RESUMEN
S-Limonene (s-Lim) is a monocyclic monoterpene found in a variety of plants and has been shown to present antioxidant and cardioprotective activity in experimental models of myocardial infarction. The aim of this study was to evaluate the potential mechanism by which s-Lim exerts its antiarrhythmic effect, focusing on the blockade of ß-adrenoceptor (ß-AR) and its effects on various in vivo and in vitro parameters, including electrocardiogram (ECG) measurements, left ventricular developed pressure (LVDP), the ß-adrenergic pathway, sarcomeric shortening and L-type calcium current (ICa,L). In isolated hearts, 10 µM of s-Lim did not alter the ECG profile or LVPD. s-Lim increased the heart rate corrected QT interval (QTc) (10.8%) at 50 µM and reduced heart rate at the concentrations of 30 (12.4%) and 50 µM (16.6%). s-Lim (10 µM) also inhibited the adrenergic response evoked by isoproterenol (ISO) (1 µM) reducing the increased of heart rate, LVDP and ECG changes. In ventricular cardiomyocyte, s-Lim antagonized the effect of dobutamine by preventing the increase of sarcomeric shortening, demonstrating a similar effect to atenolol (blocker ß1-AR). In vivo, s-Lim antagonized the effect of ISO (agonists ß1-AR), presenting a similar effect to propranolol (a non-selective blocker ß-AR). In ventricular cardiomyocyte, s-Lim did not alter the voltage dependence for ICa,L activation or the ICa,L density. In addition, s-Lim did not affect changes in the ECG effect mediated by 5 µM forskolin (an activator of adenylate cyclase). In an in vivo caffeine/ISO-induced arrhythmia model, s-Lim (1 mg/kg) presented antiarrhythmic action verified by a reduced arrhythmia score, heart rate, and occurrence of ventricular premature beats and inappropriate sinus tachycardia. These findings indicate that the antiarrhythmic activity of s-Lim is related to blockade of ß-AR in the heart.
Asunto(s)
Antiarrítmicos , Limoneno , Ratas Wistar , Receptores Adrenérgicos beta , Transducción de Señal , Animales , Ratas , Antiarrítmicos/farmacología , Masculino , Receptores Adrenérgicos beta/metabolismo , Limoneno/farmacología , Transducción de Señal/efectos de los fármacos , Terpenos/farmacología , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ciclohexenos/farmacología , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/fisiopatología , Isoproterenol/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismoRESUMEN
Introduction: The potential toxic effects of wastewater discharges containing silver nanoparticles (AgNPs) and their release into aquatic ecosystems on aquatic organisms are becoming a major concern for environmental and human health. However, the potential risks of AgNPs to aquatic organisms, especially for cardiac development by Focal adhesion pathway, are still poorly understood. Methods: The cardiac development of various concentrations of AgNPs in zebrafish were examined using stereoscopic microscope. The expression levels of cardiac development-related genes were analyzed by qRT-PCR and Whole-mount in situ hybridization (WISH). In addition, Illumina high-throughput global transcriptome analysis was performed to explore the potential signaling pathway involved in the treatment of zebrafish embryos by AgNPs after 72 h. Results: We systematically investigated the cardiac developing toxicity of AgNPs on the embryos of zebrafish. The results demonstrated that 2 or 4 mg/L AgNPs exposure induces cardiac developmental malformations, such as the appearance of pericardial edema phenotype. In addition, after 72 h of exposure, the mRNA levels of cardiac development-related genes, such as myh7, myh6, tpm1, nppa, tbx5, tbx20, myl7 and cmlc1, were significantly lower in AgNPs-treated zebrafish embryos than in control zebrafish embryos. Moreover, RNA sequencing, KEGG (Kyoto Encyclopedia of Genes) and Genomes and GSEA (gene set enrichment analysis) of the DEGs (differentially expressed genes) between the AgNPs-exposed and control groups indicated that the downregulated DEGs were mainly enriched in focal adhesion pathways. Further investigations demonstrated that the mRNA levels of focal adhesion pathway-related genes, such as igf1ra, shc3, grb2b, ptk2aa, akt1, itga4, parvaa, akt3b and vcla, were significantly decreased after AgNPs treatment in zebrafish. Conclusion: Thus, our findings illustrated that AgNPs could impair cardiac development by regulating the focal adhesion pathway in zebrafish.
Asunto(s)
Adhesiones Focales , Corazón , Nanopartículas del Metal , Plata , Pez Cebra , Animales , Pez Cebra/embriología , Nanopartículas del Metal/toxicidad , Nanopartículas del Metal/química , Corazón/efectos de los fármacos , Corazón/embriología , Plata/toxicidad , Plata/química , Adhesiones Focales/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Cardiovascular disease (CVD) represents a significant global health challenge, remaining the leading cause of illness and mortality worldwide. The adult heart's limited regenerative capacity poses a major obstacle in repairing extensive damage caused by conditions like myocardial infarction. In response to these challenges, nanomedicine has emerged as a promising field aimed at improving treatment outcomes through innovative drug delivery strategies. Nanocarriers, such as nanoparticles (NPs), offer a revolutionary approach by facilitating targeted delivery of therapeutic agents directly to the heart. This precise delivery system holds immense potential for treating various cardiac conditions by addressing underlying mechanisms such as inflammation, oxidative stress, cell death, extracellular matrix remodeling, prosurvival signaling, and angiogenic pathways associated with ischemia-reperfusion injury. In this review, we provide a concise summary of the fundamental mechanisms involved in cardiac remodeling and regeneration. We explore how nanoparticle-based drug delivery systems can effectively target the afore-mentioned mechanisms. Furthermore, we discuss clinical trials that have utilized nanoparticle-based drug delivery systems specifically designed for cardiac applications. These trials demonstrate the potential of nanomedicine in clinical settings, paving the way for future advancements in cardiac therapeutics through precise and efficient drug delivery. Overall, nanomedicine holds promise in revolutionizing the treatment landscape of cardiovascular diseases by offering targeted and effective therapeutic strategies that address the complex pathophysiology of cardiac injuries.
Asunto(s)
Nanomedicina , Medicina Regenerativa , Humanos , Medicina Regenerativa/métodos , Nanomedicina/métodos , Animales , Nanopartículas , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/terapia , Sistemas de Liberación de Medicamentos/métodos , Regeneración/efectos de los fármacos , Corazón/efectos de los fármacos , Corazón/fisiologíaRESUMEN
Advancements in human-engineered heart tissue have enhanced the understanding of cardiac cellular alteration. Nevertheless, a human model simulating pathological remodeling following myocardial infarction for therapeutic development remains essential. Here we develop an engineered model of myocardial repair that replicates the phased remodeling process, including hypoxic stress, fibrosis, and electrophysiological dysfunction. Transcriptomic analysis identifies nine critical signaling pathways related to cellular fate transitions, leading to the evaluation of seventeen modulators for their therapeutic potential in a mini-repair model. A scoring system quantitatively evaluates the restoration of abnormal electrophysiology, demonstrating that the phased combination of TGFß inhibitor SB431542, Rho kinase inhibitor Y27632, and WNT activator CHIR99021 yields enhanced functional restoration compared to single factor treatments in both engineered and mouse myocardial infarction model. This engineered heart tissue repair model effectively captures the phased remodeling following myocardial infarction, providing a crucial platform for discovering therapeutic targets for ischemic heart disease.
Asunto(s)
Dioxoles , Fibrosis , Infarto del Miocardio , Piridinas , Ingeniería de Tejidos , Animales , Infarto del Miocardio/patología , Infarto del Miocardio/terapia , Infarto del Miocardio/metabolismo , Infarto del Miocardio/genética , Ratones , Humanos , Piridinas/farmacología , Piridinas/uso terapéutico , Ingeniería de Tejidos/métodos , Dioxoles/farmacología , Dioxoles/uso terapéutico , Miocardio/patología , Miocardio/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Modelos Animales de Enfermedad , Transducción de Señal , Masculino , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Remodelación Ventricular/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Corazón/fisiopatología , Corazón/efectos de los fármacos , AmidasRESUMEN
The accumulation of the active pharmaceutical chemical in the environment usually results in environmental pollution to increase the risk to human health. Indomethacin is a non-steroidal anti-inflammatory drug that potentially causes systemic and developmental toxicity in various tissues. However, there have been few studies for its potential effects on cardiac development. In this study, we systematically determined the cardiotoxicity of acute indomethacin exposure in zebrafish at different concentrations with morphological, histological, and molecular levels. Specifically, the malformation and dysfunction of cardiac development, including pericardial oedema, abnormal heart rate, the larger distance between the venous sinus and bulbus arteriosus (SV-BA), enlargement of the pericardial area, and aberrant motor capability, were determined after indomethacin exposure. In addition, further investigation indicated that indomethacin exposure results in myocardial apoptosis in a dose-dependent manner in zebrafish at early developmental stage. Mechanistically, our results revealed that indomethacin exposure mainly regulates key cardiac development-related genes, especially genes related to the cardiac muscle contraction-related signaling pathway, in zebrafish embryos. Thus, our findings suggested that acute indomethacin exposure might cause cardiotoxicity by disturbing the cardiac muscle contraction-related signaling pathway and inducing myocardial apoptosis in zebrafish embryos.
Asunto(s)
Antiinflamatorios no Esteroideos , Apoptosis , Embrión no Mamífero , Corazón , Indometacina , Pez Cebra , Animales , Indometacina/toxicidad , Apoptosis/efectos de los fármacos , Corazón/efectos de los fármacos , Antiinflamatorios no Esteroideos/toxicidad , Embrión no Mamífero/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Contracción Miocárdica/efectos de los fármacos , Miocardio/patología , CardiotoxicidadRESUMEN
The adult mammalian heart has extremely limited cardiac regenerative capacity. Most cardiomyocytes live in a state of permanent cell-cycle arrest and are unable to re-enter the cycle. Cardiomyocytes switch from cell proliferation to a maturation state during neonatal development. Although several signaling pathways are involved in this transition, the molecular mechanisms by which these inputs coordinately regulate cardiomyocyte maturation are not fully understood. Retinoic acid (RA) plays a pivotal role in development, morphogenesis, and regeneration. Despite the importance of RA signaling in embryo heart development, little is known about its function in the early postnatal period. We found that mRNA expression of aldehyde dehydrogenase 1 family member A2 (Aldh1a2), which encodes the key enzyme for synthesizing all-trans retinoic acid (ATRA) and is an important regulator for RA signaling, was transiently upregulated in neonatal mouse ventricles. Single-cell transcriptome analysis and immunohistochemistry revealed that Aldh1a2 expression was enriched in cardiac fibroblasts during the early postnatal period. Administration of ATRA inhibited cardiomyocyte proliferation in cultured neonatal rat cardiomyocytes and human cardiomyocytes. RNA-seq analysis indicated that cell proliferation-related genes were downregulated in prenatal rat ventricular cardiomyocytes treated with ATRA, while cardiomyocyte maturation-related genes were upregulated. These findings suggest that RA signaling derived from cardiac fibroblasts is one of the key regulators of cardiomyocyte proliferation and maturation during neonatal heart development.
Asunto(s)
Familia de Aldehído Deshidrogenasa 1 , Proliferación Celular , Miocitos Cardíacos , Retinal-Deshidrogenasa , Transducción de Señal , Tretinoina , Animales , Tretinoina/farmacología , Tretinoina/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Ratones , Familia de Aldehído Deshidrogenasa 1/metabolismo , Familia de Aldehído Deshidrogenasa 1/genética , Retinal-Deshidrogenasa/metabolismo , Retinal-Deshidrogenasa/genética , Proliferación Celular/efectos de los fármacos , Ratas , Humanos , Regulación hacia Arriba , Animales Recién Nacidos , Ciclo Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Corazón/efectos de los fármacos , Corazón/crecimiento & desarrollo , Células CultivadasRESUMEN
Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARß/δ activation. Here, we assessed the impact of central leptin administration and PPARß/δ inhibition on cardiac function. Various cardiac properties, including QRS duration, R wave amplitude, heart rate (HR), ejection fraction (EF), end-diastolic left ventricular mass (EDLVM), end-diastolic volume (EDV), and cardiac output (CO) were analyzed. Central leptin infusion increased cardiac PPARß/δ protein content and decreased HR, QRS duration, and R wave amplitude. These changes induced by central leptin suggested a decrease in the ventricular wall growth, which was confirmed by MRI. In fact, the EDLVM was reduced by central leptin while increased in rats co-treated with leptin and GSK0660, a selective antagonist of PPARß/δ activity. In summary, central leptin plays a dual role in cardiac health, potentially leading to ventricular atrophy and improving heart function when PPARß/δ signaling is intact. The protective effects of leptin are lost by PPARß/δ inhibition, underscoring the importance of this pathway. These findings highlight the therapeutic potential of targeting leptin and PPARß/δ pathways to combat cardiac alterations and heart failure, particularly in the context of obesity.
Asunto(s)
Leptina , PPAR delta , PPAR-beta , Animales , Leptina/farmacología , Leptina/metabolismo , PPAR-beta/metabolismo , PPAR-beta/agonistas , PPAR delta/metabolismo , PPAR delta/agonistas , Ratas , Masculino , Corazón/efectos de los fármacos , Ratas Wistar , Atrofia , Frecuencia Cardíaca/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Sulfonas , TiofenosRESUMEN
Manganese (Mn2+) is an abundant chemical element in the earth's crust and is present in soil, water, and industrial environments, including mining, welding, and battery manufacturing. Manganese (Mn) is an essential metal needed as a cofactor for many enzymes to maintain proper biological functions. Excessive exposure to Mn in high doses can result in a condition known as manganism, which results in disorders of the neurological, cardiac, and pulmonary systems. The aim of this study was to assess cardiac susceptibility to manganese intoxication in Colossoma macropomum subjected to a fixed concentration of 4 mg/mL for a period of up to 96 h. This study used 45 Tambaquis (30.38 ± 3.5 g) divided into five groups of 9 animals/treatment. The treated groups were exposed to the manganese concentration for a period of 24, 48, 72, and 96 h, after which the animals' ECGs were recorded, showing heart rate, R-R interval, P-Q interval, QRS complex duration and S-T interval. The results showed that cardiac activity decreased as the contact time increased, with an increase in the P-Q and S-T intervals. This indicates that the breakdown of circulatory homeostasis in these animals was caused by contact time with manganese.
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Electrocardiografía , Manganeso , Animales , Manganeso/toxicidad , Frecuencia Cardíaca/efectos de los fármacos , Intoxicación por Manganeso , Corazón/efectos de los fármacos , Corazón/fisiologíaRESUMEN
The analysis of cardiac wall mechanics is of importance for understanding coronary heart diseases (CHD). The inhalation of ultrafine particles could deteriorate CHD. The aim of the study is to investigate the effects of cardiac wall mechanics on rats of myocardial infarction (MI) after long-term inhalation of ultrafine Zn particles. Cardiac wall stresses and strains were computed, based on echocardiographic and hemodynamic measurements. It was found that MI resulted in the significantly elevated stresses and the reduced strains. The short-term inhalation of ultrafine Zn particles decreased stresses and increased strains in MI rats, but the long-term inhalation had the opposite effects. Hence, the short-term inhalation of ultrafine Zn particles could alleviate the MI-induced LV dysfunction while the long-term inhalation impaired it.
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Infarto del Miocardio , Estrés Mecánico , Zinc , Infarto del Miocardio/fisiopatología , Animales , Zinc/administración & dosificación , Zinc/farmacología , Ratas , Masculino , Factores de Tiempo , Administración por Inhalación , Tamaño de la Partícula , Ratas Sprague-Dawley , Fenómenos Biomecánicos , Corazón/efectos de los fármacos , Corazón/fisiopatología , Hemodinámica/efectos de los fármacosRESUMEN
The current study aimed to explore the genotoxic impacts of the insecticide acetamiprid (ACP) on the myocardium and assess the ameliorative role of resveratrol (RSV). Male rats (10/group) were treated via oral route for 90 days: control; ACP (25â¯mg/kg); RSV (20â¯mg/kg); ACP+RSV. Peripheral blood micronucleus test, oxidative stress analysis, comet assay, 8-hydroxydeoxyguanosine and gene expression assessment were performed. The findings revealed that ACP has myocardial genotoxic effects, as demonstrated by increased micronucleus and 8-hydroxydeoxyguanosine formation and increased all comet parameters. Oxidative stress analysis demonstrated that ACP elevated H2O2 and NO levels while decreasing catalase and GST activities. Acetamiprid dysregulated the expression of genes related to oxidative stress and DNA damage response. However, RSV co-treatment resulted in significant protection against these genotoxic impacts. Resveratrol reduced DNA damage and restored the oxidative balance in the myocardium. Moreover, RSV modulated the Nrf2/HO-1 and Atm/P53 pathways, potentiating antioxidant defense and DNA repair.
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Antioxidantes , Daño del ADN , Insecticidas , Miocardio , Neonicotinoides , Estrés Oxidativo , Resveratrol , Animales , Resveratrol/farmacología , Masculino , Neonicotinoides/toxicidad , Daño del ADN/efectos de los fármacos , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Insecticidas/toxicidad , Pruebas de Micronúcleos , Ratas Wistar , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Ratas , Ensayo Cometa , 8-Hidroxi-2'-Desoxicoguanosina/metabolismo , Corazón/efectos de los fármacosRESUMEN
CONTEXT: Chlordecone (CLD) is a carcinogenic organochlorine pesticide. CLD was shown to disturb the activity of cardiac Na+-K+-ATPase and Ca2+-Mg2+-ATPase. Conditions affecting these transmembrane pumps are often associated with cardiac arrhythmias (CA). However, little is known about the role of CLD on atrial fibrillation (AF) incidence, the most common type of CA. HYPOTHESES: 1) Daily ingestion of CLD induces arrhythmogenic cardiac remodeling. 2) A phase of CLD withdrawal can reduce CLD-induced AF susceptibility. METHODS: Adult male Wistar rats (250 g-275 g) ingested daily-doses of CLD (0 µg/L, 0.1 µg/L, or 1 µg/L) diluted in their quotidian water for 4 weeks. From day (D)29 to D56, all rats received CLD-free water. Vulnerability to AF and cardiac function were evaluated at D28 and D56 by electrophysiological study, echocardiography, and optical-mapping. Levels of genes and proteins related to inflammation, fibrosis, and senescence were quantified by qPCR and immunoassays. RESULTS: Twenty-eight days of CLD exposure were associated with significantly increased AF vulnerability compared to CLD-free rats. Contamination with 1 µg/L CLD significantly reduced atrial conduction velocity (ERP, APD). CLD-weaning normalized food consumption and weight intake. However, after the CLD-withdrawal period of 28 days, AF inducibility, atrial inflammation (IL6, IL1ß), and atrial fibrosis (Masson's trichrome staining) remained significantly higher in rats exposed to 1 µg/L CLD compared to 0 µg/L. CONCLUSIONS: Prolonged CLD ingestion provokes atrial conduction slowing and increased risk of AF. Although CLD-weaning, some persistent damages occurred in the atrium like atrial fibrosis and atrial senescence signals, which are accompanied by atrial inflammation and arrhythmogenicity.
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Fibrilación Atrial , Fibrosis , Ratas Wistar , Animales , Masculino , Fibrilación Atrial/inducido químicamente , Insecticidas/toxicidad , Ratas , Corazón/efectos de los fármacos , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/patología , Miocardio/patología , Miocardio/metabolismoRESUMEN
Envenomation by reptile venom, particularly from lizards, poses significant health risks and can lead to physiological and cardiovascular changes. The venom of Heloderma horridum horridum, endemic to Colima, Mexico, was tested on Wistar rats. Electrocardiographic (ECG) data were collected pre-treatment and at 5-min intervals for 1 h post-envenomation. A specially designed computational linear regression algorithm (LRA) was used for the segmentation analysis of the ECG data to improve the detection of fiducial points (P, Q, R, S, and T) in ECG waves. Additionally, heart tissue was analyzed for macroscopic and microscopic changes. The results revealed significant electrocardiographic alterations, including pacemaker migration, junctional extrasystoles, and intraventricular conduction aberrations. By applying a linear regression algorithm, the study compensated for noise and anomalies in the isoelectric line in an ECG signal, improving the detection of P and T waves and the QRS complex with an efficiency of 97.5%. Cardiac enzyme evaluation indicated no statistically significant differences between the control and experimental groups. Macroscopic and microscopic examination revealed no apparent signs of damage or inflammatory responses in heart tissues. This study enhances our understanding of the cardiovascular impact of Heloderma venom, suggesting a greater influence on changes in conduction and arrhythmias than on direct cardiac damage to the myocardium.
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Algoritmos , Electrocardiografía , Ratas Wistar , Animales , Ratas , Modelos Lineales , Corazón/efectos de los fármacos , Lagartos , Masculino , Ponzoñas/toxicidad , México , Animales PonzoñososRESUMEN
Coronary artery disease (CAD) is often accompanied by abnormal cardiac structure and function, leading to an increased prognostic risk. However, less is known about the associations of mixed metals with abnormal cardiac structure and function in CAD patients. Here, we aimed to investigate the associations of exposure to metal mixtures with cardiac structure and function and potential interactions in a CAD population. We conducted a cross-sectional study from Southwest China that included 1555 CAD patients. The blood concentrations of 14 metals were measured via inductively coupled plasma spectrometry. CAD was defined as at least one vessel having stenosis ≥50% the vessel diameter. Echocardiography was used for cardiac structural and functional measurements. Bayesian kernel machine regression was applied to explore the overall effect, metal weight, and dose effect. Linear regression analysis was used to analyze the effects of single metals, metalâmetal interactions and metalâtraditional interactions. Finally, we found that the negative associations of mixed metals with cardiac structure was significant when the levels of all metals were below the 60th percentile. For cardiac function, changes in metals from 50th to 75th were associated with 0.954% and 0.683% decrease in left ventricular ejection fraction and left ventricular fractional shortening, respectively. Negative associations of copper and manganese with cardiac structure and function, whereas positive associations of titanium, selenium and molybdenum with several parameters were found. Antagonistic interactions between copper and tin and between selenium and several metals (manganese, copper and aluminum) (all Pinteraction terms < 0.05) were found. In conclusion, mixed metal exposure was negatively associated with cardiac structure and function in CAD patients. The main metals contributing to this negative associations were copper and manganese. Selenium or tin supplementation may reduce the adverse associations of copper and manganese with cardiac structure and function.
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Enfermedad de la Arteria Coronaria , Humanos , Estudios Transversales , Persona de Mediana Edad , Masculino , Femenino , China , Metales/sangre , Anciano , Corazón/efectos de los fármacos , Exposición a Riesgos Ambientales/estadística & datos numéricos , Contaminantes Ambientales/sangreRESUMEN
In Brazil, where Chagas disease is endemic, the most frequent form of transmission of the parasite is the oral route, associated with greater severity and worse response to benznidazole (BZ), the drug used in its treatment. This study aimed to evaluate the impact of gastrointestinal infection (GI) and BZ treatment on the parasitological and histopathological parameters in mice inoculated with a strain of T. cruzi II. Swiss mice were inoculated by GI and intraperitoneal (IP) routes with 2x106 culture-derived metacyclic trypomastigotes of the Y strain (TcII) of T. cruzi and were treated with BZ in the acute phase of the infection. Fresh blood examination, qPCR, histopathological and biochemical evaluations (enzymatic dosages and oxidative stress-OS) were performed. BZ treatment of uninfected animals caused changes in the liver, increased the activity of aspartate aminotransferase and alanine aminotransferase enzymes and OS, showing that the drug alone affects this organ. Inflammation and necrosis in the cardiac tissue were less intense and deaths occurred later in animals inoculated via the GI route than the animals inoculated via the IP route. BZ reduced the intensity of tissue lesions and avoided lethality in animals inoculated via the GI route, and decreased parasitemia and OS in those inoculated via both routes. Although BZ alone caused liver damage, it was less intense than that caused by both routes of inoculation. Infection with the Y strain of T. cruzi II via the GI route proved to be less virulent and pathogenic and responded better to treatment than the infection acquired via the IP route.
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Alanina Transaminasa , Aspartato Aminotransferasas , Enfermedad de Chagas , Corazón , Hígado , Nitroimidazoles , Parasitemia , Tripanocidas , Trypanosoma cruzi , Animales , Nitroimidazoles/uso terapéutico , Nitroimidazoles/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Ratones , Tripanocidas/uso terapéutico , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Hígado/parasitología , Hígado/patología , Alanina Transaminasa/sangre , Corazón/parasitología , Corazón/efectos de los fármacos , Aspartato Aminotransferasas/sangre , Masculino , Estrés Oxidativo/efectos de los fármacos , Miocardio/patología , Femenino , Enfermedades Gastrointestinales/parasitología , Enfermedades Gastrointestinales/tratamiento farmacológicoRESUMEN
Background and Objectives: Lower-extremity ischemia-reperfusion injury can induce distant organ ischemia, and patients with diabetes are particularly susceptible to ischemia-reperfusion injury. Sevoflurane, a widely used halogenated inhalation anesthetic, and fullerenol C60, a potent antioxidant, were investigated for their effects on heart and lung tissues in lower-extremity ischemia-reperfusion injury in streptozotocin (STZ)-induced diabetic mice. Materials and Methods: A total of 41 mice were divided into six groups: control (n = 6), diabetes-control (n = 7), diabetes-ischemia (n = 7), diabetes-ischemia-fullerenol C60 (n = 7), diabetes-ischemia-sevoflurane (n = 7), and diabetes-ischemia-fullerenol C60-sevoflurane (n = 7). Diabetes was induced in mice using a single intraperitoneal dose of 55 mg/kg STZ in all groups except for the control group. Mice in the control and diabetes-control groups underwent midline laparotomy and were sacrificed after 120 min. The DIR group underwent 120 min of lower-extremity ischemia followed by 120 min of reperfusion. In the DIR-F group, mice received 100 µg/kg fullerenol C60 intraperitoneally 30 min before IR. In the DIR-S group, sevoflurane and oxygen were administered during the IR procedure. In the DIR-FS group, fullerenol C60 and sevoflurane were administered. Biochemical and histological evaluations were performed on collected heart and lung tissues. Results: Histological examination of heart tissues showed significantly higher necrosis, polymorphonuclear leukocyte infiltration, edema, and total damage scores in the DIR group compared to controls. These effects were attenuated in fullerenol-treated groups. Lung tissue examination revealed more alveolar wall edema, hemorrhage, vascular congestion, polymorphonuclear leukocyte infiltration, and higher total damage scores in the DIR group compared to controls, with reduced injury parameters in the fullerenol-treated groups. Biochemical analyses indicated significantly higher total oxidative stress, oxidative stress index, and paraoxonase-1 levels in the DIR group compared to the control and diabetic groups. These levels were lower in the fullerenol-treated groups. Conclusions: Distant organ damage in the lung and heart tissues due to lower-extremity ischemia-reperfusion injury can be significantly reduced by fullerenol C60.
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Diabetes Mellitus Experimental , Fulerenos , Pulmón , Daño por Reperfusión , Sevoflurano , Animales , Sevoflurano/farmacología , Fulerenos/farmacología , Fulerenos/uso terapéutico , Ratones , Daño por Reperfusión/complicaciones , Diabetes Mellitus Experimental/complicaciones , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Masculino , Anestésicos por Inhalación/farmacología , Corazón/efectos de los fármacos , Extremidad Inferior/irrigación sanguínea , Miocardio/patología , Estreptozocina , Éteres Metílicos/farmacología , Éteres Metílicos/uso terapéuticoRESUMEN
BACKGROUND: Metamizole is banned in some countries because of its toxicity, although it is widely used in some European countries. In addition, there is limited information on its safety profile, and it is still debated whether it is toxic to the heart, lungs, liver, kidneys, and stomach. AIMS: Our study investigated the effects of metamizole on the heart, lung, liver, kidney, and stomach tissues of rats. METHODS: Eighteen rats were divided into three groups, wassix healthy (HG), 500 mg/kg metamizole (MT-500), and 1000 mg/kg metamizole (MT-1000). Metamizole was administered orally twice daily for 14 days. Meanwhile, the HG group received pure water orally. Biochemical, histopathologic, and macroscopic examinations were performed on blood samples and tissues. RESULTS: Malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) in the lung and gastric tissues of MT-500 and MT-1000 groups were almost the same as those of the HG (p > 0.05). However, MDA levels in the heart and liver tissues of MT-500 and MT-1000 groups were higher (p < 0.05) compared to the HG, while tGSH levels and SOD, and CAT activities were lower (p < 0.05). MDA levels of MT-500 and MT-1000 groups in the kidney tissue increased the most (p < 0.001), and tGSH levels and SOD and CAT activities decreased the most (p < 0.001) compared to HG. Metamizole did not cause oxidative damage in the lung and gastric tissue. While metamizole did not change troponin levels, it significantly increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine levels compared to HG. Histopathologically, mild damage was detected in heart tissue, moderate damage in liver tissue, and severe damage in renal tissue. However, no histopathologic damage was found in any groups' lung and gastric tissues. CONCLUSION: Metamizole should be used under strict control in patients with cardiac and liver diseases and it would be more appropriate not to use it in patients with renal disease.
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Antiinflamatorios no Esteroideos , Dipirona , Corazón , Riñón , Hígado , Pulmón , Estómago , Animales , Dipirona/toxicidad , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Antiinflamatorios no Esteroideos/toxicidad , Masculino , Ratas , Corazón/efectos de los fármacos , Estómago/efectos de los fármacos , Estómago/patología , Malondialdehído/metabolismo , Superóxido Dismutasa/metabolismo , Glutatión/metabolismo , Catalasa/metabolismo , Miocardio/patología , Miocardio/metabolismoRESUMEN
The diabetic heart is characterised by functional, morphological and metabolic alterations predisposing it to contractile failure. Chronic sympathetic activation is a feature of the pathogenesis of heart failure, however the type 1 diabetic heart shows desensitisation to ß-adrenergic stimulation. Here, we sought to understand the impact of repeated isoprenaline-mediated ß-stimulation upon cardiac mitochondrial respiratory capacity and substrate metabolism in the 90% pancreatectomy (Px) rat model of type 1 diabetes. We hypothesised these hearts would be relatively protected against the metabolic impact of stress-induced cardiomyopathy. We found that individually both Px and isoprenaline suppressed cardiac mitochondrial respiration, but that this was preserved in Px rats receiving isoprenaline. Px and isoprenaline had contrasting effects on cardiac substrate metabolism, with increased reliance upon cardiac fatty acid oxidation capacity and altered ketone metabolism in the hearts of Px rats, but enhanced capacity for glucose uptake and metabolism in isoprenaline-treated rats. Moreover, Px rats were protected against isoprenaline-induced mortality, whilst isoprenaline elevated cGMP and protected myocardial energetic status in Px rat hearts. Our work suggests that adrenergic stimulation may be protective in the type 1 diabetic heart, and underlines the importance of studying pathological features in combination when modeling complex disease in rodents.
Asunto(s)
Agonistas Adrenérgicos beta , Isoproterenol , Animales , Agonistas Adrenérgicos beta/farmacología , Ratas , Masculino , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Diabetes Mellitus Tipo 1/metabolismo , Glucosa/metabolismo , Modelos Animales de Enfermedad , Corazón/efectos de los fármacosRESUMEN
The cardioprotective effect of ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) in adult hearts is mediated by nitric oxide (NO). During the early developmental period, rat hearts exhibit higher resistance to ischemia-reperfusion (I/R) injury, contain higher levels of serum nitrates, and their resistance cannot be further increased by IPC or IPoC. NOS blocker (L-NAME) lowers their high resistance. Wistar rat hearts (postnatal Days 1 and 10) were perfused according to Langendorff and exposed to 40 min of global ischemia followed by reperfusion with or without IPoC. NO and reactive oxygen species donors (DEA-NONO, SIN-1) and L-NAME were administered. Tolerance to ischemia decreased between Days 1 and 10. DEA-NONO (low concentrations) significantly increased tolerance to I/R injury on both Days 1 and 10. SIN-1 increased tolerance to I/R injury on Day 10, but not on Day 1. L-NAME significantly reduced resistance to I/R injury on Day 1, but actually increased resistance to I/R injury on Day 10. Cardioprotection by IPoC on Day 10 was not affected by either NO donors or L-NAME. It can be concluded that resistance of the neonatal heart to I/R injury is NO dependent, but unlike in adult hearts, cardioprotective interventions, such as IPoC, are most likely NO independent.