RESUMO
Mild hyperbaric oxygen therapy (mHBOT) is an adjuvant therapy used in conditions where tissue oxygenation is reduced and is implemented using pressures less than 1.5 ATA and 100% O2 (instead of the classical HBOT at 1.9-3 ATA) which results in cheaper, easier to implement, and equally effective. mHBOT is offered for wellness and beauty and as an anti-aging strategy, in spite of the absence of studies on the cardiovascular system. Consequently, we investigated the impact of mHBOT on the cardiovascular system. Mechanical and energetic parameters of isolated heart submitted to ischemia/reperfusion injury and arterial contractile response from mHBOT-exposed rats were evaluated. In the heart, mHBOT increased pre-ischemic velocity of contraction and ischemic end-diastolic pressure and developed pressure and contractile economy during reperfusion. mHBOT decreased infarct size and increased the plasma nitrite levels. In the artery, mHBOT increased acetylcholine sensitivity. mHBOT protects the heart during ischemia/reperfusion and affects vascular relaxation.
Assuntos
Oxigenoterapia Hiperbárica , Traumatismo por Reperfusão Miocárdica , Ratos Wistar , Vasodilatação , Animais , Oxigenoterapia Hiperbárica/métodos , Ratos , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Coração/fisiologia , Coração/fisiopatologia , Contração MiocárdicaRESUMO
RESUMEN Introducción: En nuestro laboratorio hemos desarrollado implantes subcutáneos de carvedilol capaces de mantener niveles plasmáticos sostenidos del β-bloqueante durante 3 semanas. Objetivo: Evaluación de la liberación in vivo y la eficacia cardioprotectora de implantes subcutáneos de carvedilol desarrollados con poliepsilon- caprolactona (PCL) y Soluplus (SP) en ratas espontáneamente hipertensas (REH). Materiales y métodos: Se utilizaron 12 REH macho (250-300 g), a las cuales se colocó un implante subcutáneo cada 3 semanas de PCL: SP 100:50 mg (control, n = 6) o carvedilol: PCL:SP (100mg:100mg:50mg) (carvedilol, n = 6). Se evaluó el perfil plasmático y el efecto sobre la presión arterial sistólica (PAS) durante 62 días. Al final del tratamiento, se realizaron determinaciones ecocardiográficas y la medición de la PAS y. la presión arterial media (PAM) directas. Resultados: El grupo que recibió el implante conteniendo 100 mg de carvedilol presentó concentraciones plasmáticas del fármaco en el rango de 100- 500 ng/mL a lo largo de 62 días de tratamiento, luego del cual la PAS fue 20 mmHg menor que en el grupo control (217 ± 3 mmHg vs. 237 ± 6 mmHg; p <0,05). Las PAS y PAM directas fueron significativamente menores el grupo tratado que en el control. El implante de carvedilol 100 mg redujo la variabilidad de la presión arterial (VPA) de corto plazo en comparación con el control. Parámetros ecocardiográficos como la fracción de eyección del ventrículo izquierdo (FEVI), fracción de acortamiento, y relación E/A fueron significativamente mayores en las ratas tratadas. El peso del VI fue menor en las ratas que recibieron el implante con carvedilol. Conclusión: Los implantes conteniendo CAR/PCL/SP (100:100:50) mg aportan niveles plasmáticos terapéuticos de carvedilol y estables durante el transcurso del tratamiento, los cuales se correlacionan con una disminución significativa y sostenida de los valores de PA indirecta. El tratamiento con los implantes de carvedilol logró atenuar los valores de PA directa y su variabilidad en las REH. Se demostró que el tratamiento con los implantes ejerció un efecto cardioprotector evidenciado en el ecocardiograma y por una reducción de la hipertrofia ventricular izquierda.
ABSTRACT Background: In our laboratory, we have developed subcutaneous implants of carvedilol capable of maintaining stable concentrations of the β-blocker during 3 weeks. Objective: The aim of this study was to evaluate the in vivo release and the cardioprotective efficacy of subcutaneous implants of carvedilol developed with poly-epsilon-caprolactone (PCL) and Soluplus (SP) polymers in spontaneously hypertensive rats (SHR). Methods: Twelve spontaneously hypertensive male rats (250-300 g) underwent placement of subcutaneous implant of PCL:SP 100:50 mg (control group, n=6) or carvedilol:PCL:SP (100mg:100mg:50mg) (carvedilol group, n=6), every 3 weeks. The plasma profile of each implant and its effect on systolic blood pressure (SBP) was evaluated for 62 days. At the end of treatment, echocardiographic parameters were determined, and direct SBP and direct mean arterial pressure (MAP) were measured. Results: The group that received the implant containing 100 mg of carvedilol presented plasma concentrations of the drug in the range of 100- 500 ng/mL throughout 62 days of treatment, after which the SBP was 20 mmHg lower than in the control group (217±3 mm Hg vs. 237±6 mm Hg; p <0.05). Direct SBP and MAP were significantly lower in the treated group than in the control group. The implant loaded with carvedilol 100 mg reduced short-term blood pressure variability (BPV) in SHR compared with the control group. Echocardiographic parameters as left ventricular ejection fraction (LVEF), shortening fraction and E/A ratio were significantly greater in treated rats. Left ventricular weight was lower in the rats with carvedilol implant. Conclusion: Implants containing CAR/PCL/SP (100:100:50) mg provide therapeutic and stable plasma levels of carvedilol during treatment, which correlate with a significant and sustained decrease in indirect BP values. Treatment with carvedilol implants attenuated dirct BP values and blood pressure variability in SHR. Treatment with implant produced cardioprotective effects evidenced in the echocardiogram by a reduction in left ventricular hypertrophy.
RESUMO
Metabolic syndrome is considered the precursor of type 2 diabetes mellitus. Tuberculosis is a leading infection that constitutes a global threat remaining a major cause of morbi-mortality in developing countries. People with type 2 diabetes mellitus are more likely to suffer from infection with Mycobacterium tuberculosis. For both type 2 diabetes mellitus and tuberculosis, there is pulmonary production of anti-inflammatory glucocorticoids mediated by the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). The adrenal hormone dehydroepiandrosterone (DHEA) counteracts the glucocorticoid effects of cytokine production due to the inhibition of 11ß-HSD1. Late advanced tuberculosis has been associated with the suppression of the Th1 response, evidenced by a high ratio of cortisol/DHEA. In a murine model of metabolic syndrome, we determined whether DHEA treatment modifies the pro-inflammatory cytokines due to the inhibition of the 11ß-HSD1 expression. Since macrophages express 11ß-HSD1, our second goal was incubating them with DHEA and Mycobacterium tuberculosis to show that the microbicide effect was increased by DHEA. Enoyl-acyl carrier protein reductase (InhA) is an essential enzyme of Mycobacterium tuberculosis involved in the mycolic acid synthesis. Because 11ß-HSD1 and InhA are members of a short-chain dehydrogenase/reductase family of enzymes, we hypothesize that DHEA could be an antagonist of InhA. Our results demonstrate that DHEA has a direct microbicide effect against Mycobacterium tuberculosis; this effect was supported by in silico docking analysis and the molecular dynamic simulation studies between DHEA and InhA. Thus, DHEA increases the production of pro-inflammatory cytokines in the lung, inactivates GC by 11ß-HSD1, and inhibits mycobacterial InhA. The multiple functions of DHEA suggest that this hormone or its synthetic analogs could be an efficient co-adjuvant for tuberculosis treatment.
Assuntos
Anti-Infecciosos , Diabetes Mellitus Tipo 2 , Síndrome Metabólica , Mycobacterium tuberculosis , Tuberculose , Humanos , Camundongos , Animais , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desidroepiandrosterona/uso terapêutico , Glucocorticoides/metabolismo , Comorbidade , Tuberculose/tratamento farmacológico , CitocinasRESUMO
Phytochemical electrophiles are drawing significant attention due to their properties to modulate signaling pathways related to cellular homeostasis. The aim of this study was to develop new tools to examine the electrophilic activity in food and predict their beneficial effects on health. We developed a spectrophotometric assay based on the nitrobenzenethiol (NBT) reactivity, as a thiol-reactive nucleophile, to screen electrophiles in tomato fruits. The method is robust, simple, inexpensive, and could be applied to other types of food. We quantified the electrophile activity in a tomato collection and associated this activity with the pigment composition. Thus, we identified lycopene, ß- and γ-carotenes, 16 by-products of carotenoid oxidation and 18 unknown compounds as NBT-reactive by HPLC-MS/MS. The potential benefits of NBT-reactive compounds on health were evaluated in the in vivo model of C. elegans where they activated the SKN-1/Nrf2 pathway, evidencing the ability of electrophilic compounds to induce a biological response.
Assuntos
Proteínas de Caenorhabditis elegans , Solanum lycopersicum , Animais , Caenorhabditis elegans/genética , Proteínas de Ligação a DNA , Suplementos Nutricionais , Fator 2 Relacionado a NF-E2/genética , Espectrometria de Massas em Tandem , Fatores de TranscriçãoRESUMO
Tuberculosis (TB) is the leading cause of death from a single bacterial infectious agent and is one of the most relevant issues of public health. Another pandemic disease is type II diabetes mellitus (T2D) that is estimated to affect half a billion people in the world. T2D is directly associated with obesity and a sedentary lifestyle and is frequently associated with immunosuppression. Immune dysfunction induced by hyperglycemia increases infection frequency and severity. Thus, in developing countries the T2D/TB co-morbidity is frequent and represents one of the most significant challenges for the health-care systems. Several immunoendocrine abnormalities are occurring during the chronic phase of both diseases, such as high extra-adrenal production of active glucocorticoids (GCs) by the activity of 11-ß-hydroxysteroid dehydrogenase type 1 (11-ßHSD1). 11-ßHSD1 catalyzes the conversion of inactive cortisone to active cortisol or corticosterone in lungs and liver, while 11-ß-hydroxysteroid dehydrogenase type 2 (11-ßHSD2) has the opposite effect. Active GCs have been related to insulin resistance and suppression of Th1 responses, which are deleterious factors in both T2D and TB. The anabolic adrenal hormone dehydroepiandrosterone (DHEA) exerts antagonistic effects on GC signaling in immune cells and metabolic tissues; however, its anabolic effects prohibit its use to treat immunoendocrine diseases. 16α-bromoepiandrosterone (BEA) is a water miscible synthetic sterol related to DHEA that lacks an anabolic effect while amplifying the immune and metabolic properties with important potential therapeutic uses. In this work, we compared the expression of 11-ßHSD1 and the therapeutic efficacy of BEA in diabetic mice infected with tuberculosis (TB) (T2D/TB) with respect to non-diabetic TB-infected mice (TB). T2D was induced by feeding mice with a high-fat diet and administering a single low-dose of streptozotocin. After 4 weeks of T2D establishment, mice were infected intratracheally with a high-dose of Mycobacterium tuberculosis strain H37Rv. Then, mice were treated with BEA three times a week by subcutaneous and intratracheal routes. Infection with TB increased the expression of 11-ßHSD1 and corticosterone in the lungs and liver of both T2D/TB and TB mice; however, T2D/TB mice developed a more severe lung disease than TB mice. In comparison with untreated animals, BEA decreased GC and 11-ßHSD1 expression while increasing 11-ßHSD2 expression. These molecular effects of BEA were associated with a reduction in hyperglycemia and liver steatosis, lower lung bacillary loads and pneumonia. These results uphold BEA as a promising effective therapy for the T2D/TB co-morbidity.
Assuntos
Androsterona/farmacologia , Antituberculosos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Tuberculose/tratamento farmacológico , 11-beta-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Comorbidade , Corticosterona/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Hidrocortisona/metabolismo , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/metabolismoRESUMO
ß-Adrenergic blockers are no longer recommended as first-line therapy due to the reduced cardioprotection of traditional ß-blockers compared with other antihypertensive drugs. It is unknown whether third-generation ß-blockers share the limitations of traditional ß-blockers. The aim of the present study was to compare the effects of nebivolol or atenolol on central and peripheral systolic blood pressure (SBP) and its variability and target organ damage (TOD) in N-nitro-L-arginine methyl ester (L-NAME) hypertensive rats. Male Wistar rats were treated with L-NAME for 8 weeks together with oral administration of nebivolol 30 mg/kg (n = 8), atenolol 90 mg/kg (n = 8), or vehicle (n = 8). The control group was composed of vehicle-treated Wistar rats. SBP and its variability, as well as echocardiographic parameters, were assessed during the last 2 weeks of treatment. Tissue levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor ß (TGF-ß), and histopathological parameters were evaluated in the left ventricle and aorta. Nebivolol had a greater ability than atenolol to decrease central SBP and mid-term and short-term blood pressure variability (BPV) in L-NAME rats. Echocardiographic analysis showed that nebivolol was more effective than atenolol on E/A wave ratio normalization. Compared with atenolol treatment, nebivolol had a greater protective effect on different TOD markers, inducing a decrease in collagen deposition and a reduction in the proinflammatory cytokines IL-6 and TNF-α in the left ventricle and aorta. Our findings suggest that the adverse hemodynamic profile and the reduced cardiovascular protection reported with traditional ß-blockers must not be carried forward to third-generation ß-blockers.
Assuntos
Atenolol , Hipertensão , Nebivolol , Animais , Anti-Hipertensivos/farmacologia , Atenolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Hipertensão/tratamento farmacológico , Masculino , Nebivolol/farmacologia , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
A close relationship between angiotensin II (ANG II) and the renal dopaminergic system (RDS) has been reported. Our aim was to study whether renal dopamine and ANG II can interact to modify renal sodium handling and then to elucidate the related mechanism. Anesthetized male Sprague-Dawley rats were used in experiments. ANG II, exogenous dopamine, and decynium-22 (or D-22, an isocyanine that specifically blocks electrogenic organic cation transporters, OCTs), were infused in vivo for 120 min. We analyzed renal and hemodynamic parameters, renal Na+, K+-ATPase levels, OCT activity, and urinary dopamine concentrations. We also evaluated the expression of D1 receptor, electroneutral organic cation transporters (OCTNs), and OCTs. ANG II decreased renal excretion of sodium in the presence of exogenous dopamine, increased Na+, K+-ATPase activity, and decreased the urinary dopamine concentration. D-22 treatment exacerbated the ANG II-mediated decrease in renal excretion of sodium and dopamine urine excretion but did not modify ANG II stimulation of Na+, K+-ATPase activity. The infusion of ANG II did not affect the expression of D1 receptor, OCTs, or OCTNs. However, the activity of OCTs was diminished by the presence of ANG II. Although ANG II did not alter the expression of D1 receptor, OCTs, and OCTNs in renal tissues, it modified the activity of OCTs and thereby decreased the urinary dopamine concentration, showing a novel mechanism by which ANG II decreases dopamine transport and its availability in the tubular lumen to stimulate D1 receptor. This study demonstrates a relationship between ANG II and dopamine, where both agents counteract their effects on sodium excretion.
Assuntos
Angiotensina II , Cátions , Rim , Adenosina Trifosfatases/metabolismo , Angiotensina II/farmacologia , Animais , Cátions/metabolismo , Dopamina/metabolismo , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Sódio/metabolismoRESUMO
BACKGROUND: Chlorogenic acid (CGA) is a polyphenol widely distributed in plants and plant-derived food with antioxidant and protective activities against cell stress. Caenorhabditis elegans is a model organism particularly useful for understanding the molecular and biochemical mechanisms associated with aging and stress in mammals. In C. elegans, CGA was shown to improve resistance to thermal, while the underlying mechanisms that lead to this effect require further understanding. PURPOSE: The present study was conducted to investigate the underlying molecular mechanisms behind CGA response conferring thermotolerance to C. elegans. METHODS AND RESULTS: Signaling pathways that could be involved in the CGA-induced thermotolerance were evaluated in C. elegans strains with loss-of-function mutation. CGA-induced thermotolerance required hypoxia-inducible factor HIF-1 but no insulin pathway. CGA exposition (1.4⯵M CGA for 18â¯h) before thermal stress treatment increased HIF-1 levels and activity. HIF-1 activation could be partly attributed to an increase in radical oxygen species and a decrease in superoxide dismutase activity. In addition, CGA exposition before thermal stress also increased autophagy just as hormetic heat condition (HHC), worms incubated at 36 °C for 1â¯h. RNAi experiments evidenced that autophagy was increased by CGA via HIF-1, heat-shock transcription factor HSF-1 and heat-shock protein HSP-16 and HSP-70. In contrast, autophagy induced by HHC only required HSF-1 and HSP-70. Moreover, suppression of autophagy induction showed the significance of this process for adapting C. elegans to cope with thermal stress. CONCLUSION: This study demonstrates that CGA-induced thermotolerance in C. elegans is mediated by HIF-1 and downstream, by HSF-1, HSPs and autophagy resembling HHC.
Assuntos
Autofagia/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Ácido Clorogênico/farmacologia , Proteínas de Choque Térmico/metabolismo , Fatores de Transcrição/metabolismo , Animais , Antioxidantes/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Ácido Clorogênico/química , Proteínas de Choque Térmico/genética , Resposta ao Choque Térmico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Termotolerância/efeitos dos fármacos , Fatores de Transcrição/genéticaRESUMO
Methyl gallate is a gallotannin widely distributed in nature. Previous studies have demonstrated its antioxidant, anti-inflammatory, antimicrobial and anti-tumor activities. In the present study, the activity of methyl gallate on experimental models of inflammatory bowel disease has been investigated. Experimental colitis was induced in Sprague-Dawley rats through the intracolonic instillation of an acetic acid solution (2 mL, 4% v/v). Methyl gallate (100 and 300 mg/kg, p.o.) and the reference drug mesalazine (100 mg/kg, p.o.) were tested. Methyl gallate induced a significant reduction in the colon weight/length ratio and macroscopic lesion score. Besides, the malondialdehyde content and the GSSG/GSH ratio were remarkably decreased. Furthermore, the administration of methyl gallate reduced the expression of COX2, IL-6, TNFα and the severity of microscopic tissue damage induced by acetic acid, while the mean goblet cell density was significantly higher in both the group treated with methyl gallate and the one treated with mesalazine, in comparison with untreated animals. The Na+K+ATPase pump activity was recovered in treated groups (control: 827.2 ± 59.6, colitis: 311.6 ± 54.8, methyl gallate 100 mg/kg: 642.2 ± 175.0, methyl gallate 300 mg/kg: 809.7 ± 100.6, mesalazine: 525.3 ± 81.7). Methyl gallate was also found to induce a significant reduction in the castor oil-induced intestinal motility in Swiss mice, decreasing the peristalsis by 74.5 and 58.82% at 100 and 300 mg/kg p.o., respectively. This compound also antagonized the jejunum contractions induced by Ach and CaCl2. This study demonstrates that methyl gallate exerts beneficial effects in a preclinical model of intestinal disorders.
Assuntos
Colite/induzido quimicamente , Colite/tratamento farmacológico , Ácido Gálico/análogos & derivados , Extratos Vegetais/uso terapêutico , Ácido Acético/toxicidade , Animais , Colite/patologia , Relação Dose-Resposta a Droga , Feminino , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Camundongos , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Resultado do TratamentoRESUMO
PURPOSE: Zinc restriction during fetal and postnatal development could program cardiovascular diseases in adulthood. The aim of this study was to determine the effects of zinc restriction during fetal life, lactation, and/or post-weaning growth on cardiac inflammation, apoptosis, oxidative stress, and nitric oxide system of male and female adult rats. METHODS: Wistar rats were fed a low- or a control zinc diet during pregnancy and up to weaning. Afterward, offspring were fed either a low- or a control zinc diet until 81 days of life. IL-6 and TNF-α levels, TUNEL assay, TGF-ß1 expression, thiobarbituric acid-reactive substances that determine lipoperoxidation damage, NADPH oxidase-dependent superoxide anion production, antioxidant and nitric oxide synthase activity, mRNA and protein expression of endothelial nitric oxide synthase, and serine1177 phosphorylation isoform were determined in left ventricle. RESULTS: Zinc deficiency activated apoptotic and inflammatory processes and decreased TGF-ß1 expression and nitric oxide synthase activity in cardiac tissue of both sexes. Male zinc-deficient rats showed no changes in endothelial nitric oxide synthase expression, but a lower serine1177 phosphorylation. Zinc deficiency induced an increase in antioxidant enzymes activity and no differences in lipoperoxidation products levels in males. Females were less sensitive to this deficiency exhibiting lower increase in apoptosis, lower decrease in expression of TGF-ß1, and higher antioxidant and nitric oxide enzymes activities. A zinc-adequate diet during postnatal life reversed most of these mechanisms. CONCLUSION: Prenatal and postnatal zinc deficiency induces alterations in cardiac apoptotic, inflammatory, oxidative, and nitric oxide pathways that could predispose the onset of cardiovascular diseases in adult life.
Assuntos
Deficiências Nutricionais/fisiopatologia , Desenvolvimento Fetal , Lactação , Fenômenos Fisiológicos da Nutrição Materna , Miocardite/etiologia , Estresse Oxidativo , Zinco/deficiência , Animais , Apoptose , Biomarcadores/sangue , Biomarcadores/metabolismo , Vasos Coronários/imunologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Deficiências Nutricionais/imunologia , Deficiências Nutricionais/metabolismo , Deficiências Nutricionais/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Regulação Enzimológica da Expressão Gênica , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Masculino , Miométrio/imunologia , Miométrio/metabolismo , Miométrio/patologia , Miométrio/fisiopatologia , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Gravidez , Distribuição Aleatória , Ratos Wistar , DesmameRESUMO
Metabolic syndrome is an array of closely metabolic disorders that includes glucose intolerance/insulin resistance, central obesity, dyslipidemia, and hypertension. Fructose, a highly lipogenic sugar, has profound metabolic effects in adipose tissue, and has been associated with the etiopathology of many components of the metabolic syndrome. In adipocytes, the enzyme 11 ß-HSD1 amplifies local glucocorticoid production, being a key player in the pathogenesis of central obesity and metabolic syndrome. 11 ß-HSD1 reductase activity is dependent on NADPH, a cofactor generated by H6PD inside the endoplasmic reticulum. Our focus was to explore the effect of fructose overload on epididymal white adipose tissue (EWAT) machinery involved in glucocorticoid production and NADPH and oxidants metabolism. Male Sprague-Dawley rats fed with a fructose solution (10% (w/v) in tap water) during 9 weeks developed some characteristic features of metabolic syndrome, such as hypertriglyceridemia, and hypertension. In addition, high levels of plasma and EWAT corticosterone were detected. Activities and expressions of H6PD and 11 ß-HSD1, NAPDH content, superoxide anion production, expression of NADPH oxidase 2 subunits, and indicators of oxidative metabolism were measured. Fructose overloaded rats showed an increased potential in oxidant production respect to control rats. In parallel, in EWAT from fructose overloaded rats we found higher expression/activity of H6PD and 11 ß-HSD1, and NADPH/NADP+ ratio. Our in vivo results support that fructose overload installs in EWAT conditions favoring glucocorticoid production through higher H6PD expression/activity supplying NADPH for enhanced 11 ß-HSD1 expression/activity, becoming this tissue a potential extra-adrenal source of corticosterone under these experimental conditions.
Assuntos
Tecido Adiposo Branco/metabolismo , Corticosterona/metabolismo , Frutose/efeitos adversos , NADP/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Pressão Sanguínea , Peso Corporal , Corticosterona/sangue , Ingestão de Alimentos , Epididimo/efeitos dos fármacos , Epididimo/metabolismo , Frutose/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , NADPH Oxidase 2/metabolismo , Ratos Sprague-DawleyRESUMO
The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects.
Assuntos
Fator Natriurético Atrial/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Dopamina/metabolismo , Sódio/metabolismo , Animais , Transporte Biológico , Membrana Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Diurese/efeitos dos fármacos , Dopamina/urina , Rim/metabolismo , Túbulos Renais/metabolismo , Masculino , Natriurese/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Potential nutraceutical properties of hydrophilic antioxidants in fruits of tomato landraces collected in Andean valleys were characterised. Antioxidant metabolites were measured by HPLC-DAD-MS/MS in mature fruits and their biological activities were assessed by in vitro and in vivo methods. In vitro antioxidant capacities were established by TEAC and FRAP methods. For in vivo biological activities we used a procedure based on Caenorhabditis elegans subjected to thermal stress. In addition, Saccharomyces cerevisiae was also used as a rapid screening system to evaluate tomato antioxidant capacity. All tomato accessions displayed significant differences regarding metabolic composition, biological activity and antioxidant capacity. Metabolite composition was associated with geographical origin and fruit size. Antioxidant activities showed significant association with phenolic compounds, such as caffeoylquinic acids, ferulic acid-O-hexosides and rutin. Combination of in vitro and in vivo methods applied here allowed evaluation of the variability in nutraceutical properties of tomato landraces, which could be applied to other fruits or food products.
Assuntos
Antioxidantes/análise , Frutas/química , Solanum lycopersicum/química , Animais , Antioxidantes/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Ácidos Cumáricos/análise , Ácidos Cumáricos/farmacologia , Ácido Quínico/análogos & derivados , Ácido Quínico/análise , Ácido Quínico/farmacologia , Rutina/análise , Rutina/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , América do Sul , Espectrometria de Massas em TandemRESUMO
Tocopherol, a compound with vitamin E (VTE) activity, is a conserved constituent of the plastidial antioxidant network in photosynthetic organisms. The synthesis of tocopherol involves the condensation of an aromatic head group with an isoprenoid prenyl side chain. The latter, phytyl diphosphate, can be derived from chlorophyll phytol tail recycling, which depends on phytol kinase (VTE5) activity. How plants co-ordinate isoprenoid precursor distribution for supplying biosynthesis of tocopherol and other prenyllipids in different organs is poorly understood. Here, Solanum lycopersicum plants impaired in the expression of two VTE5-like genes identified by phylogenetic analyses, named SlVTE5 and SlFOLK, were characterized. Our data show that while SlFOLK does not affect tocopherol content, the production of this metabolite is >80% dependent on SlVTE5 in tomato, in both leaves and fruits. VTE5 deficiency greatly impacted lipid metabolism, including prenylquinones, carotenoids, and fatty acid phytyl esters. However, the prenyllipid profile greatly differed between source and sink organs, revealing organ-specific metabolic adjustments in tomato. Additionally, VTE5-deficient plants displayed starch accumulation and lower CO2 assimilation in leaves associated with mild yield penalty. Taken together, our results provide valuable insights into the distinct regulation of isoprenoid metabolism in leaves and fruits and also expose the interaction between lipid and carbon metabolism, which results in carbohydrate export blockage in the VTE5-deficient plants, affecting tomato fruit quality.
Assuntos
Vias Biossintéticas , Regulação para Baixo , Metabolismo dos Lipídeos , Especificidade de Órgãos , Proteínas de Plantas/metabolismo , Solanum lycopersicum/enzimologia , Tocoferóis/metabolismo , Vias Biossintéticas/genética , Metabolismo dos Carboidratos/genética , Clorofila/metabolismo , Regulação para Baixo/genética , Ésteres/metabolismo , Frutas/metabolismo , Gases/metabolismo , Regulação da Expressão Gênica de Plantas , Técnicas de Silenciamento de Genes , Genes de Plantas , Metabolismo dos Lipídeos/genética , Solanum lycopersicum/genética , Mutação/genética , Fotossíntese/genética , Complexo de Proteína do Fotossistema II/metabolismo , Fitol/metabolismo , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas , Prenilação , Interferência de RNA , Solubilidade , Amido/metabolismoRESUMO
Identificar el manejo de la infección por Helicobacter pylori usado por los gastroenterólogos peruanos mediante una encuesta. Material y métodos: Se presentó una encuesta sobre el manejo de Helicobacter pylori a los gastroenterólogos. Resultados: Se obtuvo 177 encuestas válidas (29,6% de la población). Entre los resultados principales se observó que 77,4% usa la endoscopía digestiva alta + biopsia (histología) para el diagnóstico, 95,5% opta por un inhibidor de la bomba de protones + amoxicilina + claritromicina como tratamiento de primera línea y 50,0% revalúa a sus pacientes para determinar erradicación 4-6 semanas luego de culminarlo. Conclusiones: La mayoría de gastroenterólogos en el Perú maneja adecuadamente la infección por Helicobacter pylori, aunque lo referente a la revaluación podría mejorar...
This study seeks to identify, through a survey, how Peruvian gastroenterologists deal with Helicobacter pylori infection. Material and Methods: Gastroenterologists answered a survey concerning diagnosis and treatment of Helicobacter pylori infection. Results: 177 valid answers were obtained (29.6% of the population). Within the main results, 77.4% use endoscopy + biopsy (histology) for diagnosis, 95.5% choose proton pump inhibitor + clarithromycin + amoxicillin as first line treatment and 50.0% check for eradication 4-6 weeks after treatment. Conclusions: Most gastroenterologists in Peru deal adequately with Helicobacter pylori infection, although follow-up aspects could be improved...
Assuntos
Humanos , Inquéritos Epidemiológicos , Gastroenterologia/métodos , Infecções por Helicobacter/diagnóstico , PeruRESUMO
Con el objetivo en este estudio de evaluar los efectos cardiovasculares y la farmacocinética del nebivolol en ratas hipertensas por sobrecarga de fructosa y en ratas control, se registraron los efectos de la administración intravenosa de nebivolol, 3 mg/kg o 10 mg/kg, sobre la presión arterial, la frecuencia cardíaca y la variabilidad de la presión arterial a corto plazo y latido-a-latido, y se evaluó la farmacocinética enantioselectiva a partir del análisis de la concentración plasmática de los enantiómeros d-nebivolol y l-nebivolol. La variabilidad de la presión arterial a corto plazo y latido-a-latido se evaluó mediante la desviación estándar y el análisis espectral del registro de la presión arterial, respectivamente. El estado hipertensivo alteró la farmacocinética del nebivolol, evidenciado por una reducción en el aclaramiento del nebivolol en el grupo fructosa respecto del grupo control luego de la administración de la dosis más alta. El efecto antihipertensivo del nebivolol fue similar en ambos grupos, en tanto que el efecto bradicardizante fue mayor en las ratas del grupo control. Aunque no se observaron diferencias significativas en la variabilidad de la presión arterial latido-a-latido, la reducción de la variabilidad de la presión arterial a corto plazo inducida por el nebivolol fue significativamente superior en las ratas del grupo fructosa en comparación con los animales normotensos (-57,9% ± 11,8% vs. -19,6% ± 9,2%; p < 0,05). En conclusión, si bien el nebivolol reduce la presión arterial y la variabilidad de la presión arterial en ambos grupos, no se encontraron diferencias significativas en las ratas con sobrecarga de fructosa en cuanto a la farmacocinética y los efectos cardiovasculares, a excepción de una eficacia bradicardizante menor y una reducción mayor de la variabilidad de la presión arterial a corto plazo.
The cardiovascular and pharmacokinetic effects of nebivolol were evaluated in hypertensive fructose-fed and control rats, analyzing the effect of intravenously administered nebivolol 3 or 10 mg/kg on blood pressure, heart rate, and short-term and beat-to-beat blood pressure variability. The enantioselective pharmacokinetic profile of d- and l-nebivolol enantiomers was evaluated. Short-term and beat-to-beat blood pressure variability was assessed using standard deviation and blood pressure spectral analysis, respectively. The hypertensive state altered the pharmacokinetics of nebivolol, evidenced by reduction of nebivolol clearance in the fructose group compared to the control group after administration of the highest dose. The antihypertensive effect of nebivolol was similar in both groups, while the bradycardic effect was greater in control rats. Although no significant differences were found in beat-to-beat blood pressure variability, short-term blood pressure variability showed greater reduction after nebivolol administration in fructose-fed rats compared to control normotensive animals (-57.9%±11.8% vs.-19.6%±9.2%; p<0.05). In conclusion, although nebivolol reduces blood pressure and blood pressure variability in both groups, no significant differences were found in the pharmacokinetics and cardiovascular effects of fructose-fed rats, except for lower bradycardic efficacy and greater reduction in short-term blood pressure variability.
RESUMO
OBJECTIVE: This study seeks to identify, through a survey, how Peruvian gastroenterologists deal with Helicobacter pylori infection. MATERIAL AND METHODS: Gastroenterologists answered a survey concerning diagnosis and treatment of Helicobacter pylori infection. RESULTS: 177 valid answers were obtained (29.6% of the population). Within the main results, 77.4% use endoscopy + biopsy (histology) for diagnosis, 95.5% choose proton pump inhibitor + clarithromycin + amoxicillin as first line treatment and 50.0% check for eradication 4-6 weeks after treatment. CONCLUSIONS: Most gastroenterologists in Peru deal adequately with Helicobacter pylori infection, although follow-up aspects could be improved.
Assuntos
Gastroenterologistas , Infecções por Helicobacter , Padrões de Prática Médica/estatística & dados numéricos , Assistência ao Convalescente/métodos , Assistência ao Convalescente/estatística & dados numéricos , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Biópsia/estatística & dados numéricos , Claritromicina/uso terapêutico , Quimioterapia Combinada , Endoscopia Gastrointestinal/estatística & dados numéricos , Feminino , Pesquisas sobre Atenção à Saúde , Infecções por Helicobacter/diagnóstico por imagem , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/patologia , Humanos , Masculino , Peru , Inibidores da Bomba de Prótons/uso terapêuticoRESUMO
In the kidney, a high salt intake favors oxidative stress and hypoxia and causes the development of fibrosis. Both atrial natriuretic peptide (ANP) and hypoxia inducible factor (HIF-1α) exert cytoprotective effects. We tested the hypothesis that renal expression of ANP and HIF-1α is involved in a mechanism responding to the oxidative stress produced in the kidneys of rats chronically fed a high sodium diet. Sprague-Dawley rats were fed with a normal salt (0.4% NaCl) (NS) or a high salt (8% NaCl) (HS) diet for 3 weeks, with or without the administration of tempol (T), an inhibitor of oxidative stress, in the drinking water. We measured the mean arterial pressure (MAP), glomerular filtration rate (GFR), and urinary sodium excretion (UVNa). We evaluated the expression of ANP, HIF-1α, and transforming growth factor (TGF-ß1) in renal tissues by western blot and immunohistochemistry. The animals fed a high salt diet showed increased MAP and UVNa levels and enhanced renal immunostaining of ANP, HIF-1α, and TGF-ß1. The administration of tempol together with the sodium overload increased the natriuresis further and prevented the elevation of blood pressure and the increased expression of ANP, TGF-ß1, and HIF-1α compared to their control. These findings suggest that HIF-1α and ANP, synthesized by the kidney, are involved in an adaptive mechanism in response to a sodium overload to prevent or attenuate the deleterious effects of the oxidative stress and the hypoxia on the development of fibrosis.
Assuntos
Fator Natriurético Atrial/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/metabolismo , Cloreto de Sódio na Dieta/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Fator Natriurético Atrial/sangue , Western Blotting , Peso Corporal/efeitos dos fármacos , Córtex Renal/metabolismo , Masculino , Ratos Sprague-Dawley , Sódio/sangue , Sódio/urina , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Angiotensin (Ang)-(1-7) stimulates proteins belonging to the insulin signaling pathway and ameliorates the Ang II negative effects at this level. However, up to date, receptors involved and mechanisms behind these observations remain unknown. Accordingly, in the present study, we explored the in vivo effects of antagonism of the Ang-(1-7) specific Mas receptor on insulin signal transduction in rat insulin-target tissues. We evaluated the acute modulation of insulin-stimulated phosphorylation of Akt, GSK-3ß (Glycogen synthase kinase-3ß) and AS160 (Akt substrate of 160kDa) by Ang-(1-7) and/or Ang II in the presence and absence of the selective Mas receptor antagonist A-779 in insulin-target tissues of normal rats. Also using A-779, we determined whether the Mas receptor mediates the improvement of insulin sensitivity exerted by chronic Ang-(1-7) treatment in fructose-fed rats (FFR), a model of insulin resistance, dyslipidemia and mild hypertension. The two major findings of the present work are as follows; 1) Ang-(1-7) attenuates acute Ang II-mediated inhibition of insulin signaling components in normal rats via a Mas receptor-dependent mechanism; and 2). The Mas receptor appears to be involved in beneficial effects of Ang-(1-7) on the phosphorylation of crucial insulin signaling mediators (Akt, GSK-3ß and AS160), in liver, skeletal muscle and adipose tissue of FFR. These results shed light into the mechanism by which Ang-(1-7) exerts its positive physiological modulation of insulin actions in classical metabolic tissues and reinforces the central role of Akt in these effects.