological activities. The aim of this study was to investigate the effects of carbon monoxide on proliferation of human pancreatic cancer. METHODS: In vitro studies were performed on human pancreatic cancer cells (CAPAN-2, BxPc3, and PaTu-8902) treated with a carbon monoxide-releasing molecule or its inactive counterpart, or exposed to carbon monoxide gas (500 ppm/24h). For in vivo studies, pancreatic cancer cells (CAPAN-2/PaTu-8902) were xenotransplanted subcutaneously into athymic mice, subsequently treated with carbon monoxide-releasing molecule (35 mg/kg b.w. i.p./day), or exposed to safe doses of carbon monoxide (500 ppm 1h/day; n = 6 in each group). RESULTS: Both carbon monoxide-releasing molecule and carbon monoxide exposure significantly inhibited proliferation of human pancreatic cancer cells (p<0.05). A substantial decrease in Akt phosphorylation was observed in carbon monoxide-releasing molecule compared with inactive carbon monoxide-releasing molecule treated cancer cells (by 30-50%, p<0.05). Simultaneously, carbon monoxide-releasing molecule and carbon monoxide exposure inhibited tumour proliferation and microvascular density of xenotransplanted tumours (p<0.01), and doubled the survival rates (p<0.005). Exposure of mice to carbon monoxide led to an almost 3-fold increase in carbon monoxide content in tumour tissues (p=0.006). CONCLUSION: These data suggest a new biological function for carbon monoxide in carcinogenesis, and point to the potential chemotherapeutic/chemoadjuvant use of carbon monoxide in pancreatic cancer.


Assuntos
Monóxido de Carbono/farmacologia , Carcinoma Ductal Pancreático , Proliferação de Células/efeitos dos fármacos , Gasotransmissores/farmacologia , Compostos Organometálicos/farmacologia , Neoplasias Pancreáticas , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Animais , Humanos , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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