Navegando por Autor "Cruz, Jader dos Santos"

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Basal and β-Adrenergic cardiomyocytes contractility dysfunction induced by dietary protein restriction is associated with downregulation of SERCA2a expression and disturbance of endoplasmic reticulum Ca2+ regulation in rats.
(2014) Penitente, Arlete Rita; Novaes, Rômulo Dias; Silva, Marcelo Eustáquio; Silva, Márcia Ferreira da; Quintão Júnior, Judson Fonseca; Guatimosim, Silvia; Cruz, Jader dos Santos; Chianca Júnior, Deoclécio Alves; Natali, Antônio José; Neves, Clóvis Andrade
Background: The mechanisms responsible for the cardiac dysfunction associated with dietary protein restriction (PR) are poorly understood. Thus, this study was designed to evaluate the effects of PR on calcium kinetics, basal and β-adrenergic contractility in murine ventricular cardiomyocytes. Methods: After breastfeeding male Fisher rats were distributed into a control group (CG, n = 20) and a protein-restricted group (PRG, n = 20), receiving isocaloric diets for 35 days containing 15% and 6% protein, respectively. Biometric and hemodynamic variables were measured. After euthanasia left ventricles (LV) were collected for histopathological evaluation, SERCA2a expression, cardiomyocytes contractility and Ca2+ sparks analysis. Results: PRG animals showed reduced general growth, increased heart rate and arterial pressure. These animals presented extracellular matrix expansion and disorganization, cardiomyocytes hypotrophy, reduced amplitudes of shortening and maximum velocity of contraction and relaxation at baseline and after β-adrenergic stimulation. Reduced SERCA2a expression as well as higher frequency and lower amplitude of Ca2+ sparks were observed in PRG cardiomyocytes. Conclusion: The observations reveal that protein restriction induces marked myocardial morphofunctional damage. The pathological changes of cardiomyocyte mechanics suggest the potential involvement of the β-adrenergic system, which is possibly associated with changes in SERCA2a expression and disturbances in Ca2+ intracellular kinetics.
Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure.
(2010) Gomes, Aline Alves Lara; Damasceno, Dênis Derly; Pires, Rita Gomes Wanderley; Gros, Robert; Gomes, Enéas Ricardo de Morais; Gavioli, Mariana; Lima, Ricardo de Freitas; Guimarães, Diogo Aparecido da Silva; Lima, Patrícia Maria d'Almeida; Bueno Júnior, Carlos Roberto; Vasconcelos, Anilton Cesar; Campos, Danilo Roman; Menezes, Cristiane Alves da Silva; Sirvente, Raquel de Assis; Salemi, Vera Maria Cury; Mady, Charles; Caron, Marc G.; Ferreira, Anderson José; Brum, Patricia Chakur; Resende, Rodrigo Ribeiro; Cruz, Jader dos Santos; Gomez, Marcus Vinicius; Prado, Vânia Ferreira; Almeida, Alvair Pinto de; Prado, Marco Antônio Maximo; Fonseca, Silvia Carolina Guatimosim
Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.
Mechanisms of artemether toxicity on single cardiomyocytes and protective effect of nanoencapsulation.
(2020) Souza, Ana Carolina Moreira; Guimarães, Andrea Grabe; Cruz, Jader dos Santos; Miranda, Artur Santos; Farah, Charlotte; Oliveira, Liliam Teixeira; Lucas, Alexandre; Aimond, Franck; Sicard, Pierre; Mosqueira, Vanessa Carla Furtado; Richard, Sylvain
Background and Purpose: The artemisinin derivative, artemether, has antimalarial activity with potential neurotoxic and cardiotoxic effects. Artemether in nanocapsules (NC-ATM) is more efficient than free artemether for reducing parasitaemia and increasing survival of Plasmodium berghei-infected mice. NCs also prevent prolongation of the QT interval of the ECG. Here, we assessed cellular cardiotoxicity of artemether and how this toxicity was prevented by nanoencapsulation. Experimental Approach: Mice were treated with NC-ATM orally (120 mg kg−1 twice daily) for 4 days. Other mice received free artemether, blank NCs, and vehicle for comparison. We measured single-cell contraction, intracellular Ca2+ transient using fluorescent Indo-1AM Ca2+ dye, and electrical activity using the patch-clamp tech nique in freshly isolated left ventricular myocytes. The acute effect of free artemether was also tested on cardiomyocytes of untreated animals. Key Results: Artemether prolonged action potentials (AP) upon acute exposure (at 0.1, 1, and 10 μM) of cardiomyocytes from untreated mice or after in vivo treatment. This prolongation was unrelated to blockade of K+ currents, increased Ca2 + currents or promotion of a sustained Na+ current. AP lengthening was abolished by the NCX inhibitor SEA-0400. Artemether promoted irregular Ca2+ transients during pacing and spontaneous Ca2+ events during resting periods. NC-ATM prevented all effects. Blank NCs had no effects compared with vehicle. Conclusion and Implications: Artemether induced NCX-dependent AP lengthening (explaining QTc prolongation) and disrupted Ca2+ handling, both effects increasing pro-arrhythmogenic risks. NCs prevented these adverse effects, providing a safe alternative to the use of artemether alone, especially to treat malaria.
Modificação da farmacocinética, biodistribuição e cardiotoxicidade de uma nova tiazolidinodiona, Lyso-7, pelo uso de nanocápsulas preparadas com derivados do ácido poliláctico.
(2015) Garcia, Giani Martins; Mosqueira, Vanessa Carla Furtado; Abdalla, Dulcineia Saes Parra; Mosqueira, Vanessa Carla Furtado; Farsky, Sandra Helena Poliselli; Barcellos, Neila Marcia Silva; Isoldi, Mauro César; Cruz, Jader dos Santos
As tiazolidinodionas (TZD) são fármacos usados no tratamento do diabetes mellitus tipo 2 como agentes que aumentam a sensibilidade à insulina. A Lyso-7 é uma nova TZD sintética que possui atividade anti-inflamatória, além de ser (pan) agonista dos receptores PPAR α, β/δ e γ. Nanocápsulas (NC) poliméricas contendo Lyso-7 obtidas a partir do ácido poliláctico (PLA) e seus derivados dibloco ligados covalentemente ao polietilenoglicol (PLA-PEG), foram preparadas pelo método de nanoprecipitação. Foram também utilizados copolímeros em bloco funcionalizados ao longo da cadeia de PLA pela inserção randômica de monômeros contendo grupos hidroxilas (OH-PLA-PEG) ou benzila (BZO-PLA-PEG). As NC PLA (273 nm) tiveram tamanho médio superior às NC PLA-PEG com e sem funcionalização (164- 227 nm), indicando que a presença do PEG reduziu o tamanho médio das NC. Todas as formulações apresentaram-se monodispersas e encapsularam eficientemente a Lyso-7 (0,5 mg/mL), com um rendimento de aproximadamente 85% e porcentagem de encapsulação próximos a 100%. As análises morfológicas realizadas por microscopia de força atômica e microscopia eletrônica de varredura indicaram a presença de estruturas esféricas e deformáveis. A farmacocinética da Lyso-7 livre e associada às diferentes formulações de NC na dose de 1,6 mg/Kg foi estudada. A área sob a curva da concentração versus tempo da Lyso-7 associada às NC aumentou significativamente em relação à Lyso-7 livre, 14 vezes para NC de PLA e 35 vezes para NC de PLA-PEG. Para avaliar o destino destas NC após a administração intravenosa, foi desenvolvida e validada uma nova metodologia bioanalítica para o doseamento da Lyso-7 por cromatografia líquida de alta eficiência com detecção UV no plasma e em diferentes órgãos. A Lyso-7 livre e encapsulada nas NC de PLA e PLA-PEG foi quantificada no fígado, baço, coração, pulmão e rim. A nanoencapsulação aumentou a exposição da Lyso-7 em todos os órgãos avaliados. Devido às restrições clínicas do uso de TZD, particularmente referentes à indução indesejada de insuficiência cardíaca (rosiglitazona), os eventuais efeitos cardiotóxicos da Lyso-7 livre e nanoencapsulada foram avaliados por medidas de alteração da fisiologia e funcionamento de cardiomiócitos murinos recém-isolados. Os testes in vitro indicaram que a Lyso-7 livre reduziu os níveis de Ca2+ diastólico em todas as concentrações testadas (4,5, 45 e 450 μM) e sendo correlacionado com o aumento da velocidade de recaptura de Ca2+ na concentração de 450 μM. Além isso, foram observadas ondas ectópicas localizadas de Ca2+ (sparks), na concentração de 450 μM, que podem eventualmente induzir arritmias. Com relação à segurança, a Lyso-7, quando administrada em NC de PLA na dose de 1,6 mg/Kg/dia durante 7 dias em camundongos, não induziu cardiotoxicidade nas condições experimentais empregadas, ao passo que sua administração em solução acelerou o decaimento do transiente de Ca2+ (TAU) e reduziu os níveis de Ca2+ diastólico. O teste de toxicidade aguda indicou um possível efeito tóxico da Lyso-7, uma vez que camundongos fêmeas tratados com a Lyso-7 em NC PLA e NC PLAPEG tiveram alteração de alguns parâmetros hematológicos, e o grupo de machos tratados com Lyso-7 em NC PLA apresentaram alteração do índice uréia/creatinina, indicador de alteração renal. Dessa forma, a associação da Lyso-7 às NC poliméricas se mostrou promissora em relação ao aumento do tempo de meia vida plasmática, à exposição tecidual e à redução da cardiotoxicidade in vitro e in vivo. Esses dados poderão influenciar na eficácia terapêutica e na toxicidade em estudos posteriores e se mostram promissores para esta nova classe de moléculas sintéticas.
Plasma cytokine response, lipid peroxidation and NF-κB activation in skeletal muscle following maximum progressive swimming.
(2011) Cleto, Lorena Sabino; Oleto, A. F.; Sousa, L. P.; Barreto, Tatiane Oliveira; Cruz, Jader dos Santos; Penaforte, Claudia Lopes; Magalhães, José Carlos de; Franco, Junia de Sousa; Pinto, Kelerson Mauro de Castro; Azevedo, Ana Carolina Campi; Vieira, Etel Rocha
Our objective was to determine lipid peroxidation and nuclear factor-κB (NF-κB) activation in skeletal muscle and the plasma cytokine profile following maximum progressive swimming. Adult male Swiss mice (N = 15) adapted to the aquatic environment were randomly divided into three groups: immediately after exercise (EX1), 3 h after exercise (EX2) and control. Animals from the exercising groups swam until exhaustion, with an initial workload of 2% of body mass attached to the tail. Control mice did not perform any exercise but were kept immersed in water for 20 min. Maximum swimming led to reactive oxygen species (ROS) generation in skeletal muscle, as indicated by increased thiobarbituric acid reactive species (TBARS) levels (4062.67 ± 1487.10 vs 19,072.48 ± 8738.16 nmol malondialdehyde (MDA)/mg protein, control vs EX1). Exercise also promoted NF-κB activation in soleus muscle. Cytokine secretion following exercise was marked by increased plasma interleukin-6 (IL-6) levels 3 h post-exercise (P < 0.05). Interleukin-10 (IL-10) levels were reduced following exercise and remained reduced 3 h post-exercise (P < 0.05). Plasma levels of other cytokines investigated, monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-12 (IL-12), were not altered by exercise. The present findings showed that maximum swimming, as well as other exercise models, led to lipid peroxidation and NF-κB activation in skeletal muscle and increased plasma IL-6 levels. The plasma cytokine response was also marked by reduced IL-10 levels. These results were attributed to exercise type and intensity.
A potential role of cholinergic dysfunction on Impaired Colon Motility in experimental intestinal Chagas disease.
(2022) Ricci, Mayra Fernanda; Béla, Samantha Ribeiro; Barbosa, Joana Lobato; Moraes, Michele Macedo; Mazzeti, Ana Lia; Bahia, Maria Terezinha; Horta, Laila Sampaio; Santiago, Helton da Costa; Cruz, Jader dos Santos; Capettini, Luciano dos Santos Aggum; Arantes, Rosa Maria Esteves
Background/Aims Chagasic megacolon is caused by Trypanosoma cruzi, which promotes in several cases, irreversible segmental colonic dilation. This alteration is the major anatomic-clinical disorder, characterized by the enteric nervous system and muscle wall structural damage. Herein, we investigate how T. cruzi-induced progressive colonic structural changes modulate the colonic contractile pattern activity. Methods We developed a murine model of T. cruzi-infection that reproduced long-term modifications of the enlarged colon. We evaluated colonic and total intestinal transit time in animals. The patterns of motor response at several time intervals between the acute and chronic phases were evaluated using the organ bath assays. Enteric motor neurons were stimulated by electric field stimulation. The responses were analyzed in the presence of the nicotinic and muscarinic acetylcholine receptor antagonists. Western blot was performed to evaluate the expression of nicotinic and muscarinic receptors. The neurotransmitter expression was analyzed by real-time polymerase chain reaction. Results In the chronic phase of infection, there was decreased intestinal motility associated with decreased amplitude and rhythmicity of intestinal contractility. Pharmacological tests suggested a defective response mediated by acetylcholine receptors. The contractile response induced by acetylcholine was decreased by atropine in the acute phase while the lack of its action in the chronic phase was associated with tissue damage, and decreased expression of choline acetyltransferase, nicotinic subunits of acetylcholine receptors, and neurotransmitters. Conclusions T. cruzi-induced damage of smooth muscles was accompanied by motility disorders such as decreased intestinal peristalsis and cholinergic system response impairment. This study allows integration of the natural history of Chagasic megacolon motility disorders and opens new perspectives for the design of effective therapeutic.
Swim training does not protect mice from skeletal muscle oxidative damage following a maximum exercise test.
(2011) Barreto, Tatiane Oliveira; Cleto, Lorena Sabino; Gioda, Carolina Rosa; Silva, Renata Sabino da; Azevedo, Ana Carolina Campi; Franco, Junia de Sousa; Magalhães, José Carlos de; Penaforte, Claudia Lopes; Pinto, Kelerson Mauro de Castro; Cruz, Jader dos Santos; Vieira, Etel Rocha
We investigated whether swim training protects skeletal muscle from oxidative damage in response to a maximum progressive exercise. First, we investigated the effect of swim training on the activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), in the gastrocnemius muscle of C57Bl/6 mice, 48 h after the last training session. Mice swam for 90 min, twice a day, for 5 weeks at 31C (±1C). The activities of SOD and CAT were increased in trained mice (P\0.05) compared to untrained group. However, no effect of training was observed in the activity of GPx. In a second experiment, trained and untrained mice were submitted to a maximum progressive swim test. Compared to control mice (untrained, not acutely exercised), malondialdehyde (MDA) levels were increased in the skeletal muscle of both trained and untrained mice after maximum swim. The activity of GPx was increased in the skeletal muscle of both trained and untrained mice, while SOD activity was increased only in trained mice after maximum swimming. CAT activity was increased only in the untrained compared to the control group. Although the trained mice showed increased activity of citrate synthase in skeletal muscle, swim performance was not different compared to untrained mice. Our results show an imbalance in the activities of SOD, CAT and GPx in response to swim training, which could account for the oxidative damage observed in the skeletal muscle of trained mice in response to maximum swim, resulting in the absence of improved exercise performance.
The positive inotropic effect of the ethyl acetate fraction from Erythrina velutina leaves on the mammalian myocardium : the role of adrenergic receptors.
(2013) Passos, Amilton Gustavo da Silva; Gondim, Antônio Nei Santana; Campos, Danilo Roman; Cruz, Jader dos Santos; Garcia, Eduardo Antônio Conde; Araújo Neto, Vitor; Estevam, Charles dos Santos; Cerqueira, Sandra Valéria Santos; Brandão, Geraldo Célio; Oliveira, Alaíde Braga de; Vasconcelos, Carla Maria Lins de
Objectives We studied the effects of ethyl acetate fraction (EAcF) obtained from Erythrina velutina leaves on mammalian myocardium. Methods The effect of EAcF on the contractility was studied using guinea-pig left atria mounted in a tissue bath (Tyrode’s solution, 29°C, 95% CO2, 5% O2) and electrically stimulated (1 Hz). Concentration-response curves of EAcF were obtained in the presence of propranolol (1 mm), nifedipine (1 mm) and in reserpinized animals (5 mg/kg). The involvement of l-type calcium current (ICa,L) on the EAcF effect was observed in cardiomyocytes of mice assessed using patch-clamp technique. Key findings EAcF (550 mg/ml) had a positive inotropic effect, increasing the atrial force by 164% (EC50 = 157 44 mg/ml, n = 6), but it was less potent than isoproterenol (EC50 = 0.0036 0.0019 mg/ml, n = 8). The response evoked by EAcF was abolished by propranolol or nifedipine. Reserpine did not alter the inotropic response of EAcF. Furthermore, an enhancement of the ICa,L peak (31.2%) with EAcF was observed. Chemical analysis of EAcF revealed the presence of at least 10 different flavonoid glycoside derivatives. Two were identified as vicenin II and isorhoifolin. Conclusions We conclude that EAcF increases the cardiac contractile force by increasing the l-type calcium current and activating the adrenergic receptor pathway.