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1.
Steroids ; 137: 1-13, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30031853

RESUMO

New 3,20-dihydroxy-13α-19-norpregna-1,3,5(10)-trienes were synthesized. The effects of these compounds on breast cancer cells and ERα activation were investigated. The scaffold of compounds containing the six-membered ring D' annulated at 16α,17α-positions was constructed via the Lewis acid catalyzed Diels-Alder reaction of butadiene with 3-methoxy-13α-19-norpregna-1,3,5(10),16-tetraen-20-one 5 under a pressure of 600 MPa. The hydrogenation of primary cyclohexene adduct 6 followed by the one-pot reduction-demethylation (DIBAH) gave target epimeric 3,20-dihydroxy steroids 8a and 8b. The Corey-Chaykovsky reaction of the same conjugated ketone 5 gave a 16α,17α-methylene-substituted compound. The reaction of the latter with DIBAH yielded 3,20(R,S)-dihydroxy-16α,17α-methyleno-13α-19-norpregna-1,3,5(10)-triene 10. The hydrogenation of the 16,17-double bond of compound 5 produced a mixture of 17α- and 17ß-epimeric ketones, reduction-demethylation of which gave 3,20(S)-dihydroxy-13α,17α-19-norpregna-1,3,5(10)-triene 12a and 3,20(R)-dihydroxy-13α,17ß-19-norpregna-1,3,5(10)-triene 12b. All compounds were fully characterized by 1D and 2D NMR, HRMS, and X-ray diffraction. All target compounds showed pronounced cytotoxic effect against MCF-7 breast cancer cells and NCI/ADR-RES doxorubicin-resistant cells at micromolar concentrations. The ERα-mediated luciferase reporter gene assay demonstrated that all compounds, except for compound 10, are ERα inhibitors, while cyclopropane compound 10 proved to be an ERα activator. Docking experiments showed that all compounds are well accommodated to LBD ERα but have some differences in the binding mode.


Assuntos
Pregnatrienos/síntese química , Pregnatrienos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Técnicas de Química Sintética , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/metabolismo , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Estrogênios/síntese química , Estrogênios/química , Estrogênios/metabolismo , Estrogênios/farmacologia , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Pregnatrienos/química , Pregnatrienos/metabolismo , Domínios Proteicos , Estereoisomerismo
2.
Int J Surg ; 55: 156-161, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29860124

RESUMO

INTRODUCTION: Lung ischemia-reperfusion injury after thoracoabdominal aortic occlusion represents a major complication, which increases morbidity and mortality. In the present study we hypothesized that lazaroid U-74389G intravenous administration protects from lung ischemia-reperfusion injury through lipid peroxidation inhibition. MATERIALS AND METHODS: A total of 24 pigs were randomized in three groups. Group I (n = 8) underwent sham operation, group II (n = 8) underwent thoracoabdominal aortic occlusion for 45min and received placebo and group III (n = 8) received 3 doses of lazaroid (3 mg/kg) 60 and 30min before thoracoabdominal aortic occlusion and at 30min during thoracoabdominal aortic occlusion (duration 45min). Aortic occlusion was performed with aortic balloon-catheters under fluoroscopic guidance. All animals were sacrificed at the 7 t h postoperative day and lung specimens were harvested for molecular analysis. RESULTS: mRNA levels of leukotrienes LB4 (LTB4R2), LC4 (LTC4S) and nitric oxide synthase (NOS) isoforms including iNOS, nNOS and eNOS were determined with real-time RT-qPCR. Nitric oxide can either induce (iNOS) or inhibit (nNOS and eNOS) lipid peroxidation based on its specific isoform origin. Group III showed significantly reduced mRNA levels of LTB4R2 (-63.7%), LTC4S (-35.9%) and iNOS (-60.2%) when compared with group II (P < 0.05, for all). The mRNA levels of nNOS was significantly increased (+37.4%), while eNOS was slightly increased (+2.1%) in group III when compared with group II (P < 0.05 and P = 0.467 respectively). CONCLUSION: Lazaroid U-74389G may represent an effective pharmacologic intervention in reducing lung ischemia-reperfusion injury following thoracoabdominal aortic occlusion.


Assuntos
Antioxidantes/farmacologia , Arteriopatias Oclusivas/complicações , Lesão Pulmonar/tratamento farmacológico , Pregnatrienos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Aorta Torácica , Arteriopatias Oclusivas/metabolismo , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Masculino , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/síntese química , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Suínos
3.
Br J Pharmacol ; 175(15): 3144-3161, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29723408

RESUMO

BACKGROUND AND PURPOSE: Sperm from many species share the sperm-specific Ca2+ channel CatSper that controls the intracellular Ca2+ concentration and, thereby, the swimming behaviour. A growing body of evidence suggests that the mechanisms controlling the activity of CatSper and its role during fertilization differ among species. A lack of suitable pharmacological tools has hampered the elucidation of the function of CatSper. Known inhibitors of CatSper exhibit considerable side effects and also inhibit Slo3, the principal K+ channel of mammalian sperm. The compound RU1968 was reported to suppress Ca2+ signaling in human sperm by an unknown mechanism. Here, we examined the action of RU1968 on CatSper in sperm from humans, mice, and sea urchins. EXPERIMENTAL APPROACH: We resynthesized RU1968 and studied its action on sperm from humans, mice, and the sea urchin Arbacia punctulata by Ca2+ fluorimetry, single-cell Ca2+ imaging, electrophysiology, opto-chemistry, and motility analysis. KEY RESULTS: RU1968 inhibited CatSper in sperm from invertebrates and mammals. The compound lacked toxic side effects in human sperm, did not affect mouse Slo3, and inhibited human Slo3 with about 15-fold lower potency than CatSper. Moreover, in human sperm, RU1968 mimicked CatSper dysfunction and suppressed motility responses evoked by progesterone, an oviductal steroid known to activate CatSper. Finally, RU1968 abolished CatSper-mediated chemotactic navigation in sea urchin sperm. CONCLUSION AND IMPLICATIONS: We propose RU1968 as a novel tool to elucidate the function of CatSper channels in sperm across species.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/fisiologia , Pregnatrienos/farmacologia , Espermatozoides/efeitos dos fármacos , Animais , Cálcio/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ouriços-do-Mar , Espermatozoides/fisiologia
4.
Int J Pharm ; 544(1): 265-277, 2018 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-29689367

RESUMO

The current study was designed to develop and optimize lazaroid loaded nano-structured lipid carriers (LAZ-NLCs) using design of experiment approach for enhancing lazaroid brain exposure. Response surface plots were used to determine the effects of independent variables (amount of PEGylating agent and liquid lipid) on dependent variables (particle size, zeta potential and encapsulation efficiency), while numerical optimization was used for optimizing LAZ-NLCs composition. The optimal LAZ-NLCs were spherical in shape with measured size of 172.3 ±â€¯3.54 nm, surface charge of -4.54 ±â€¯0.87 mV and encapsulation efficiency of 85.01 ±â€¯2.60%. The optimal LAZ-NLCs were also evaluated for hemolytic potential, storage stability and solid-state properties. The plasma pharmacokinetics along with brain and hepatic distributions of control lazaroid citrate solution and optimal LAZ-NLCs formulation were evaluated in Sprague-Dawley rats after the single bolus intravenous administration. The optimized LAZ-NLCs and the control lazaroid citrate solution had similar plasma pharmacokinetic profiles; however, differential organ bio-distributions were observed. The lazaroid exposure in brain was enhanced by two times with a decreased liver exposure by half for the NLCs group compared to the solution group.


Assuntos
Encéfalo/metabolismo , Portadores de Fármacos/administração & dosagem , Nanoestruturas/administração & dosagem , Pregnatrienos/administração & dosagem , Animais , Citratos/administração & dosagem , Citratos/farmacocinética , Portadores de Fármacos/farmacocinética , Composição de Medicamentos , Estabilidade de Medicamentos , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Lipídeos/administração & dosagem , Lipídeos/farmacocinética , Fígado/metabolismo , Masculino , Tamanho da Partícula , Pregnatrienos/farmacocinética , Ratos Sprague-Dawley , Distribuição Tecidual
5.
PLoS One ; 12(7): e0181521, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28727832

RESUMO

BACKGROUND: Surgeon-dependent factors such as experience and volume are associated with patient outcomes. However, it is unknown whether a surgeon's research productivity could be related to outcomes. The main aim of this study is to investigate the association between the surgeon's academic productivity and clinical outcomes following neurosurgical clipping of ruptured aneurysms. METHODS: We performed a post-hoc analysis of 3567 patients who underwent clipping of ruptured intracranial aneurysms in the randomized trials of tirilazad mesylate from 1990 to 1997. These trials included 162 centers and 156 surgeons from 21 countries. Primary and secondary outcomes were: Glasgow outcome scale score and mortality, respectively. Total publications, H-index, and graduate degrees were used as academic indicators for each surgeon. The association between outcomes and academic factors were assessed using a hierarchical logistic regression analysis, adjusting for patient covariates. RESULTS: Academic profiles were available for 147 surgeons, treating a total of 3307 patients. Most surgeons were from the USA (62, 42%), Canada (18, 12%), and Germany (15, 10%). On univariate analysis, the H-index correlated with better functional outcomes and lower mortality rates. In the multivariate model, patients under the care of surgeons with higher H-indices demonstrated improved neurological outcomes (p = 0.01) compared to surgeons with lower H-indices, without any significant difference in mortality. None of the other academic indicators were significantly associated with outcomes. CONCLUSION: Although prognostication following surgery for ruptured intracranial aneurysms primarily depends on clinical and radiological factors, the academic impact of the operating neurosurgeon may explain some heterogeneity in surgical outcomes.


Assuntos
Aneurisma Roto/cirurgia , Bibliometria , Aneurisma Intracraniano/cirurgia , Neurocirurgiões , Procedimentos Neurocirúrgicos , Editoração , Aneurisma Roto/tratamento farmacológico , Aneurisma Roto/mortalidade , Escolaridade , Feminino , Escala de Resultado de Glasgow , Humanos , Aneurisma Intracraniano/tratamento farmacológico , Aneurisma Intracraniano/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fármacos Neuroprotetores/uso terapêutico , Neurocirurgiões/educação , Pregnatrienos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
6.
Cardiovasc Hematol Disord Drug Targets ; 17(1): 24-27, 2017 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-28155601

RESUMO

AIM: This study compared the hematopoietic capacities of erythropoietin (Epo) and antioxidant drug U-74389G, based on 2 preliminary studies. The provided results on hematocrit levels augmentation were co-evaluated in a hypoxia reoxygenation protocol of an animal model. MATERIALS AND METHODS: Hematocrit levels were evaluated at the 60th reoxygenation min (for groups A, C and E) and at the 120th reoxygenation min (for groups B, D and F) in 60 rats. Groups A and B received no drugs, rats from groups C and D were administered with Epo; whereas rats from groups E and F were administered with U-74389G. RESULTS: The first preliminary study of Epo non-significantly increased the hematocrit levels by 0.24%+1.38% (p-value=0.8586). The second preliminary study of U-74389G significantly raised the hematocrit levels by 3.16%+1.33% (p-value=0.0196). These 2 studies were co-evaluated since they came from the same experimental setting. The outcome of the co-evaluation was that U-74389G has approximately 12.66-fold higher hematopoietic potency than Epo (p-value=0.0000). CONCLUSION: The anti-oxidant capacities of U-74389G provide satisfactory acute hematopoietic properties; presenting approximately 12.66-fold hematocrit level rise than epo (p-value=0.0000).


Assuntos
Antioxidantes/uso terapêutico , Eritropoetina/uso terapêutico , Hematócrito , Hematopoese/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Pregnatrienos/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Eritropoetina/farmacologia , Feminino , Humanos , Hipóxia/sangue , Hipóxia/complicações , Masculino , Pregnatrienos/farmacologia , Ratos Wistar , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/complicações
7.
J Surg Res ; 207: 164-173, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27979473

RESUMO

BACKGROUND: The adverse effects of myocardial ischemia and reperfusion during cardiopulmonary bypass (CPB) have been thoroughly described. Lazaroid U-74389G, a 21 aminosteroid, has been shown to attenuate ischemia and reperfusion injury and improve recovery in a variety of experimental models. METHODS: Sixteen male swine were randomly divided in two groups. All animals underwent 45 min of ischemic cardioplegic arrest, with U-74389G addition to the standard cardioplegic solution, whereas controls underwent the same procedure without U-74389G. Creatine kinase-MB isoenzyme (CK-MB) and cardiac troponin T levels were measured immediately before CPB (time point 0), during the ischemic period (time point 1) and 30 (time point 2), 60 (time point 3), and 120 (time point 4) min after reperfusion. Myocardial biopsies were obtained at time points 0 and 4. RESULTS: CK-MB levels (in U/L) at time points 0-4 were 205 (186-235) versus 219 (196-269; P = 0.72), 215 (167-248) versus 253 (193-339; P = 0.23), 234 (198-255) versus 338 (249-441; P = 0.02), 244 (217-272) versus 354 (269-496; P = 0.01), and 285 (230-321) versus 439 (432-530; P < 0.01) in lazaroid-treated animals versus controls, respectively. Cardiac troponin T levels (in ng/L) at time points 0-4 were 58 (26-287) versus 237 (26-395; P = 0.72), 129 (61-405) versus 265 (145-525; P = 0.23), 261 (123-467) versus 474 (427-1604; P = 0.04), 417 (204-750) versus 841 (584-1818; P = 0.11), and 643 (353-1259) versus 1600 (1378-2313; P < 0.01), respectively. Necrosis grades at time point 4 were 0.0 (0.0-1.0) versus 1.5 (1.0-2.0; P < 0.01) in lazaroid-treated animals versus controls, respectively. CONCLUSIONS: The present study, in addition to reconfirming the well-described adverse effects of CPB, demonstrates the efficacy of the newer generation lazaroid U-74389G in alleviating these effects.


Assuntos
Cardiotônicos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Pregnatrienos/uso terapêutico , Animais , Biomarcadores/metabolismo , Biópsia , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Necrose , Distribuição Aleatória , Suínos , Resultado do Tratamento
9.
J Pharm Biomed Anal ; 122: 90-7, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26848737

RESUMO

Lazaroids are potent inhibitors of lipid peroxidation, both in vitro and in vivo. Additionally, a member of the lazaroid family, U-74389G (LAZ) has been shown to have specific radio-protective and anti-proliferative effects. However, there is no quantitative analytical method developed for measuring the therapeutic levels of LAZ for the aforementioned effects. This article highlights the development and validation of a sensitive UPLC-MS/MS method for the quantification of LAZ, and its subsequent application in pharmacokinetic studies in rats with the lower limit of quantification (LLOQ) of 1.95 ng/mL. LAZ and internal standard diadzein (IS) were separated using ACQUITY UPLC(®) BEH C18 column. Gradient elution was used at a flow rate of 0.45 mL/min with mobile phases consisting of 0.1% formic acid in water and 0.1% formic in acetonitrile. LAZ (m/z 612→260) and IS (m/z 255→199) were detected by electrospray ionization (ESI) using multiple reaction monitoring (MRM) in a positive mode on QTRAP(®) 5500 System. The UPLC-MS/MS method was validated as per the US FDA Guidelines for Bio-analytical Validation. LAZ was extracted from rat plasma (100 µL) using protein precipitation by acetonitrile with mean recovery and matrix factor in range of 47.7-56.1%, and 85.6-89.4%, respectively. The calibration curve for LAZ was linear in the range of 1.95-250 ng/mL. The inter-day and intra-day accuracy and precision values for LLOQ, low, medium, high and very high concentration QC samples were within ±15%. LAZ was tested under different storage conditions, for short-term bench-top stability (1h and 3h at 25°C), long-term stability (1 month at -80°C), freeze-thaw cycle stability (1 cycle and 3 cycles) and stability of processed samples in auto-sampler (24h at 10°C) with stability values within ±15% range of nominal concentrations. The validated UPLC-MS/MS method was further applied to a pharmacokinetic study in rats after a single intravenous dose of LAZ at 5 mg/kg.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Pregnatrienos/química , Pregnatrienos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Calibragem , Estabilidade de Medicamentos , Limite de Detecção , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
10.
Mol Endocrinol ; 30(2): 173-88, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26745667

RESUMO

Glucocorticoid receptor (GR) gene mutations may cause familial or sporadic generalized glucocorticoid resistance syndrome. Most of the missense forms distribute in the ligand-binding domain and impair its ligand-binding activity and formation of the activation function (AF)-2 that binds LXXLL motif-containing coactivators. We performed molecular dynamics simulations to ligand-binding domain of pathologic GR mutants to reveal their structural defects. Several calculated parameters including interaction energy for dexamethasone or the LXXLL peptide indicate that destruction of ligand-binding pocket (LBP) is a primary character. Their LBP defects are driven primarily by loss/reduction of the electrostatic interaction formed by R611 and T739 of the receptor to dexamethasone and a subsequent conformational mismatch, which deacylcortivazol resolves with its large phenylpyrazole moiety and efficiently stimulates transcriptional activity of the mutant receptors with LBP defect. Reduced affinity of the LXXLL peptide to AF-2 is caused mainly by disruption of the electrostatic bonds to the noncore leucine residues of this peptide that determine the peptide's specificity to GR, as well as by reduced noncovalent interaction against core leucines and subsequent exposure of the AF-2 surface to solvent. The results reveal molecular defects of pathologic mutant receptors and provide important insights to the actions of wild-type GR.


Assuntos
Proteínas Mutantes/química , Proteínas Mutantes/genética , Mutação/genética , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/genética , Motivos de Aminoácidos , Sequência de Aminoácidos , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Dexametasona/farmacologia , Células HCT116 , Humanos , Leucina/química , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Mutantes/agonistas , Proteínas Mutantes/metabolismo , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Pregnatrienos/farmacologia , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Receptores de Glucocorticoides/agonistas , Eletricidade Estática , Termodinâmica , Transcrição Genética/efeitos dos fármacos
11.
Vestn Ross Akad Med Nauk ; (4): 408-12, 2015.
Artigo em Russo | MEDLINE | ID: mdl-26710522

RESUMO

OBJECTIVE: The aim of this experimental study was to examine the effect of the antioxidant drug U-74389G in a rat model of hypoxia-reoxygenation using the previously established protocol. Effects of treatments were evaluated by magnesium (Mg2+) levels in blood. METHODS: Non-randomized controlled study was performed. Mg2+ levels were determined in 60 min (groups A and C) and 120 min (groups B and D) after starting the reoxygenation. Groups A and B received no drugs, whereas rats from groups C and D were administered with U-74389G. RESULTS: 40 rats 16-18 weeks old of a mean weight of 2312 g were employed in the study. It is demonstrated that U-74389G administration did not alter the Mg2+ levels (decrease in Mg2+ concentration was 0.28±2.75%; p=0.917). Reoxygenation non-significantly increased the Mg2+ levels by 4.27±2.66% (p=0.107). Together, the U-74389G administration and reoxygenation non-significantly increased the Mg2+ levels by 0.36±1.64% (p=0.823). CONCLUSION: U-74389G administration, alone or in concert with reoxygenation did not significantly affect Mg2+ level in blood after experimental hypoxia in rats.


Assuntos
Hipóxia/tratamento farmacológico , Magnésio/sangue , Pregnatrienos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Feminino , Hipóxia/sangue , Ratos , Ratos Wistar , Traumatismo por Reperfusão/sangue
12.
In Vivo ; 29(5): 585-94, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26359418

RESUMO

BACKGROUND/AIM: The free radical-scavenging effects of the lazaroid U-74389G have been shown in several experimental models to protect the liver from ischemia/reperfusion (I/R), however, the mechanism of cytoprotection is not fully understood. Similar findings were observed when ascorbic acid was administered. This study investigates the effects of infusion of lazaroid U-74389G and ascorbic acid on cytokines and liver structure in a liver I/R rat model. MATERIALS AND METHODS: Sixty male Wistars rats, weighting 220-290 g, were used in the study. Six experimental groups were formed: Group 1 (control group): ischemia for 30 min and reperfusion for 60 min; group 2 (control group): ischemia for 30 min and reperfusion for 120 min; group 3: ischemia for 30 min, intraportal injection of ascorbic acid, and reperfusion for 60 min; group 4: ischemia for 30 min, ascorbic acid administration, and reperfusion for 120 min; group 5: ischemia for 30 min, U-74389G administration, and reperfusion for 60 min; and group 6: ischemia for 30 min, U-74389G administration, and reperfusion for 120 min. Tissue and blood sampling took place upon completion of each model's reperfusion. U-74389G was administered at 10 mg/kg animal body weight and ascorbic acid at 100 mg/kg. Anesthesia was induced with ketamine and xylazine. Surgery was performed through a midline laparotomy. The portal vein and the common hepatic artery were isolated and prepared for occlusion. Blood samples and wedge liver biopsies were taken to measure levels of liver enzymes, cytokines and for microscopic analysis upon completion of reperfusion once for each model. RESULTS: Histopathological evaluation revealed a statistically significant reduction in the degree of necrosis of liver tissue in the treated groups compared to the control groups 1 and 2 [groups 3, 5 (p=0.010) and 4, 6 (p<0.0005)]. On the other hand, tissue malondialdehyde levels (MDA) were statistically significantly increased only between control group 2 and groups 4, 6 (p<0.0005). There was no statistically significant difference in tumor necrosis factor-α between groups. As for liver enzymes, only alkaline phosphatase (ALP) and gamma-glutamyl transferase (gGT) were statistically significantly reduced in treated groups 3 and 5 (ALP: p=0.027, and gGT: p=0.002) and 4 and 6 (ALP: p=0.004, and gGT: p=0.015) compared to control groups 1 and 2. CONCLUSION: Based on histological data and the reduction of some of the liver enzymes, in spite of a rise of malondialdehyde, in this rat model, administration of U-74389G in liver ischemia/reperfusion (I/R) injury has potential in attenuating liver damage.


Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pregnatrienos/farmacologia , Traumatismo por Reperfusão/metabolismo , Animais , Antioxidantes/administração & dosagem , Ácido Ascórbico/administração & dosagem , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/metabolismo , Biomarcadores , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/irrigação sanguínea , Fígado/patologia , Testes de Função Hepática , Masculino , Malondialdeído/metabolismo , Necrose/tratamento farmacológico , Necrose/metabolismo , Necrose/patologia , Estresse Oxidativo/efeitos dos fármacos , Pregnatrienos/administração & dosagem , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia
13.
Neurochem Res ; 40(8): 1699-708, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26168778

RESUMO

Aluminium (Al) is neurotoxic primarily because of its interference with biological enzymes in key mechanisms of metabolic pathways. Mitochondria being a major site of reactive oxygen species (ROS) production, it seems that the oxidative damage to mitochondrial proteins may underlie the pathogenesis of Al induced neurodegeneration. The present study investigates the effectiveness of the anti-oxidant property of lazaroids (U-74500A), a known lipid peroxidation inhibitor as neuroprotective agent against Al induced neurotoxicity. Al chloride was administered orally at a dose level of 100 mg/kg body wt/day in water and U-74500A was administered at a dose of 0.25 mg/kg body wt i.p. in citrate buffer for a period of 8 weeks on alternate days. Following Al exposure there was a significant increase in lipid peroxidation (LPO), ROS levels and reduction in the activity of mitochondrial complexes in all the three regions of rat brain, i.e., cerebral cortex, mid brain, and cerebellum. This decrease in the activities of electron transport complexes in turn affected the ATP synthesis and ATP levels adversely in the mitochondria. These alterations were also depicted in the histology which shows signs of hypoxia, paucity of neurons in cortical region and loosening of fibers in the white matter. U-74500A co-administration was able to restore alterations in the LPO, ROS levels as well as all the three mitochondrial complexes and caspase expression. Therefore, it is suggested that 21-aminosteroids (lazaroids), by attenuating LPO and mitochondrial dysfunction, holds a promise as an agent that can potentially reduce Al-induced adverse effects in brain.


Assuntos
Compostos de Alumínio/envenenamento , Antioxidantes/farmacologia , Cloretos/envenenamento , Fármacos Neuroprotetores/farmacologia , Pregnatrienos/farmacologia , Cloreto de Alumínio , Animais , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
14.
J Steroid Biochem Mol Biol ; 152: 114-23, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25957738

RESUMO

BACKGROUND: Aortic valve calcification is characterized as the active process of aortic valve interstitial cells (AVICs), and considered as an inflammatory disease. As an antioxidant, the anti-inflammatory activity of Lazaroid has been exhibited in various models. We hypothesized that Lazaroid U-74389G would inhibit the osteoblastic differentiation of AVICs induced by IL-1ß. METHODS: Normal tricuspid aortic valve leaflets were collected from patients with acute aortic dissection (Type A) undergoing the Bentall procedure. AVICs were isolated and stimulated with IL-1ß in presence or absence of U-74389G in culture. Cell lysates were analyzed for osteogenic markers and nuclear factor-κB using real-time PCR and Immunoblotting. Culture media was analyzed for IL-6 and IL-8 with enzyme-linked immunosorbent assay. Alizarin Red Staining was adopted to demonstrate the calcium deposition. RESULTS: The expression of alkaline phosphatase and bone morphogenetic protein, accompanied by the production of IL-6 and IL-8, was up-regulated in response to IL-1ß and was inhibited by the addition of U-74389G. The NF-κB pathway was activated by IL-1ß and involved in the suppression of U-74389G on osteoblastic differentiation in AVICs. The negative effects of U-74389G on ostengenic gene expression and mineralization of AVICs were blocked by glucocorticoid receptor antagonist mifepristone and the NF-κB inhibitor Bay 11-7082. CONCLUSIONS: U-74389G inhibits the pro-osteogenic response to IL-1ß stimulation in AVICs. The osteoblastic differentiation and mineralization of AVICs were inhabited by U-74389G though the modulation of NF-κB activation, and this pathway could be potential therapeutic targets for medical treatment of calcified aortic valve disease.


Assuntos
Interleucina-1beta/farmacologia , Osteogênese/efeitos dos fármacos , Pregnatrienos/farmacologia , Receptores de Glucocorticoides/metabolismo , Fator de Transcrição RelA/antagonistas & inibidores , Fosfatase Alcalina/biossíntese , Valva Aórtica/citologia , Valva Aórtica/patologia , Estenose da Valva Aórtica/patologia , Proteínas Morfogenéticas Ósseas/biossíntese , Calcinose/patologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Mifepristona/farmacologia , Miócitos de Músculo Liso/metabolismo , Nitrilos/farmacologia , Osteoblastos/citologia , Fosforilação/efeitos dos fármacos , Receptores de Glucocorticoides/antagonistas & inibidores , Sulfonas/farmacologia , Valva Tricúspide/citologia
15.
Brain Res ; 1615: 98-105, 2015 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-25916578

RESUMO

Tumour necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) are important mediators of intracerebral haemorrhage (ICH) inflammatory response. Lazaroids, established antioxidants and neuroprotectants, have been studied in several brain pathologies. The present study was designed to investigate: a) TNF-α and IL-1ß changes, in neurons and b) U-74389G effects, 4 and 24h after haematoma induction in a porcine model of intracerebral haemorrhage. In twenty male landrace pigs (swines) aged 135-150 days old, autologous whole blood was injected around the right basal ganglia territory; in ten of the pigs the lazaroid compound U-74389G was administered. Brain TNF-α and IL-1ß immunopositive neurons were determined by immunoarray techniques at 4 and 24h timepoints. After the haematoma induction the number of TNF-α immunopositive neurons ipsilateral to the haematoma was significantly higher compared to the contralateral site at 4h (p<0.0005), while U-74389G significantly reduced the number of TNF-α immunopositive neurons, ipsilateral to the haematoma, at 4h (p=0.002); at 24h, TNF-α immunopositive neurons were found significantly lower in the control group ipsilateral to the haematoma in comparison to 4h timepoint(p<0.0005). The number of IL-1ß immunopositive neurons at 4h after the hematoma induction was significantly higher ipsilateral to the haematoma site (p<0.0005). U-74389G had no statistical significant effect. TNF-α and IL-1ß, increase in neurons, 4h after the haematoma induction, ipsilateral to the haematoma site. The administration of the antioxidant compound U-74389G, results in early (at 4h) decrease of TNF-α immunopositive neurons but shows no statistical significant effect to IL-1ß immunopossitive neurons.


Assuntos
Antioxidantes/administração & dosagem , Hemorragia Cerebral/metabolismo , Interleucina-1beta/metabolismo , Neurônios/metabolismo , Pregnatrienos/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismo , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Hemorragia Cerebral/prevenção & controle , Masculino , Neurônios/efeitos dos fármacos , Suínos
16.
World Neurosurg ; 84(1): 28-35, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25701766

RESUMO

Subarachnoid hemorrhage (SAH) remains a condition with suboptimal functional outcomes, especially in the young population. Pharmacotherapy has an accepted role in several aspects of the disease and an emerging role in several others. No preventive pharmacologic interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events after endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence-based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as statins have demonstrated early potential; however, they failed to provide significant evidence for the use in preventing DCI. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase 2 trial. Clazosentane, a potent endothelin receptor antagonist, did not translate to improve functional outcomes. Various other neuroprotective agents have been used to prevent DCI; however, the results have been, at best inconclusive. The prevention of DCI and improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by which DCI is propagated is clearly needed. In this article, we review the current pharmacologic approaches that have been evaluated in SAH and highlight the areas in which further research is needed.


Assuntos
Corticosteroides/uso terapêutico , Anticoagulantes/uso terapêutico , Isquemia Encefálica/prevenção & controle , Bloqueadores dos Canais de Cálcio/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Apoptose , Isquemia Encefálica/etiologia , Ensaios Clínicos como Assunto , Dexametasona/administração & dosagem , Dioxanos/administração & dosagem , Dioxanos/farmacologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Estrogênios/administração & dosagem , Estrogênios/efeitos adversos , Medicina Baseada em Evidências , Depuradores de Radicais Livres/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Sulfato de Magnésio/uso terapêutico , Nimodipina/uso terapêutico , Pregnatrienos/administração & dosagem , Progesterona/administração & dosagem , Progesterona/efeitos adversos , Piridinas/administração & dosagem , Piridinas/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Receptor de Endotelina A/efeitos dos fármacos , Hemorragia Subaracnóidea/complicações , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Tetrazóis/administração & dosagem , Tetrazóis/farmacologia
17.
Folia Med (Plovdiv) ; 57(3-4): 235-42, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27180351

RESUMO

UNLABELLED: The AIM of this experimental study was to evaluate the effect of the antioxidant drug "U-74389G" in a rat model of hypoxia reoxygenation (HR) using the previously established protocol. Effects of treatment were evaluated by mean red blood cell distribution width (RDW) levels. MATERIALS AND METHODS: 40 rats of a mean weight of 231.875 g were employed in the study. RDW levels were determined at 60 min (groups A and C) and at 120 min (groups B and D) after starting the reoxygenation. Groups A and B received no drugs, whereas rats from groups C and D were administered with U-74389G. RESULTS: demonstrated that U-74389G administration significantly decreased the RDW levels by 4.96% + 2.27% (p = 0.0175). Reoxygenation time non-significantly decreased the RDW levels by 0.27% + 2.41% (p = 0.8889). Together, U-74389G administration and reoxygenation time non-significantly decreased the RDW levels by 2.54% + 1.39% (p = 0.0679). CONCLUSIONS: U-74389G administration particulary in concert without reperfusion declines the RDW levels even within the short - time context of 1.5 hours reperfusion.


Assuntos
Antioxidantes/farmacologia , Índices de Eritrócitos/efeitos dos fármacos , Hipóxia/sangue , Pregnatrienos/farmacologia , Traumatismo por Reperfusão/sangue , Animais , Feminino , Oxigênio/sangue , Oxigênio/metabolismo , Ratos , Ratos Wistar
18.
Folia Med Cracov ; 55(1): 25-34, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26774629

RESUMO

AIM: The aim of this experimental study was to examine the effect of the antioxidant drug "U-74389G", on rat model and particularly in a hypoxia-reoxygenation protocol. The beneficial effect or non-effectiveness of that molecule were studied hematologically using blood mean platelet count. Results were that U-74389G administration interacted or not with reoxygenation time decreased the platelet count by 6.12% ± 3.58% (p = 0.0857) and 12.83% ± 5.79% (p = 0.0303) respectively. CONCLUSIONS: U-74389G administration interacted or not with reoxygenation time decreases the platelet count within short-term time of 2 hours by different significance levels.


Assuntos
Antioxidantes/farmacologia , Depuradores de Radicais Livres/farmacologia , Hipóxia/tratamento farmacológico , Pregnatrienos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/administração & dosagem , Modelos Animais de Doenças , Depuradores de Radicais Livres/administração & dosagem , Hipóxia/sangue , Contagem de Plaquetas , Pregnatrienos/administração & dosagem , Ratos , Ratos Wistar , Traumatismo por Reperfusão/sangue
19.
J Surg Res ; 193(2): 667-74, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25277360

RESUMO

BACKGROUND: Crohn disease is still incurable. Compounds with anti-inflammatory and/or antioxidative effects are tested in various preclinical models of the disease. Our aim was to investigate the effects of sildenafil and lazaroid U-74389G in an experimental rat model of trinitrobenzenesulfonic acid-induced colitis. MATERIALS AND METHODS: Trinitrobenzenesulfonic acid was instilled into the colon of all male Wistar rats except for the rats belonging to the first group. For 6 days, the animals in group 3 were administered daily sildenafil orally, the rats in group 4 were administered daily U-74389G intravenously, and the rats in group 5 were coadministered daily sildenafil orally and intravenous U-74389G. The rats in groups 1 and 2 were not administered any treatment. During the study, the weights were recorded as a marker of clinical condition. The colon damage was evaluated using macroscopic colon mucosal damage index (CMDI), microscopic (Geboes score), and biochemical methods (tissue tumor necrosis factor [TNF]-α and malondialdehyde [MDA]). RESULTS: Sildenafil reduced TNF-α tissue levels and increased body weight. U-74389G reduced TNF-α, the macroscopic index of mucosal damage score (CMDI) and increased body weight. The combined treatment with sildenafil and U-74389G reduced tissue levels of both TNF-α and MDA, lowered CMDI and microscopic Geboes score, and increased body weight. CONCLUSIONS: U-74389G demonstrated a significant anti-inflammatory activity related to its ability to reduce colonic TNF-α, CMDI score, and improve weight change. We confirmed that sildenafil has anti-inflammatory capacity by reducing colonic TNF-α and by improving body weight. Finally, the combined treatment showed superior effects by reducing colonic TNF-α, colonic MDA, CMDI score, Geboes score, and by improving weight.


Assuntos
Antioxidantes/uso terapêutico , Colite/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/uso terapêutico , Pregnatrienos/uso terapêutico , Sulfonas/uso terapêutico , Animais , Colite/induzido quimicamente , Colite/patologia , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Masculino , Malondialdeído/metabolismo , Purinas/uso terapêutico , Distribuição Aleatória , Ratos Wistar , Citrato de Sildenafila , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/metabolismo
20.
Int J Surg ; 13: 42-48, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25438077

RESUMO

BACKGROUND: The readmission of molecular oxygen into an ischemic tissue promotes the oxidation of resuscitated tissue with certain pathophysiologic mechanisms. MATERIALS AND METHODS: Twenty four pigs (male or female) were randomized in this study. The animals were allocated to four groups with an equal number (n = 6) in each group: (1) control group-ischemia for 30 min and reperfusion for 60 min. (2) control group-ischemia for 30 min and reperfusion for 120 min. (3) ischemia for 30 min and immediate iv injection of lazaroid U-74389G and reperfusion for 60 min. (4) ischemia for 30 min and immediate iv injection of lazaroid U-74389G and reperfusion for 120 min. RESULTS: We investigated further the role of an antioxidant molecule such as U-74389G and we concluded that there is statistically significant relation in MDA (malondialdeyde), TNF -α (tumor necrosis factor-α) measurement in tissue, while the histological score in the groups that the lazaroid was administered was improved. CONCLUSIONS: In many emergency clinical situations, such as reperfusion of the intestine, the role of U-74389G can be protective.


Assuntos
Antioxidantes/uso terapêutico , Pregnatrienos/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Feminino , Masculino , Malondialdeído/sangue , Modelos Teóricos , Pregnatrienos/farmacologia , Traumatismo por Reperfusão/fisiopatologia , Suínos , Fator de Necrose Tumoral alfa
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