RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Mountain-cultivated Panax ginseng C.A.Mey. (MCG) with high market price and various properties was valuable special local product in Northeast of Asia. MCG has been historically used to mitigate heart failure (HF) for thousand years, HF is a clinical manifestation of deficiency of "heart-qi" in traditional Chinese medicine. However, there was little report focus on the activities of extracted residue of MCG. AIM OF THE STUDY: A novel glycopeptide (APMCG-1) was isolated from step ethanol precipitations of alkaline protease-assisted extract from MCG residue. MATERIALS AND METHODS: The molecular weight and subunit structure of APMCG-1 were determined by FT-IR, HPLC and GPC technologies, as well as the H9c2 cells, Tg (kdrl:EGFP) zebrafish were performed to evaluated the protective effect of APMCG-1. RESULTS: APMCG-1 was identified as a glycopeptide containing seven monosaccharides and seven amino acids via O-lined bonds. Further, in vitro, APMCG-1 significantly decreased reactive oxygen species production and lactate dehydrogenase contents in palmitic acid (PA)-induced H9c2 cells. APMCG-1 also attenuated endoplasmic reticulum stress and mitochondria-mediated apoptosis in H9c2 cells via the PI3K/AKT signaling pathway. More importantly, APMCG-1 reduced the blood glucose, lipid contents, the levels of heart injury, oxidative stress and inflammation of 5 days post fertilization Tg (kdrl:EGFP) zebrafish with type 2 diabetic symptoms in vivo. CONCLUSIONS: APMCG-1 protects PA-induced H9c2 cells while reducing cardiac dysfunction in zebrafish with type 2 diabetic symptoms. The present study provides a new insight into the development of natural glycopeptides as heart-related drug therapies.
Assuntos
Diabetes Mellitus Tipo 2 , Glicopeptídeos , Insuficiência Cardíaca , Panax , Peixe-Zebra , Animais , Panax/química , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ratos , Linhagem Celular , Glicopeptídeos/farmacologia , Glicopeptídeos/química , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Cardiotônicos/farmacologia , Cardiotônicos/química , Cardiotônicos/isolamento & purificação , Cardiotônicos/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacosRESUMO
The clinical application of 5-fluorouracil (5-Fu), a potent chemotherapeutic agent, is often hindered by its well-documented cardiotoxic effects. Nevertheless, natural polyphenolic compounds like resveratrol (RES), known for their dual anti-tumor and cardioprotective properties, are potential adjunct therapeutic agents. In this investigation, we examined the combined utilization of RES and 5-Fu for the inhibition of gastric cancer using both in vitro and in vivo models, as well as their combined impact on cardiac cytotoxicity. Our study revealed that the co-administration of RES and 5-Fu effectively suppressed MFC cell viability, migration, and invasion, while also reducing tumor weight and volume. Mechanistically, the combined treatment prompted p53-mediated apoptosis and autophagy, leading to a considerable anti-tumor effect. Notably, RES mitigated the heightened oxidative stress induced by 5-Fu in cardiomyocytes, suppressed p53 and Bax expression, and elevated Bcl-2 levels. This favorable influence enhanced primary cardiomyocyte viability, decreased apoptosis and autophagy, and mitigated 5-Fu-induced cardiotoxicity. In summary, our findings suggested that RES holds promise as an adjunct therapy to enhance the efficacy of gastric cancer treatment in combination with 5-Fu, while simultaneously mitigating cardiotoxicity.
Assuntos
Apoptose , Sobrevivência Celular , Fluoruracila , Resveratrol , Neoplasias Gástricas , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Fluoruracila/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Humanos , Estresse Oxidativo/efeitos dos fármacos , Antimetabólitos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Camundongos , Movimento Celular/efeitos dos fármacosRESUMO
Myocardial ischemia-reperfusion (I/R) injury exacerbates cellular damage upon restoring blood flow to ischemic cardiac tissue, causing oxidative stress, inflammation, and apoptosis. This study investigates Nicotinamide Riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), for its cardioprotective effects. Administering NR to mice before I/R injury and evaluating heart function via echocardiography showed that NR significantly improved heart function, increased left ventricular ejection fraction (LVEF) and fractional shortening (FS), and reduced left ventricular end-diastolic (LVDd) and end-systolic diameters (LVSd). NR also restored E/A and E/e' ratios. It reduced cardiomyocyte apoptosis both in vivo and in vitro, inhibiting elevated caspase-3 activity and returning Bax protein levels to normal. In vitro, NR reduced the apoptotic rate in hydrogen peroxide (H2O2)-treated HL-1 cells from 30% to 10%. Mechanistically, NR modulated the SIRT3/mtROS/JNK pathway, reversing H2O2-induced SIRT3 downregulation, reducing mitochondrial reactive oxygen species (mtROS), and inhibiting JNK activation. Using SIRT3-knockout (SIRT3-KO) mice, we confirmed that NR's cardioprotective effects depend on SIRT3. Echocardiography showed that NR's benefits were abrogated in SIRT3-KO mice. In conclusion, NR provides significant cardioprotection against myocardial I/R injury by enhancing NAD+ levels and modulating the SIRT3/mtROS/JNK pathway, suggesting its potential as a novel therapeutic agent for ischemic heart diseases, meriting further clinical research.
Assuntos
Apoptose , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica , Niacinamida , Compostos de Piridínio , Espécies Reativas de Oxigênio , Sirtuína 3 , Animais , Sirtuína 3/metabolismo , Sirtuína 3/genética , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Camundongos , Compostos de Piridínio/farmacologia , Compostos de Piridínio/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Humanos , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Modelos Animais de Doenças , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: In pediatric critical care, vasoactive/inotropic support is widely used in patients with heart failure, but it remains controversial because the influence of multiple medications and the interplay between their inotropic and vasoactive effects on a given patient are hard to predict. Robust evidence supporting their use and quantifying their effects in this group of patients is scarce. STUDY QUESTION: The aim of this study was to characterize the effect of vasoactive medications on various cardiovascular parameters in pediatric patient with decreased ejection fraction. STUDY DESIGN: Clinical-data based physiologic simulator study. MEASURE AND OUTCOMES: We used a physics-based computer simulator for quantifying the response of cardiovascular parameters to the administration of various types of vasoactive/inotropic medications in pediatric patients with decreased ejection fraction. The simulator allowed us to study the impact of increasing medication dosage and the simultaneous administration of some vasoactive agents. Correlation and linear regression analyses yielded the quantified effects on the vasoactive/inotropic support. RESULTS: Cardiac output and systemic venous saturation significantly increased with the administration of dobutamine and milrinone in isolation, and combination of milrinone with dobutamine, dopamine, or epinephrine. Both parameters decreased with the administration of epinephrine and norepinephrine in isolation. No significant change in these hemodynamic parameters was observed with the administration of dopamine in isolation. CONCLUSIONS: Milrinone and dobutamine were the only vasoactive medications that, when used in isolation, improved systemic oxygen delivery. Milrinone in combination with dobutamine, dopamine, or epinephrine also increased systemic oxygen delivery. The induced increment on afterload can negatively affect systemic oxygen delivery.
Assuntos
Cardiotônicos , Simulação por Computador , Dobutamina , Epinefrina , Insuficiência Cardíaca Sistólica , Monitorização Hemodinâmica , Milrinona , Humanos , Criança , Milrinona/uso terapêutico , Milrinona/administração & dosagem , Milrinona/farmacologia , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Cardiotônicos/administração & dosagem , Dobutamina/farmacologia , Dobutamina/administração & dosagem , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Insuficiência Cardíaca Sistólica/fisiopatologia , Epinefrina/administração & dosagem , Monitorização Hemodinâmica/métodos , Dopamina/farmacologia , Dopamina/administração & dosagem , Dopamina/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Norepinefrina/administração & dosagem , Norepinefrina/uso terapêutico , Norepinefrina/farmacologia , Masculino , Volume Sistólico/efeitos dos fármacos , Feminino , Pré-Escolar , Quimioterapia CombinadaRESUMO
Traditionally, garlic has a valuable role in preventing and reducing the incidence of many diseases and pathophysiological disorders. Consequently, some researchers have focused on the beneficial cardiovascular properties of diallyl trisulfide (DATS), the most potent polysulfide isolated from garlic. Therefore, in this review, we collected the available data on DATS, its biochemical synthesis, metabolism and pharmacokinetics, and gathered the current knowledge and the role of DATS in cardiovascular diseases. Overall, this review summarizes the cardioprotective effects of DATS and brings together all previous findings on its protective molecular mechanisms, which are mainly based on the potent anti-apoptotic, anti-inflammatory, and antioxidant potential of this polysulfide. Our review is an important cornerstone for further basic and clinical research on DATS as a new therapeutic agent for the treatment of numerous heart diseases.
Assuntos
Compostos Alílicos , Doenças Cardiovasculares , Sulfetos , Sulfetos/uso terapêutico , Sulfetos/farmacologia , Compostos Alílicos/farmacologia , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Alho/química , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/metabolismoRESUMO
Cardiotonic steroids are known to bind to Na+/K+-ATPase and regulate several biological processes, including the immune response. The synthetic cardiotonic steroid γ-Benzylidene Digoxin 8 (BD-8) is emerging as a promising immunomodulatory molecule, although it has remained largely unexplored. Therefore, we tested the immunomodulatory potential of BD-8 both in vitro and in vivo. Hence, primary mouse macrophages were incubated with combinations of BD-8 and the pro-inflammatory fungal protein zymosan (ZYM). Nitric oxide (NO) production was determined by Griess reagent and cytokines production was assessed by enzyme-linked immunosorbent assay. Inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), p-nuclear factor kappa B p65 (NF-κB p65), p-extracellular signal-regulated kinase (p-ERK), and p-p38 were evaluated by flow cytometry. Macrophages exposed to BD-8 displayed reduced phagocytic activity, NO levels, and production of the proinflammatory cytokine IL-1ß induced by ZYM. Furthermore, BD-8 diminished the expression of iNOS and phosphorylation of NF-κB p65, ERK, and p38. Additionally, BD-8 exhibited anti-inflammatory capacity in vivo in a carrageenan-induced mouse paw edema model. Taken together, these findings demonstrate the anti-inflammatory activity of BD-8 and further reinforce the potential of cardiotonic steroids and their derivatives as immunomodulatory molecules.
Assuntos
Anti-Inflamatórios , Digoxina , Macrófagos , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Digoxina/farmacologia , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismo , Masculino , Citocinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Cardiotônicos/farmacologia , Fator de Transcrição RelA/metabolismo , Interleucina-1beta/metabolismo , Zimosan , Edema/tratamento farmacológico , Edema/patologia , Inflamação/tratamento farmacológico , Inflamação/patologiaRESUMO
Despite extensive progress in the knowledge and understanding of cardiovascular diseases and significant advances in pharmacological treatments and procedural interventions, cardiovascular diseases (CVD) remain the leading cause of death globally. Mitochondrial dynamics refers to the repetitive cycle of fission and fusion of the mitochondrial network. Fission and fusion balance regulate mitochondrial shape and influence physiology, quality and homeostasis. Mitophagy is a process that eliminates aberrant mitochondria. Melatonin (Mel) is a pineal-synthesized hormone with a range of pharmacological properties. Numerous nonclinical trials have demonstrated that Mel provides cardioprotection against ischemia/reperfusion, cardiomyopathies, atherosclerosis and cardiotoxicity. Recently, interest has grown in how mitochondrial dynamics contribute to melatonin cardioprotective effects. This review assesses the literature on the protective effects of Mel against CVD via the regulation of mitochondrial dynamics and mitophagy in both in-vivo and in-vitro studies. The signalling pathways underlying its cardioprotective effects were reviewed. Mel modulated mitochondrial dynamics and mitophagy proteins by upregulation of mitofusin, inhibition of DRP1 and regulation of mitophagy-related proteins. The evidence supports a significant role of Mel in mitochondrial dynamics and mitophagy quality control in CVD.
Assuntos
Doenças Cardiovasculares , Melatonina , Dinâmica Mitocondrial , Mitofagia , Melatonina/farmacologia , Mitofagia/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Humanos , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/prevenção & controle , Cardiotônicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacosRESUMO
Cardiovascular diseases remain the leading cause of death in the world, and that is why finding an effective and multi-functional treatment alternative to combat these diseases has become more important. Fibrates and thiazolidinediones, peroxisome proliferator-activated receptors alpha and gamma are the pharmacological therapies used to treat dyslipidemia and type 2 diabetes, respectively. New mechanisms of action of these drugs have been found, demonstrating their pleiotropic effects, which contribute to preserving the heart by reducing or even preventing myocardial damage. Here, we review the mechanisms underlying the cardioprotective effects of PPAR agonists and regulating morphological and physiological heart alterations (metabolic flexibility, mitochondrial damage, apoptosis, structural remodeling, and inflammation). Moreover, clinical evidence regarding the cardioprotective effect of PPAR agonists is also addressed.
Assuntos
Miocárdio , PPAR alfa , PPAR gama , Humanos , PPAR gama/agonistas , PPAR gama/metabolismo , PPAR alfa/agonistas , PPAR alfa/metabolismo , Miocárdio/patologia , Miocárdio/metabolismo , Animais , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêuticoRESUMO
Myocardial ischaemia reperfusion injury (IRI) occurring from acute coronary artery disease or cardiac surgical interventions such as bypass surgery can result in myocardial dysfunction, presenting as, myocardial "stunning", arrhythmias, infarction, and adverse cardiac remodelling, and may lead to both a systemic and a localised inflammatory response. This localised cardiac inflammatory response is regulated through the nucleotide-binding oligomerisation domain (NACHT), leucine-rich repeat (LRR)-containing protein family pyrin domain (PYD)-3 (NLRP3) inflammasome, a multimeric structure whose components are present within both cardiomyocytes and in cardiac fibroblasts. The NLRP3 inflammasome is activated via numerous danger signals produced by IRI and is central to the resultant innate immune response. Inhibition of this inherent inflammatory response has been shown to protect the myocardium and stop the occurrence of the systemic inflammatory response syndrome following the re-establishment of cardiac circulation. Therapies to prevent NLRP3 inflammasome formation in the clinic are currently lacking, and therefore, new pharmacotherapies are required. This review will highlight the role of the NLRP3 inflammasome within the myocardium during IRI and will examine the therapeutic value of inflammasome inhibition with particular attention to carbon monoxide, nitric oxide, and hydrogen sulphide as potential pharmacological inhibitors of NLRP3 inflammasome activation.
Assuntos
Monóxido de Carbono , Sulfeto de Hidrogênio , Inflamassomos , Infarto do Miocárdio , Proteína 3 que Contém Domínio de Pirina da Família NLR , Óxido Nítrico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Humanos , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Inflamassomos/metabolismo , Óxido Nítrico/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Animais , Monóxido de Carbono/metabolismo , Gasotransmissores/metabolismo , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/patologiaRESUMO
ABSTRACT: The effects of the calcium sensitizer levosimendan on hemodynamics and survival in guinea pigs intoxicated with the calcium blockers verapamil or diltiazem were evaluated in a randomized controlled study. One hundred four animals were randomized to be intoxicated with either verapamil (2.0 mg/kg) or diltiazem (4.5 mg/kg) and thereafter further randomized into 6 groups which received either saline (control), 3 different regimes of levosimendan, calcium chloride, and levosimendan combined with calcium chloride. The hemodynamics and survival of the animals were followed for 60 minutes after intoxication.The negative inotropic effect of calcium blockers was seen as a decrease by over 70% of the positive derivative of the left ventricular pressure. This was reversed by levosimendan. Moreover, both verapamil and diltiazem-induced marked hypotension (-69% and -63% of the baseline value, respectively) which was also reversed by levosimendan. The combined levosimendan and calcium chloride treatment had a synergistic effect in reversing verapamil or diltiazem-induced deterioration in hemodynamics.Both verapamil and diltiazem intoxications decreased the survival rate of guinea pigs to 13%. Levosimendan addition improved survival dose-dependently up to a survival rate of 75% and 88% in the verapamil and diltiazem groups, respectively. Low dose of levosimendan combined with calcium chloride improved survival in verapamil and diltiazem group to 88% and 100%, respectively.In conclusion, the administration of levosimendan improved hemodynamics and survival in calcium channel blocker intoxicated guinea pigs. The synergistic effect of levosimendan and calcium chloride suggests that this combination could be an effective antidote in calcium channel blocker intoxications.
Assuntos
Antídotos , Bloqueadores dos Canais de Cálcio , Diltiazem , Hidrazonas , Piridazinas , Simendana , Verapamil , Animais , Simendana/farmacologia , Cobaias , Bloqueadores dos Canais de Cálcio/farmacologia , Hidrazonas/farmacologia , Piridazinas/farmacologia , Diltiazem/farmacologia , Verapamil/farmacologia , Antídotos/farmacologia , Masculino , Hemodinâmica/efeitos dos fármacos , Cloreto de Cálcio , Cardiotônicos/farmacologia , Sinergismo Farmacológico , Modelos Animais de Doenças , Quimioterapia Combinada , Taxa de SobrevidaRESUMO
BACKGROUND: Mitochondria are known to be involved in mediating the calorigenic effects of thyroid hormones. With an abundance of these hormones, alterations in energy metabolism and cellular respiration take place, leading to the development of cardiac hypertrophy. Vitamin D has recently gained attention due to its involvement in the regulation of mitochondrial function, demonstrating promising potential in preserving the integrity and functionality of the mitochondrial network. The present study aimed to investigate the therapeutic potential of Vitamin D on cardiac hypertrophy induced by hyperthyroidism, with a focus on the contributions of mitophagy and apoptosis as possible underlying molecular mechanisms. METHODS AND RESULTS: The rats were divided into three groups: control; hyperthyroid; hyperthyroid + Vitamin D. Hyperthyroidism was induced by Levothyroxine administration for four weeks. Serum thyroid hormones levels, myocardial damage markers, cardiac hypertrophy indices, and histological examination were assessed. The assessment of Malondialdehyde (MDA) levels and the expression of the related genes were conducted using heart tissue samples. Vitamin D pretreatment exhibited a significant improvement in the hyperthyroidism-induced decline in markers indicative of myocardial damage, oxidative stress, and indices of cardiac hypertrophy. Vitamin D pretreatment also improved the downregulation observed in myocardial expression levels of genes involved in the regulation of mitophagy and apoptosis, including PTEN putative kinase 1 (PINK1), Mitofusin-2 (MFN2), Dynamin-related Protein 1 (DRP1), and B cell lymphoma-2 (Bcl-2), induced by hyperthyroidism. CONCLUSIONS: These results suggest that supplementation with Vitamin D could be advantageous in preventing the progression of cardiac hypertrophy and myocardial damage.
Assuntos
Apoptose , Cardiomegalia , Cardiotônicos , Modelos Animais de Doenças , Hipertireoidismo , Mitofagia , Tiroxina , Vitamina D , Animais , Hipertireoidismo/complicações , Hipertireoidismo/metabolismo , Hipertireoidismo/tratamento farmacológico , Mitofagia/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ratos , Tiroxina/farmacologia , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Vitamina D/farmacologia , Masculino , Cardiotônicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas Quinases/metabolismo , Proteínas Quinases/genética , Malondialdeído/metabolismo , Hormônios Tireóideos/metabolismoRESUMO
Combination therapy is increasingly favored by pharmaceutical companies and researchers as an effective way to quickly discover new drugs with excellent efficacy, especially in the treatment of complex diseases. Previously, we successfully developed a computational screening method to identify such combinations, although it fell short in elucidating their synergistic mechanisms. In this work, we have transitioned to a highest single agent (HSA) synergy model for network screening, which streamlines the discovery of promising combinations and facilitates the investigation of their synergistic effects. Through this refined approach, the trimebutine-methoxsalen combination emerged as a promising candidate for heart failure (HF) treatment, exhibiting significant in vitro cardioprotective effects and effectively mitigating isoproterenol (ISO)-induced structural remodeling in the mouse heart. Further mechanistic studies have demonstrated that trimebutine and methoxsalen could synergistically inhibit intracellular calcium overload in myocardial cells and reduce the production of ROS, thus exerting cardioprotective effects. Overall, this study introduces an advanced computational strategy that not only identifies a novel combination therapy against HF but also sheds light on its underlying synergistic mechanisms.
Assuntos
Insuficiência Cardíaca , Animais , Insuficiência Cardíaca/tratamento farmacológico , Camundongos , Sinergismo Farmacológico , Quimioterapia Combinada , Avaliação Pré-Clínica de Medicamentos , Cardiotônicos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Isoproterenol/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Cálcio/metabolismoRESUMO
The use of non-vitamin K antagonist oral anticoagulants (NOACs) has brought a significant progress in the management of cardiovascular diseases, considered clinically superior to vitamin K antagonists (VKAs) particularly in the prevention and treatment of thromboembolic events. In addition, numerous advantages such as fixed dosing, lack of laboratory monitoring, and fewer food and drug-to-drug interactions make the use of NOACs superior to VKAs. While NOACs are synthetic drugs prescribed for specific conditions, nattokinase (NK) is a natural enzyme derived from food that has potential health benefits. Various experimental and clinical studies reported the positive effects of NK on the circulatory system, including the thinning of blood and the dissolution of blood clots. This enzyme showed not only fibrinolytic activity due to its ability to degrade fibrin, but also an affinity as a substrate for plasmin. Recent studies have shown that NK has additional cardioprotective effects, such as antihypertensive and anti-atherosclerotic effects. In this narrative review, we presented the cardioprotective properties of two different approaches that go beyond anticoagulation: NOACs and NK. By combining evidence from basic research with clinical findings, we aim to elucidate the comparative cardioprotective efficacy of these interventions and highlight their respective roles in modern cardiovascular care.
Assuntos
Anticoagulantes , Cardiotônicos , Doenças Cardiovasculares , Subtilisinas , Animais , Humanos , Administração Oral , Anticoagulantes/uso terapêutico , Anticoagulantes/farmacologia , Cardiotônicos/uso terapêutico , Cardiotônicos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Subtilisinas/farmacologia , Subtilisinas/uso terapêuticoRESUMO
Clinical studies have previously established the role of olive products in cardiovascular disease (CVD) prevention, whilst the identification of the responsible constituents for the beneficial effects is still pending. We sought to assess and compare the cardioprotective potential of oleuropein (OL), hydroxytyrosol (HT), oleocanthal (OC) and oleanolic Acid (OA), regarding Ischemia/Reperfusion Injury (IRI) and CVD risk factors alleviation. The scope of the study was to design a potent and safe combinatorial therapy for high-cardiovascular-risk patients on a bench-to-bedside approach. We evaluated the IRI-limiting potential of 6-weeks treatment with OL, HT, OC or OA at nutritional doses, in healthy and metabolic syndrome (MS)-burdened mice. Three combinatorial regimens were designed and the mixture with preponderant benefits (OL-HT-OC, Combo 2), including infarct sparing and antiglycemic potency, compared to the isolated compounds, was further investigated for its anti-atherosclerotic effects. In vivo experiments revealed that the combination regimen of Combo 2 presented the most favorable effects in limiting infarct size and hyperglycemia, which was selected to be further investigated in the clinical setting in Chronic Coronary Artery Syndrome (CCAS) patients. Cardiac function, inflammation markers and oxidative stress were assessed at baseline and after 4 weeks of treatment with the OL-HT-OC supplement in the clinical study. We found that OL, OC and OA significantly reduced infarct size in vivo compared to Controls. OL exhibited antihyperglycemic properties and OA attenuated hypercholesterolemia. OL-HT-OA, OL-HT-OC and OL-HT-OC-OA combination regimens were cardioprotective, whereas only OL-HT-OC mitigated hyperglycemia. Combo 2 cardioprotection was attributed to apoptosis suppression, enhanced antioxidant effects and upregulation of antioxidant enzymes. Additionally, it reduced atherosclerotic plaque extent in vivo. OL-HT-OC supplement ameliorated cardiac, vascular and endothelial function in the small-scale clinical study. Conclusively, OL-HT-OC combination therapy exerts potent cardioprotective, antihyperglycemic and anti-atherosclerotic properties in vivo, with remarkable and clinically translatable cardiovascular benefits in high-risk patients.
Assuntos
Cardiotônicos , Glucosídeos Iridoides , Síndrome Metabólica , Infarto do Miocárdio , Álcool Feniletílico , Animais , Camundongos , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Cardiotônicos/administração & dosagem , Masculino , Iridoides/farmacologia , Iridoides/uso terapêutico , Modelos Animais de Doenças , Humanos , Estresse Oxidativo/efeitos dos fármacos , Monoterpenos CiclopentânicosRESUMO
Pimobendan is not currently approved for use in cats, although its usefulness in feline hypertrophic cardiomyopathy has been suggested. Reports indicate an increase in arrhythmic events following oral administration to healthy cats. Given the greater potency of intravenous administration compared to oral intake, it is conceivable that the incidence of arrhythmias may be increased following pimobendan injection. Therefore, this study aimed to investigate the proarrhythmic effects of pimobendan injection in cats. Five clinically healthy cats underwent physical examination, echocardiography, blood pressure measurements, and 24-hour Holter electrocardiography immediately before and after receiving pimobendan as an intravenous bolus dose of 0.15 mg/kg twice daily for 3 days. Additionally, a 24-hour Holter electrocardiography recording was conducted on the third day of pimobendan or placebo IV administration to assess heart rate, arrhythmias, and heart rate variability. Following pimobendan administration, there was a significant increase in total 24-hour heart rate. Echocardiography revealed a significant increase in mitral valve annulus systolic velocity (S') on the ventricular septal wall side, indicative of enhanced contractility. Only one cat exhibited paroxysmal ventricular tachycardia and an increase in the frequency of arrhythmic events. Conversely, in the remaining cats, a decreasing trend in the number of arrhythmias was observed. These findings indicate that intravenous administration of pimobendan may not be implicated in the onset of arrhythmias. Nevertheless, further research is warranted to explore the effects of intravenous pimobendan administration in cats with myocardial disease.
Assuntos
Arritmias Cardíacas , Frequência Cardíaca , Piridazinas , Animais , Piridazinas/administração & dosagem , Piridazinas/farmacologia , Piridazinas/efeitos adversos , Gatos , Arritmias Cardíacas/veterinária , Arritmias Cardíacas/induzido quimicamente , Projetos Piloto , Masculino , Frequência Cardíaca/efeitos dos fármacos , Feminino , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Ecocardiografia/veterinária , Injeções Intravenosas/veterinária , Doenças do Gato/induzido quimicamente , Eletrocardiografia Ambulatorial/veterináriaRESUMO
This study aimed to evaluate the cardioprotective effects of ghrelin in septic mice, focusing on its anti-inflammatory and antioxidant properties. Thirty-five male Swiss mice (8-12 weeks old, 23-33g) were randomly assigned to five groups (n = 7 each): (1) Normal, fed usual diets, (2) Sham, subjected to anesthesia and laparotomy, (3) Sepsis, subjected to cecal ligation and puncture, (4) Vehicle, given an equivalent volume of intraperitoneal saline injections immediately after cecal ligation and puncture, and (5) Ghrelin-treated, administered 80 µg/kg ghrelin intraperitoneal injections immediately following cecal ligation and puncture. Serum levels of tumor necrosis factor-alpha (TNF-α), macrophage migration inhibitory factor (MIF), toll-like receptor 4 (TLR4), and 8-epi-prostaglandin F2 alpha (8-epi-PGF2α) were measured. The extent of cardiac damage was also evaluated histologically. The mean serum levels of TNF-α, MIF, TLR4, and 8-epi-PGF2α levels were significantly higher in the sepsis and vehicle groups than in the normal and sham groups. The levels were significantly lower in the ghrelin-treated group than in the vehicle and sepsis groups. Histological analysis revealed normal myocardial architecture in the normal and sham groups, whereas the sepsis and vehicle groups had severe myocardial injury. The ghrelin-treated group displayed histological features similar to the sham group, indicating reduced myocardial damage. Ghrelin ameliorated sepsis-induced cardiotoxicity in mice by exhibiting strong anti-inflammatory and antioxidant effects. These findings suggest that ghrelin may be a promising therapeutic candidate for the prevention of sepsis-induced cardiotoxicity.
Assuntos
Cardiotônicos , Endotoxemia , Grelina , Fator de Necrose Tumoral alfa , Animais , Camundongos , Masculino , Grelina/sangue , Endotoxemia/sangue , Endotoxemia/tratamento farmacológico , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Fator de Necrose Tumoral alfa/sangue , Receptor 4 Toll-Like/metabolismo , Modelos Animais de Doenças , Dinoprosta/análogos & derivados , Dinoprosta/sangue , Fatores Inibidores da Migração de Macrófagos/sangue , Sepse/tratamento farmacológico , Sepse/complicações , Antioxidantes/farmacologiaRESUMO
BACKGROUND: Although blood flow is restored after treatment of myocardial infarction (MI), myocardial ischemia and reperfusion (I/R) can cause cardiac injury, which is a leading cause of heart failure. Gastrodin (GAS) exerts protective effects against brain, heart, and kidney I/R. However, its pharmacological mechanism in myocardial I/R injury (MIRI) remains unclear. PURPOSE: GAS regulates autophagy in various diseases, such as acute hepatitis, vascular dementia, and stroke. We hypothesized that GAS could repair mitochondrial damage and regulate autophagy to protect against MIRI. STUDY DESIGN: Male C57BL/6 mice and H9C2 cells were subjected to I/R and hypoxia-reoxygenation (H/R) injury after GAS administration, respectively, to assess the impact of GAS on cardiomyocyte phenotypes, heart, and mitochondrial structure and function. The effect of GAS on cardiac function and mitochondrial structure in patients undergoing cardiac surgery has been observed in clinical practice. METHODS: The effects of GAS on cardiac structure and function, mitochondrial structure, and expression of related molecules in an animal model of MIRI were evaluated using immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), transmission electron microscopy, western blotting, and gene sequencing. Its effects on the morphological, molecular, and functional phenotypes of cardiomyocytes undergoing H/R were observed using immunohistochemical staining, real-time quantitative PCR, and western blotting. RESULTS: GAS significantly reduces myocardial infarct size and improves cardiac function in MIRI mice in animal models and increases cardiomyocyte viability and reduces cardiomyocyte damage in cellular models. In clinical practice, myocardial injury was alleviated with better cardiac function in patients undergoing cardiac surgery after the application of GAS; improvements in mitochondria and autophagy activation were also observed. GAS primarily exerts cardioprotective effects through activation of the PINK1/Parkin pathway, which promotes mitochondrial autophagy to clear damaged mitochondria. CONCLUSION: GAS can promote mitophagy and preserve mitochondria through PINK1/Parkin, thus indicating its tremendous potential as an effective perioperative myocardial protective agent.
Assuntos
Álcoois Benzílicos , Glucosídeos , Camundongos Endogâmicos C57BL , Mitofagia , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Proteínas Quinases , Ubiquitina-Proteína Ligases , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Álcoois Benzílicos/farmacologia , Glucosídeos/farmacologia , Mitofagia/efeitos dos fármacos , Masculino , Ubiquitina-Proteína Ligases/metabolismo , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Quinases/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Humanos , Miocárdio/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Cardiotônicos/farmacologiaRESUMO
Baicalin, a flavonoid glycoside from Scutellaria baicalensis Georgi., exerts anti-hypertensive effects. The present study aimed to assess the cardioprotective role of baicalin and explore its potential mechanisms. Network pharmacology analysis pointed out a total of 477 potential targets of baicalin were obtained from the PharmMapper and SwissTargetPrediction databases, while 11,280 targets were identified associating with hypertensive heart disease from GeneCards database. Based on the above 382 common targets, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed enrichment in the regulation of cardiac hypertrophy, cardiac contraction, cardiac relaxation, as well as the mitogen-activated protein kinase (MAPK) and other signaling pathways. Moreover, baicalin treatment exhibited the amelioration of increased cardiac index and pathological alterations in angiotensin II (Ang II)-infused C57BL/6 mice. Furthermore, baicalin treatment demonstrated a reduction in cell surface area and a down-regulation of hypertrophy markers (including atrial natriuretic peptide and brain natriuretic peptide) in vivo and in vitro. In addition, baicalin treatment led to a decrease in the expression of phosphorylated c-Jun N-terminal kinase (p-JNK)/JNK, phosphorylated p38 (p-p38)/p38, and phosphorylated extracellular signal-regulated kinase (p-ERK)/ERK in the cardiac tissues of Ang II-infused mice and Ang II-stimulated H9c2 cells. These findings highlight the cardioprotective effects of baicalin, as it alleviates hypertensive cardiac injury, cardiac hypertrophy, and the activation of the MAPK pathway.
Assuntos
Angiotensina II , Cardiomegalia , Flavonoides , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Animais , Flavonoides/farmacologia , Angiotensina II/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Masculino , Farmacologia em Rede , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Linhagem Celular , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêuticoRESUMO
Phosphocreatine (PCr), a naturally occurring creatine phosphorylated molecule, is a high-energy phosphate compound that is one of the most important substances involved in cell energy metabolism, and also has anti-apoptosis and anti-oxidative stress effects. It is precisely because of its role in maintaining energy homeostasis that PCr is widely used in diseases related to energy damage. In the regulation of cell signal, PCr mainly plays a role through MAPK, NF-κB, PI3K/AKT, ERK/Nrf2/HO-1 and JAK2/STAT3. In clinical applications, PCr is commonly used as a cardioprotective drug, such as ischemic heart disease, myocardial fibrosis, myocardial infarction, arrhythmia, and myocarditis. In recent years, further research on PCr has found that PCr also has a positive role in the treatment of other diseases, including diabetes-induced liver injury, kidney injury, cerebral ischemia-reperfusion injury, and neurodegenerative diseases. In this paper, the literature on PCr in three databases, Web of Sciences, SciFinder, and PubMed, was summarized and analyzed, and the research progress of PCr in recent years was reviewed, hoping to provide help for the expansion of its application in clinical therapy.