Biological Activity of a Coumarin Derivative on Heart Failure Using an Ischemia/Reperfusion Injury Model.

Heart failure is a health problem worldwide. There are some drugs for it, including digoxin, spironolactone, captopril, and valsartan, but some of these drugs can produce secondary effects, such as arrhythmia, cough, hyperkalemia, hyponatremia and hypotension. The aim of this research was to evaluate the biological activity of coumarin (2H-chromen-2-one) and its derivatives (3BrAcet-C, 3-4Br-Ph-C, 4-CN-7D-C, 4-Me-7-Ph-C and 6Br-3-D-C) against ischemia/reperfusion injury as a therapeutic alternative for heart failure. In addition, the biological activity of the coumarin derivative 4-Me-7-Ph-C on left ventricular pressure (LVP) was determined in the absence or presence of ouabain and nifedipine at a dose of 1 nM using an isolated rat heart model. The results showed that i) the coumarin derivative 4-Me-7-Ph-C significantly decreased the infarct area (p+=+0.05) compared with 3BrAcet-C, 3-4Br-Ph-C, 4-CN-7D-C, and 6Br-3-D-C; and ii) 4-Me-7-Ph-C increased LVP in a dose-dependent manner, which effect was inhibited by nifedipine. These data suggest that coumarin 4-Me-7-Ph-C may act as a type-L calcium channel activator, so it could be a good agent to treat heart failure.

Interaction of Some Amino-Nitrile Derivatives with Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) Using a Theoretical Model.

BACKGROUND: Some studies indicate that the angiogenesis process is related to vascular endothelial growth factor, which can interact with endothelial cell surface receptors (VEGF-R1, VEGF-R2, and VEGF-R3); this biochemical process and other factors result in the promotion and growth of new blood vessels under normal conditions. However, some studies indicate that this phenomenon could also occur in cancer cells. It is important to mention that some amino derivatives have been prepared as VEGF-R1 inhibitors; however, their interaction with VEGF-R1 is not clear, perhaps due to different experimental approaches or differences in their chemical structure. OBJECTIVE: The aim of this study was to evaluate the theoretical interaction of several amino-nitrile derivatives (Compounds 1 to 38) with VEGF-R1. METHODS: The theoretical interaction of amino-nitrile derivatives with VEGF-R1 was carried out using the 3hng protein as the theoretical model. In addition, cabozantinib, pazopanib, regorafenib, and sorafenib were used as controls in the DockingServer program. RESULTS: The results showed different amino acid residues involved in the interaction of amino-nitrile derivatives with the 3hng protein surface compared with the controls. In addition, the inhibition constant (Ki) was lower for Compounds 10 and 34 than for cabozantinib. Other results show that Ki for Compounds 9, 10, 14, 27-29 and 34-36 was lower in comparison with pazopanib, regorafenib, and sorafenib. CONCLUSIONS: All theoretical data suggest that amino-nitrile derivatives could produce changes in the growth of some cancer cell lines through VEGFR-1 inhibition. Therefore, these amino-nitrile derivatives could be a therapeutic alternative to treat some types of cancer.

Evaluation of Biological Activity Exerted by Dibenzo[b,e]Thiophene-11(6H)-One on Left Ventricular Pressure Using an Isolated Rat Heart Model.

BACKGROUND: Some studies show that some Dibenzo derivatives can produce changes in the cardiovascular system; however, its molecular mechanism is not very clear. OBJECTIVE: The objective of this investigation was to evaluate the inotropic activity of ten Dibenzo derivatives (compounds 1 to 10) on either perfusion pressure or left ventricular pressure. METHODS: Biological activity produced by the Dibenzo derivatives on either perfusion pressure or coronary resistance was evaluated using an isolated rat heart. In addition, the molecular mechanism of biological activity produced by compound 4 (Dibenzo[b,e]thiophene-11(6H)-one) on left ventricular pressure was determined using both Bay-k8644 and nifedipine as pharmacological tools in an isolated rat heart model. RESULTS: The results showed that Dibenzo[b,e]thiophene-11(6H)-one increases perfusion pressure and coronary resistance at a dose of 0.001 nM. Besides, other data display that Dibenzo[b,e]thiophene-11(6H)-one increases left ventricular pressure in a dose-dependent manner (0.001 to 100 nM) and this effect was similar to biological activity produced by Bay-k8644 drug on left ventricular pressure. However, the effect exerted by Dibenzo[b,e]thiophene-11(6H)-one was inhibited in the presence of nifedipine at a dose of 1 nM. CONCLUSIONS: All these data suggest that Dibenzo[b,e]thiophene-11(6H)-one increase left ventricular pressure through calcium channel activation. In this way, Dibenzo[b,e]thiophene-11(6H)-one could be a good candidate as positive inotropic agent to heart failure.

Assessment of executive functions and physical activity in girls and boys with normal weight, overweight and obesity.

OBJECTIVE: To evaluate the association between body mass index (BMI) and performance of executive functions (EFs) in girls and boys with 9- and 10-year-old schoolchildren with moderate- to vigorous-intensity physical activity (MVPA) and sedentary behaviour. METHODS: A total of 120 schoolchildren (61 girls and 59 boys) were evaluated anthropometrically. The MVPA was evaluated with a self-report questionnaire. EFs were measured using a neuropsychological battery of Executive Functions and Frontal Lobes-2 (BANFE-2). RESULTS: A high BMI was associated with longer delay in completing inhibitory control tests (p = 0.00, rp  = 0.32) and working memory (p = 0.00, rp  = 0.26). We observed correlations in time (p = 0.00, rp  = -0.43) and hits (p = 0.04, rp  = -0.27) of self-directed signalling test in boys; and girls in alphabetical words order (p = 0.00, rp  = -0.39). Active normal weight schoolchildren (ANw) performed better by successfully completed the working memory tasks (H = 26.97, p = 0.00) than sedentary schoolchildren with overweight and obesity. In addition, overweight-active schoolchildren (AOw) showed better performance on working memory tests in time (p = 0.00) and hits (p = 0.01) than their sedentary peers. Multiple linear regression analysis revealed a significant association between BMI and EFs scores (F = 2.41, df = 98, p = 0.001). CONCLUSIONS: EFs are affected by a high BMI and sedentary behaviour in school children. Boys and girls reflected differences to solve the same challenges. The MVPA has a positive effect on executive control skills mainly in overweight children.

Design and synthesis of a new steroid-macrocyclic derivative with biological activity.

The aims of this study were to evaluate the positive inotropic effect of a new macrocyclic derivative (compound 11) and characterize the molecular mechanism involved in its biological activity. The first step was achieved by synthesis of a macrocyclic derivative involving a series of reactions for the preparation of several steroid derivatives such as (a) steroid-pyrimidinone (3 and 4), (b) steroid-amino (5), (c) steroid-imino (6), (d) ester-steroid (7 and 8), and (e) amido-steroid (9 and 10). Finally, 11 was prepared by removing the tert-butyldimethylsilane fragment of 10. The biological activity of compounds on perfusion pressure and vascular resistance was evaluated on isolated rat heart using the Langendorff model. The inotropic activity of 11 was evaluated in presence of prazosin, metoprolol, indomethacin, nifedipine, and flutamide to characterize its molecular mechanism. Theoretical experiments were carried out with a Docking model, to assess potential interactions of androgen receptor with 11. The results showed that only this macrocyclic derivative exerts changes on perfusion pressure and vascular resistance translated as the positive inotropic effect, and this effect was blocked with flutamide; these data indicate that the positive inotropic activity induced by this macrocyclic derivative was via androgen receptor activation. The theoretical results indicated that the interaction of the macrocyclic derivative with the androgen receptor involves several amino acid residues such as Leu704, Asn705, Met780, Cys784, Met749, Leu762, Phe764, Ser778, and Met787. In conclusion, all these data suggest that the positive inotropic activity of the macrocyclic derivative may depend on its chemical structure.

Experimental, Theoretical and Biological Activity of a Triazonine- Derivative on Left Ventricular Pressure.

BACKGROUND: There are data indicating that several azonine-derivatives may exert effects on some biological systems; however, there is very low information on the biological activity induced by these compounds on left ventricular pressure. OBJECTIVE: The aim of this study was to synthesize and evaluate the biological activity of new triazoninederivative on left ventricular pressure. MATERIAL AND METHODS: The first stage involved: 1) preparation of two azepine-benzamide derivatives (Z or E) by reaction of the nitrobenzoyl azide with adrenosterone; and 2) reaction of (Z)-azepine-benzamide derivative with ethylenediamine to form the triazonine derivative. The structure of compounds was confirmed by spectroscopy and spectrometry data. The second stage involved the biologic activity on left ventricular pressure was evaluated in a model of rat heart isolated. In addition, some physicochemical parameters were evaluated to characterize the possible molecules involved in its effect. RESULTS: The results showed that only the triazonine increased left ventricular pressure via androgen receptor. CONCLUSIONS: In conclusion, this phenomenon is conditioned by the functional groups involved in the chemical structure of triazonine derivative and their interaction with residues of amino acids involved on the androgen receptor surface.

One month of omega-3 fatty acid supplementation improves lipid profiles, glucose levels and blood pressure in overweight schoolchildren with metabolic syndrome.

BACKGROUND: This study sought to investigate the effects of omega (ω)-3 polyunsaturated fatty acid (PUFA) supplementation on the lipid profiles and glucose (GLU) levels of overweight (OW) schoolchildren with metabolic syndrome (MS). METHODS: Thirty-nine OW schoolchildren with MS, including 19 girls and 20 boys, received 1-month of dietary supplementation with gel capsules containing ω-3 fatty acids. Fasting lipid profiles and GLU levels were measured before and after supplementation. RESULTS: Both sexes of OW schoolchildren with MS who received daily supplementation with 2.4 g of ω-3 fatty acids for 1 month displayed improved lipid profiles, reduced fasting GLU levels and reduced blood pressure (BP). CONCLUSIONS: These findings support the addition of omega-3 fatty acid supplementation to programs aiming to improve the metabolic status of OW children with MS, although additional research on the longer-term safety and efficacy of this treatment in this population is required.

Efecto inotrópico positivo ejercido por el derivado de brucina en un modelo de corazón aislado de rata / Inotropic effect exerted by the brucine derivativein an isolated rat heart mode / Efeito inotrópico exercida pelo derivado de brucinaem um modelo de corações isolados de ratos

Existen pocos datos con respecto a los efectos de la brucina y sus derivados en el aparato cardiovascular; además, el mecanismo molecular y su sitio de acción celular no son claros. Para proporcionar información adicional acerca de este fenómeno, en este trabajo fue evaluado el efecto inducido por un derivado de la brucina sobre la presión de perfusión, la resistencia vascular y la presión ventricular izquierda en corazón aislado de rata a flujo constante (modelo de Langendorff). Los resultados mostraron que; 1) el derivado brucina (1×10-9 mM) incrementa la presión de perfusión y la resistencia vascular en comparación con la brucina (1×10-9 mM) y las condiciones de control; 2) los efectos del derivado de brucina en dosis de 1×10-9 a 1×10-4 mM sobre la presión intraventricular no fueron inhibidos por metoprolol, prazosina o nifedipino a dosis de 1×10-6 mM; y 3) la furosemida a dosis de 1×10-6 mM bloquea los efectos ejercidos por el derivado de brucina (1×10-9 a 1×10-4 mM) sobre la presión intraventricular. En conclusión, la actividad ejercida por el derivado de brucina sobre la presión ventricular izquierda, involucra inhibición de la bomba Na+/K+-ATPasa, lo que trae indirectamente cambios en los niveles de calcio intracelular y subsecuentemente un efecto inotrópico positivo.

Few data exist with respect to the effects of brucine and its derivatives at a cardiovascular level; furthermore, the molecular mechanism and its site of cellular action are still unclear. In order to provide additional information about this phenomenon, the effect induced by a brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure was evaluated in anisolated rat heart at constant flow (Langendorff model). The results showed that: 1) The brucine derivative [1×10-9 mM] increased perfusion pressure and vascular resistance in comparison with the brucine [1×10-9 mM] and the control conditions; 2) the effects of brucine derivative [1×10-9 to 1×10-4 mM] on intraventricular pressure were not inhibited by metoprolol, prazosin or nifedipine at a 1×10-6 mM dose; 3) furosemide [1×10-6 mM] blocked the effects exerted by the brucine derivative [1×10-9 a 1×10-4 mM] on intraventricular pressure. In conclusion, the activity exerted by the brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure, involves inhibition of Na+/K+-ATPase, consequently resulting in indirect changes in intracellular calcium levels and subsequently inducing a positive inotropic effect.

Existem poucos dados no que diz respeito aos efeitos da brucina e seus derivados no nível cardiovascular; além disso, o mecanismo molecular e seu local de ação celular não são claros. Para fornecer informações adicionais sobre este fenômeno, neste trabalho foi avaliado o efeito induzido por um derivado de brucina sobre a pressão de perfusão, a resistência vascular e a pressão ventricular esquerda em coração isolado de ratos em fluxo constante (modelo Langendorff). Os resultados mostraram que: 1) o derivado brucina (1×10-9 mM) aumenta a pressão de perfusão e a resistência vascular em comparação com a brucina (1×10-9 mM) e as condições de controle; 2) os efeitos do derivado de brucina em doses de 1×10-9 a 1×10-4 mM sobre a pressão intraventricular não foram inibidos por metoprolol, prazosina ou nifedipino em doses de 1×10-6 mM; e 3) a furosemida, em doses de 1×10-6 mM, bloqueia os efeitos exercidos pelo derivado de brucina (1×10-9 a 1×10-4 mM) sobre a pressão intraventricular. Em conclusão, a atividade exercida pelo derivado de brucina sobre a pressão ventricular esquerda, envolve a inibição da bomba de Na+/K+-ATPase, o que indiretamente traz alterações nos níveis de cálcio intracelular e, subsequentemente, um efeito inotrópico positivo.

Efecto inotrópico positivo ejercido por el derivado de brucina en un modelo de corazón aislado de rata / Inotropic effect exerted by the brucine derivativein an isolated rat heart mode / Efeito inotrópico exercida pelo derivado de brucinaem um modelo de coraþ§es isolados de ratos

Existen pocos datos con respecto a los efectos de la brucina y sus derivados en el aparato cardiovascular; además, el mecanismo molecular y su sitio de acción celular no son claros. Para proporcionar información adicional acerca de este fenómeno, en este trabajo fue evaluado el efecto inducido por un derivado de la brucina sobre la presión de perfusión, la resistencia vascular y la presión ventricular izquierda en corazón aislado de rata a flujo constante (modelo de Langendorff). Los resultados mostraron que; 1) el derivado brucina (1Î10-9 mM) incrementa la presión de perfusión y la resistencia vascular en comparación con la brucina (1Î10-9 mM) y las condiciones de control; 2) los efectos del derivado de brucina en dosis de 1Î10-9 a 1Î10-4 mM sobre la presión intraventricular no fueron inhibidos por metoprolol, prazosina o nifedipino a dosis de 1Î10-6 mM; y 3) la furosemida a dosis de 1Î10-6 mM bloquea los efectos ejercidos por el derivado de brucina (1Î10-9 a 1Î10-4 mM) sobre la presión intraventricular. En conclusión, la actividad ejercida por el derivado de brucina sobre la presión ventricular izquierda, involucra inhibición de la bomba Na+/K+-ATPasa, lo que trae indirectamente cambios en los niveles de calcio intracelular y subsecuentemente un efecto inotrópico positivo.(AU)

Few data exist with respect to the effects of brucine and its derivatives at a cardiovascular level; furthermore, the molecular mechanism and its site of cellular action are still unclear. In order to provide additional information about this phenomenon, the effect induced by a brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure was evaluated in anisolated rat heart at constant flow (Langendorff model). The results showed that: 1) The brucine derivative [1Î10-9 mM] increased perfusion pressure and vascular resistance in comparison with the brucine [1Î10-9 mM] and the control conditions; 2) the effects of brucine derivative [1Î10-9 to 1Î10-4 mM] on intraventricular pressure were not inhibited by metoprolol, prazosin or nifedipine at a 1Î10-6 mM dose; 3) furosemide [1Î10-6 mM] blocked the effects exerted by the brucine derivative [1Î10-9 a 1Î10-4 mM] on intraventricular pressure. In conclusion, the activity exerted by the brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure, involves inhibition of Na+/K+-ATPase, consequently resulting in indirect changes in intracellular calcium levels and subsequently inducing a positive inotropic effect.(AU)

Existem poucos dados no que diz respeito aos efeitos da brucina e seus derivados no nível cardiovascular; além disso, o mecanismo molecular e seu local de aþÒo celular nÒo sÒo claros. Para fornecer informaþ§es adicionais sobre este fen¶meno, neste trabalho foi avaliado o efeito induzido por um derivado de brucina sobre a pressÒo de perfusÒo, a resistÛncia vascular e a pressÒo ventricular esquerda em coraþÒo isolado de ratos em fluxo constante (modelo Langendorff). Os resultados mostraram que: 1) o derivado brucina (1Î10-9 mM) aumenta a pressÒo de perfusÒo e a resistÛncia vascular em comparaþÒo com a brucina (1Î10-9 mM) e as condiþ§es de controle; 2) os efeitos do derivado de brucina em doses de 1Î10-9 a 1Î10-4 mM sobre a pressÒo intraventricular nÒo foram inibidos por metoprolol, prazosina ou nifedipino em doses de 1Î10-6 mM; e 3) a furosemida, em doses de 1Î10-6 mM, bloqueia os efeitos exercidos pelo derivado de brucina (1Î10-9 a 1Î10-4 mM) sobre a pressÒo intraventricular. Em conclusÒo, a atividade exercida pelo derivado de brucina sobre a pressÒo ventricular esquerda, envolve a inibiþÒo da bomba de Na+/K+-ATPase, o que indiretamente traz alteraþ§es nos níveis de cálcio intracelular e, subsequentemente, um efeito inotrópico positivo.(AU)