RESUMEN
Ferroptosis is an important pathological mechanism of chronic heart failure (CHF). This study aimed to investigate the protective mechanism of Astragaloside IV (AS-IV) on CHF rats by integrating bioinformatics and ferroptosis. CHF-related targets and ferroptosis-related targets were collected. After the intersection, the common targets were obtained. The PPI network of the common targets was constructed, and topological analysis of the network was carried out. The target with the highest topological parameter values was selected as the key target. The key target p53 was obtained through bioinformatics analysis, and its molecular docking model with AS-IV was obtained, as well as molecular dynamics simulation analysis. The rat models of CHF after myocardial infarction were established by ligation of left coronary artery and treated with AS-IV for 4 weeks. AS-IV treatment significantly improved cardiac function in CHF rats, improved cardiomyocyte morphology and myocardial fibrosis, reduced mitochondrial damage, decreased myocardial MDA and Fe2+ content, increased GSH content, inhibited the expression of p53 and p-p53, and up-regulated the expression of SLC7A11 and GPX4. In conclusion, AS-IV improved cardiac function in CHF rats, presumably by regulating p53/SLC7A11/GPX4 signaling pathway and inhibiting myocardial ferroptosis.
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Biología Computacional , Ferroptosis , Insuficiencia Cardíaca , Saponinas , Triterpenos , Animales , Ferroptosis/efectos de los fármacos , Triterpenos/farmacología , Saponinas/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Ratas , Biología Computacional/métodos , Masculino , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Simulación del Acoplamiento Molecular , Enfermedad Crónica , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Simulación de Dinámica Molecular , Miocardio/metabolismo , Miocardio/patologíaRESUMEN
BACKGROUND: Effective medication adherence is vital for managing acute myocardial infarction (AMI) and enhancing patient well-being. This study aimed to evaluate medication adherence levels and associated factors among AMI patients using standardized assessment tools. METHODS: Employing a cross-sectional descriptive design, the study involved 210 patients diagnosed with acute myocardial infarction. Participants completed the General Medication Adherence Scale (GMAS), Hospital Anxiety and Depression Scale (HADS), and provided socio-demographic details. RESULTS: The study revealed partial adherence to medications among AMI patients, with mean scores of 24.89 (± 3.64) out of 33. Notably, good adherence was observed in non-adherence due to patient behavior (mean ± SD = 11.8 ± 2.3 out of 15) and additional disease burden (mean ± SD = 8.65 ± 2.21 out of 12), while partial adherence was noted in non-adherence due to financial constraints (mean ± SD = 4.44 ± 1.34 out of 6). Patients reported mild anxiety (mean ± SD = 8.38 ± 2.81) and no depressive symptoms (mean ± SD = 7.43 ± 2.42). Multiple linear regression analysis indicated that employed status, younger age, shorter duration of MI, lower anxiety, and depression levels were associated with higher medication adherence. However, factors such as monthly income, gender, educational level, and marital status did not predict medication adherence. CONCLUSION: The study highlights the significance of addressing anxiety and depression levels and considering socio-demographic factors when designing interventions to enhance medication adherence among AMI patients. Further research is needed to explore additional determinants of medication adherence and develop tailored interventions to improve patient outcomes post-AMI.
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Ansiedad , Depresión , Cumplimiento de la Medicación , Infarto del Miocardio , Humanos , Masculino , Infarto del Miocardio/psicología , Infarto del Miocardio/tratamiento farmacológico , Cumplimiento de la Medicación/estadística & datos numéricos , Cumplimiento de la Medicación/psicología , Femenino , Persona de Mediana Edad , Estudios Transversales , Ansiedad/psicología , Ansiedad/tratamiento farmacológico , Depresión/psicología , Depresión/tratamiento farmacológico , Anciano , AdultoRESUMEN
BACKGROUND: Myocardial infarction (MI) is the main contributor to most cardiovascular diseases (CVDs), and the available post-treatment clinical therapeutic options are limited. The development of nanoscale drug delivery systems carrying natural small molecules provides biotherapies that could potentially offer new treatments for reactive oxygen species (ROS)-induced damage in MI. Considering the stability and reduced toxicity of gold-phenolic core-shell nanoparticles, this study aims to develop ellagic acid-functionalized gold nanoparticles (EA-AuNPs) to overcome these limitations. RESULTS: We have successfully synthesized EA-AuNPs with enhanced biocompatibility and bioactivity. These core-shell gold nanoparticles exhibit excellent ROS-scavenging activity and high dispersion. The results from a label-free imaging method on optically transparent zebrafish larvae models and micro-CT imaging in mice indicated that EA-AuNPs enable a favorable excretion-based metabolism without overburdening other organs. EA-AuNPs were subsequently applied in cellular oxidative stress models and MI mouse models. We found that they effectively inhibit the expression of apoptosis-related proteins and the elevation of cardiac enzyme activities, thereby ameliorating oxidative stress injuries in MI mice. Further investigations of oxylipin profiles indicated that EA-AuNPs might alleviate myocardial injury by inhibiting ROS-induced oxylipin level alterations, restoring the perturbed anti-inflammatory oxylipins. CONCLUSIONS: These findings collectively emphasized the protective role of EA-AuNPs in myocardial injury, which contributes to the development of innovative gold-phenolic nanoparticles and further advances their potential medical applications.
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Ácido Elágico , Oro , Nanopartículas del Metal , Infarto del Miocardio , Estrés Oxidativo , Especies Reactivas de Oxígeno , Pez Cebra , Animales , Oro/química , Nanopartículas del Metal/química , Infarto del Miocardio/tratamiento farmacológico , Ratones , Especies Reactivas de Oxígeno/metabolismo , Ácido Elágico/farmacología , Ácido Elágico/química , Estrés Oxidativo/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Masculino , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Ratones Endogámicos C57BLRESUMEN
Interleukin-6 (IL-6) plays a crucial role in the pathogenesis of cardiovascular disease (CVD), and IL-6 receptor (IL-6R) blockade has emerged as a promising therapeutic option. However, their specific therapeutic effects in different types of CVDs remain unclear. This study aimed to assess the efficacy of IL-6R blockade in the management of various CVDs, including hypertension (HTN), coronary heart disease (CHD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF). The Mendelian randomization (MR) approach was utilized to investigate the therapeutic impact of IL-6R blockade on HTN, CHD, MI, AF, and HF based on the genome-wide association study (GWAS) summary statistics. MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis were used for sensitivity analysis to verify the reliability of the MR results. The Bonferroni method was used to correct for bias caused by multiple comparisons. Inverse variance weighted (IVW) results demonstrated that IL-6R blockade significantly influenced CHD (odds ratio (OR) = 0.757, 95% confidence interval (CI): 0.690 - 0.832, P = 5.804 × 10-9) and MI (OR = 0.840, 95% CI: 0.744 - 0.949, P = 0.005). However, IL-6R blockade had no significant effect on HTN (OR = 1.015, 95% CI: 0.950 - 1.084, P = 0.663), AF (OR = 0.905, 95% CI: 0.800 - 1.025, P = 0.116) and HF (OR = 1.012, 95% CI: 0.921 - 1.113, P = 0.805). Genetically predicted IL-6R blockade was associated with a protective effect on CHD and MI, but not HTN, AF and HF. This study's findings offer valuable insights for tailoring IL-6R blockade treatment for different types of CVD, and serve as a reference for future research.
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Enfermedades Cardiovasculares , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Receptores de Interleucina-6 , Humanos , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/genética , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Interleucina-6/antagonistas & inhibidores , Interleucina-6/genética , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Infarto del Miocardio/genética , Infarto del Miocardio/tratamiento farmacológicoRESUMEN
Local inflammatory microenvironment in the early stage of myocardial infarction (MI) severely impaired cardiac recovery post-MI. Macrophages play a pivotal role in this process. A classical glycolytic inhibitor, 2-Deoxy-Glucose (2-DG), has been found to regulate the excessive pro-inflammatory macrophage polarization in the infarcted myocardium. This study investigated the effect of 2-DG-loaded chitosan/gelatin composite patch on the infarct microenvironment post-MI and its impact on cardiac repair. The results showed that the 2-DG patch significantly inhibited the expression of inflammatory cytokines, alleviated reactive oxygen species (ROS) accumulation, repressed the proinflammatory polarization of macrophages, attenuated local inflammatory microenvironment in the ischemic hearts, as well as improved cardiac function, reduced scar size, and promoted angiogenesis post-MI. In terms of mechanism, 2-DG exerts anti-inflammatory effects through inhibiting the NF-κB signaling pathway and reducing the assembly and activation of the NLRP3 inflammasome. These findings suggest that 2-DG composite patch may represent a promising therapeutic strategy for cardiac repair after MI.
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Desoxiglucosa , Infarto del Miocardio , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Desoxiglucosa/farmacología , Desoxiglucosa/administración & dosificación , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ratones , Masculino , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Transducción de Señal/efectos de los fármacos , Quitosano/farmacología , Quitosano/química , Gelatina/química , Citocinas/metabolismo , Miocardio/metabolismo , Miocardio/patología , Modelos Animales de Enfermedad , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Mineralocorticoid receptor (MR) induces cardiac inflammation cooperatively with nuclear factor-κB and signal transducer and activator of transcription 3 (STAT3); MR blockers exert anti-inflammatory effects. However, the underlying mechanism remains unclear. We investigated the anti-inflammatory effect of esaxerenone, a novel MR blocker, in experimental myocardial infarction (MI) and its underlying mechanisms. METHODS AND RESULTS: Male C57BL/6J mice subjected to ligation of the left anterior descending artery were randomly assigned to either the vehicle or esaxerenone group. Esaxerenone was provided with a regular chow diet. The mice were euthanized at either 4 or 15 days after MI. Cardiac function, fibrosis, and inflammation were evaluated. Esaxerenone significantly improved cardiac function and attenuated cardiac fibrosis at 15 days after MI independently of its antihypertensive effect. Inflammatory cell infiltration, inflammatory-related gene expression, and elevated serum interleukin-6 levels at 4 days after MI were significantly attenuated by esaxerenone. In vitro experiments using mouse macrophage-like cell line RAW264.7 cells demonstrated that esaxerenone- and spironolactone-attenuated lipopolysaccharide-induced interleukin-6 expression without altering the posttranslational modification and nuclear translocation of p65 and STAT3. Immunoprecipitation assays revealed that MR interacted with both p65 and STAT3 and enhanced the p65-STAT3 interaction, leading to a subsequent increase in interleukin-6 promoter activity, which was reversed by esaxerenone. CONCLUSIONS: Esaxerenone ameliorated postinfarct remodeling in experimental MI through its anti-inflammatory properties exerted by modulating the transcriptional activity of the MR-p65-STAT3 complex. These results suggest that the MR-p65-STAT3 complex can be a novel therapeutic target for treating MI.
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Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Antagonistas de Receptores de Mineralocorticoides , Infarto del Miocardio , Receptores de Mineralocorticoides , Factor de Transcripción STAT3 , Sulfonas , Factor de Transcripción ReIA , Animales , Factor de Transcripción STAT3/metabolismo , Masculino , Receptores de Mineralocorticoides/metabolismo , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/genética , Antagonistas de Receptores de Mineralocorticoides/farmacología , Ratones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/prevención & control , Infarto del Miocardio/genética , Factor de Transcripción ReIA/metabolismo , Células RAW 264.7 , Sulfonas/farmacología , Transducción de Señal/efectos de los fármacos , Fibrosis , Transcripción Genética/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Antiinflamatorios/farmacología , Interleucina-6/metabolismo , Interleucina-6/genética , PirrolesRESUMEN
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.
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Monóxido de Carbono , Sulfuro de Hidrógeno , Inflamasomas , Infarto del Miocardio , Proteína con Dominio Pirina 3 de la Familia NLR , Óxido Nítrico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Humanos , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/farmacología , Inflamasomas/metabolismo , Óxido Nítrico/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Animales , Monóxido de Carbono/metabolismo , Gasotransmisores/metabolismo , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/patologíaRESUMEN
The neonatal mammalian heart can regenerate following injury through cardiomyocyte proliferation but loses this potential by postnatal day 7. Stimulating adult cardiomyocytes to reenter the cell cycle remains unclear. Here we show that cardiomyocyte proliferation depends on its metabolic state. Given the connection between the tricarboxylic acid cycle and cell proliferation, we analyzed these metabolites in mouse hearts from postnatal day 0.5 to day 7 and found that α-ketoglutarate ranked highest among the decreased metabolites. Injection of α-ketoglutarate extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-ketoglutarate levels. Mechanistically, α-ketoglutarate decreases H3K27me3 deposition at the promoters of cell cycle genes in cardiomyocytes. Thus, α-ketoglutarate promotes cardiomyocyte proliferation through JMJD3-dependent demethylation, offering a potential approach for treating myocardial infarction.
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Proliferación Celular , Histona Demetilasas con Dominio de Jumonji , Ácidos Cetoglutáricos , Infarto del Miocardio , Miocitos Cardíacos , Regeneración , Animales , Ácidos Cetoglutáricos/metabolismo , Ácidos Cetoglutáricos/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Regeneración/efectos de los fármacos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Animales Recién Nacidos , Células Cultivadas , Histonas/metabolismo , Ratones , Complejo Cetoglutarato Deshidrogenasa/metabolismo , Complejo Cetoglutarato Deshidrogenasa/genética , MasculinoRESUMEN
ABSTRACT: The role of intravenous immunoglobulin in protecting the diabetic heart from ischemia/reperfusion (I/R) injury is unclear. Hearts isolated from adult diabetic and nondiabetic Wistar rats (n = 8 per group) were treated with intravenous immunoglobulin (IVIG) either 2 hours before euthanasia, before ischemia, or at reperfusion. Hemodynamic data were acquired using the Isoheart software version 1.524-S. Ischemia/reperfusion (I/R) injury was evaluated by 2,3,5-triphenyltetrazolium chloride staining and troponin T levels. The levels of apoptosis markers, caspases-3/8, antioxidant enzymes, superoxide dismutase and catalase, glucose transporters, GLUT-1 and GLUT-4, phosphorylated ERK1/2, and phosphorylated eNOS were estimated by Western blotting. Proinflammatory and anti-inflammatory cytokine levels were evaluated using enzyme-linked immunosorbent assays. Intravenous immunoglobulin administration abolished the effects of I/R injury in hearts subjected to hyperglycemia when infused at reperfusion, before ischemia, or at reperfusion in 4-week diabetic rat hearts and only at reperfusion in 6-week diabetic rat hearts. IVIG infusion resulted in a significant (P < 0.05) recovery of cardiac hemodynamics and decreased infarct size. IVIG also reduced the levels of troponin T, apoptotic enzymes, and proinflammatory cytokines. IVIG significantly (P < 0.05) increased the levels of anti-inflammatory cytokines, antioxidant enzymes, GLUT-4, and phosphorylated eNOS. Intravenous immunoglobulin protected the hearts from I/R injury if infused at reperfusion in the presence of hyperglycemia, in 4- and 6-week diabetic rat hearts, and when infused before ischemia in 4-week diabetic rat hearts. IVIG exerts its cardioprotective effects associated with the upregulated phosphorylated eNOS/GLUT-4 pathway.
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Diabetes Mellitus Experimental , Transportador de Glucosa de Tipo 4 , Daño por Reperfusión Miocárdica , Óxido Nítrico Sintasa de Tipo III , Ratas Wistar , Transducción de Señal , Animales , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Transportador de Glucosa de Tipo 4/metabolismo , Masculino , Inmunoglobulinas Intravenosas/farmacología , Apoptosis/efectos de los fármacos , Miocardio/patología , Miocardio/metabolismo , Miocardio/enzimología , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/prevención & control , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/tratamiento farmacológico , Ratas , Estrés Oxidativo/efectos de los fármacos , Citocinas/metabolismo , Preparación de Corazón Aislado , Mediadores de Inflamación/metabolismoRESUMEN
Background and Purpose: Growth hormone-releasing hormone (GHRH) agonist, a 29-amino acid peptide, shows significant potential in treating myocardial infarction (MI) by aiding the repair of injured heart tissue. The challenge lies in the effective on-site delivery of GHRH agonist. This study explores the use of a targetable delivery system employing ROS-responsive PEG-PPS-PEG polymers to encapsulate and deliver GHRH agonist MR409 for enhanced therapeutic efficacy. Methods: We synthesized a self-assembling poly (ethylene glycol)-poly (propylene sulfide)-poly (ethylene glycol) polymer (PEG-PPS-PEG) amphiphilic polymer responsive to reactive oxygen species (ROS). The hydrophilic peptide GHRH agonist MR409 was encapsulated within these polymers to form nano PEG-PPS-PEG@MR409 vesicles (NPs). Cardiomyocyte apoptosis was induced under hypoxia and serum-free culture condition for 24 hours, and their production of ROS was detected by fluorescence dye staining. The cellular uptake of PEG-PPS-PEG@MR409 NPs was observed using fluorescence-labeled MR409. Targeting ability and therapeutic efficacy were evaluated using a mouse MI model. Results: PEG-PPS-PEG@MR409 NPs were efficiently internalized by cardiomyocytes, reducing ROS levels and apoptosis. These NPs exhibited superior targeting to the infarcted heart compared to naked MR409 peptide. With a reduced injection frequency (once every three days), PEG-PPS-PEG@MR409 NPs significantly promoted cardiac function recovery post-MI, matching the efficacy of daily MR409 injections. Conclusion: ROS-responsive PEG-PPS-PEG polymers provide a novel and effective platform for the targeted delivery of GHRH agonist peptides, improving cardiac function and offering a new approach for peptide therapy in MI treatment.
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Infarto del Miocardio , Miocitos Cardíacos , Polietilenglicoles , Especies Reactivas de Oxígeno , Animales , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polietilenglicoles/farmacología , Especies Reactivas de Oxígeno/metabolismo , Ratones , Infarto del Miocardio/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Modelos Animales de Enfermedad , Hormona Liberadora de Hormona del Crecimiento/agonistas , Hormona Liberadora de Hormona del Crecimiento/farmacocinética , Hormona Liberadora de Hormona del Crecimiento/administración & dosificación , Apoptosis/efectos de los fármacos , Sulfuros/química , Sulfuros/farmacocinética , Sulfuros/farmacología , Sulfuros/administración & dosificación , Péptidos/química , Péptidos/farmacología , Péptidos/farmacocinética , Péptidos/administración & dosificación , Masculino , Ratones Endogámicos C57BLRESUMEN
CONTEXT: Myocardial infarction is one of the major health challenges. It is of great significance to develop potential delivery carriers for new anti-myocardial infarction drugs. In this paper, based on first-principles calculations, monolayer WS2 with excellent photoelectric properties was verified as a carrier for the anti-myocardial infarction drug amiodarone (AMD). Studies have shown that the WS2-adsorbed AMD system (WS2@AMD) maintains structural stability and produces an adsorption energy of-2.12 eV. Mulliken charge analysis shows that electrons are transferred from WS2 atoms to AMD atoms. Among them, C, N and O obtained the maximum values of 0.51,0.37 and 0.56 e electrons, respectively, while H and I lost the maximum values of 0.32 and 0.24 e electrons, respectively. The optical response of WS2 adsorbed AMD system is similar to that of WS2. The light absorption coefficients of the two materials in the near ultraviolet region and the visible region can reach the order of 105 cm-1 and 104 cm-1, and the strain makes the light absorption peak red-shifted. The feasibility of temperature-controlled release mechanism of WS2 as AMD carrier was discussed. This theoretical work helps to improve the performance of two-dimensional nanomaterials and make them better as drug delivery carriers to improve the therapeutic effect of myocardial infarction. These results indicate that the WS2 monolayer has potential applications in the development of drug delivery carriers. METHODS: In this study, based on first-principles calculations, the CASTEP simulation software package was used to study the structure and properties of materials. The interaction between electrons and ions is considered by using Ultrasoft pseudopotentials. In order to eliminate the spurious interaction between adjacent structures caused by periodic calculations, a vacuum space no less than 18 Å is placed in the vertical direction if necessary. Different functions may produce different density functional calculation results. Due to the low sensitivity of the crystal structure to the calculation details, the PBE functional under the generalized gradient approximation (GGA) was initially used for structural optimization, and the energy cutoff value was set to 500 eV. Grimme 's dispersion correction was used to make the results more accurate. The Brillouin zone (BZ) is sampled by a 7 × 7 × 1 K-point grid to ensure the reliability of the original lattice calculation. The lattice vector and atomic coordinates are relaxed, and the tolerance of each atom is less than 0.01 eV/Å. The energy tolerance at the atomic position is less than 10-7 eV/atom. When calculating the band gap, the HSE06 hybrid functional is used to modify the optimized structure of the PBE functional to obtain more accurate results. Spin-polarized DFT calculations were performed to calculate the electronic structure.
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Portadores de Fármacos , Infarto del Miocardio , Infarto del Miocardio/tratamiento farmacológico , Portadores de Fármacos/química , Modelos Moleculares , Compuestos de Tungsteno/química , Adsorción , Sistemas de Liberación de MedicamentosRESUMEN
AIMS: This study evaluates the therapeutic potential of emodin in enhancing the anti-inflammatory phenotype of macrophages, proposing a novel treatment strategy for myocardial infarction (MI). Our objective is to overcome the challenge of myocardial repair post-MI by developing an innovative in-situ myocardial drug delivery system that reduces associated hepatotoxicity. MATERIALS AND METHODS: Through network pharmacology, it was identified that emodin primarily treats MI through anti-inflammatory actions. We investigated the influence of emodin on macrophage polarization using cellular assays and examined its therapeutic impacts and hepatotoxicity in animal models across various doses. A novel in-situ drug delivery system was devised using Pluronic F-127, a thermosensitive hydrogel, to enhance solubility and enable localized delivery to the myocardium. KEY FINDINGS: In vitro studies confirmed that emodin effectively induces macrophage polarization toward an anti-inflammatory phenotype. In vivo analyses demonstrated a dose-dependent therapeutic effect on the myocardium, although higher doses led to significant hepatotoxicity. The innovative drug delivery system increased emodin's solubility, facilitated precise myocardial targeting, and markedly reduced systemic exposure and liver toxicity. SIGNIFICANCE: This study introduces an advanced approach to treating MI by leveraging the natural anti-inflammatory properties of emodin combined with drug delivery technology. This strategy not only enhances the clinical feasibility of emodin for MI treatment but also represents a significant advancement in therapeutic methods. It focuses on increasing the drug concentration in the myocardium while minimizing the systemic side effects of the drug.
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Sistemas de Liberación de Medicamentos , Emodina , Hidrogeles , Infarto del Miocardio , Poloxámero , Animales , Emodina/farmacología , Emodina/administración & dosificación , Infarto del Miocardio/tratamiento farmacológico , Poloxámero/química , Ratones , Masculino , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Humanos , Células RAW 264.7 , Miocardio/metabolismo , Miocardio/patologíaRESUMEN
Injectable extracellular matrix (iECM) is a versatile biological material with beneficial properties such as good degradability, promotion of cell survival, immunomodulation, and facilitation of vascular formation. However, intravenous injection of iECM faces challenges like a short retention time in vivo and low concentration at the lesion site. To address these issues, we prepared a composite hydrogel composed of sodium alginate and iECM and administered it via intrapericardial injection, forming a structure akin to cardiac patches within the pericardium. Compared with intramyocardial injection, intrapericardial injection avoids direct myocardial injury and ectopic tumor formation, offering less invasiveness and better biocompatibility. This study demonstrates that the sodium alginate/infusible extracellular matrix (SA/iECM) composite hydrogel can effectively prolong the local retention time of iECM in the heart, enhance electrical conduction between cardiomyocytes, promote angiogenesis at ischemic myocardial sites, inhibit apoptosis in the infarcted region, mitigate left ventricular remodeling postmyocardial infarction (MI), and improve cardiac function after infarction. Precise coordination of cardiomyocyte contraction and relaxation depends on the rhythmic occurrence of calcium-dependent action potentials. Cardiac dysfunction is partially attributed to the disruption of the excitation-contraction coupling (ECC) mechanism, which is associated with prolonged intracellular Ca2+ transients and alterations in contraction and relaxation Ca2+ levels. Our results show that the SA/iECM composite hydrogel improves electrical conduction, as evidenced by increased Cx43 expression and enhanced intercellular electrical connectivity. This research establishes that intrapericardial injection of a SA/iECM composite hydrogel is a safe and effective treatment modality, providing a theoretical basis for the use of biomaterials in MI therapy.
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Alginatos , Matriz Extracelular , Hidrogeles , Infarto del Miocardio , Neovascularización Fisiológica , Pericardio , Alginatos/química , Alginatos/farmacología , Animales , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Hidrogeles/química , Hidrogeles/farmacología , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/química , Pericardio/efectos de los fármacos , Ratones , Neovascularización Fisiológica/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Masculino , Ratas , AngiogénesisRESUMEN
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.
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Alcoholes Bencílicos , Glucósidos , Ratones Endogámicos C57BL , Mitofagia , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Proteínas Quinasas , Ubiquitina-Proteína Ligasas , Animales , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Alcoholes Bencílicos/farmacología , Glucósidos/farmacología , Mitofagia/efectos de los fármacos , Masculino , Ubiquitina-Proteína Ligasas/metabolismo , Ratones , Miocitos Cardíacos/efectos de los fármacos , Proteínas Quinasas/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Humanos , Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Cardiotónicos/farmacologíaRESUMEN
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have a variety of cardiovascular and renoprotective effects and have been developed as novel agents for the treatment of heart failure. However, the beneficial mechanisms of SGLT2i on cardiac tissue need to be investigated further. In this study, we established a mouse model of acute myocardial infarction (AMI) using coronary artery constriction surgery and investigated the role of dapagliflozin (DAPA) in protecting cardiomyocytes from hypoxic injury induced by AMI. In vitro experiments were done using hypoxic cultured H9c2 ventricular cells to verify this potential mechanism. Expression of the SIRT family and related genes and proteins was verified by qPCR, Western blotting and immunofluorescence staining, and the intrinsic potential mechanism of cardiomyocyte death due to AMI and hypoxia was comprehensively investigated by RNA sequencing. The RNA sequencing results of cardiomyocytes from AMI mice showed that the SIRT family may be mainly involved in the mechanisms of hypoxia-induced cardiomyocyte death. In vitro hypoxia-induced ventricular cells showed the role of dapagliflozin in conferring resistance to hypoxic injury in cardiomyocytes. It showed that SIRT1/3/6 were downregulated in H9c2 cells in a hypoxic environment, and the addition of dapagliflozin significantly increased the gene and protein expression of SIRT1, 3 and 6. We then verified the underlying mechanisms induced by dapagliflozin in hypoxic cardiomyocytes using RNA-seq, and found that dapagliflozin upregulated the hypoxia-induced gene downregulation, which includes ESRRA, EPAS1, AGTRAP, etc., that associated with SIRTs-related and apoptosis-related signaling to prevent H9c2 cell death. This study provides laboratory data for SGLT2i dapagliflozin treatment of AMI and confirms that dapagliflozin can be used to treat hypoxia-induced cellular necrosis in cardiomyocytes, in which SIRT1 and SIRT3 may play an important role. This opens up further opportunities for SGLT2i in the treatment of heart disease.
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Compuestos de Bencidrilo , Glucósidos , Infarto del Miocardio , Miocitos Cardíacos , Transducción de Señal , Sirtuina 1 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Glucósidos/farmacología , Glucósidos/uso terapéutico , Animales , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Ratones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Sirtuina 1/metabolismo , Sirtuina 1/genética , Transducción de Señal/efectos de los fármacos , Masculino , Sirtuina 3/metabolismo , Sirtuina 3/genética , Sirtuinas/metabolismo , Sirtuinas/genética , Línea Celular , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Hipoxia de la Célula/efectos de los fármacos , Ratas , Apoptosis/efectos de los fármacosRESUMEN
The present study evaluated the cardioprotective effect of astaxanthin (ASX) against isoproterenol (ISO) induced myocardial infarction in rats via the pathway of mitochondrial biogenesis as the possible molecular target of astaxanthin. The control group was injected with normal physiological saline subcutaneously for 2 days. The second group was injected with ISO at a dose of 85 mg/kg bwt subcutaneously for 2 days. The third, fourth and fifth groups were supplemented with ASX at doses of 10, 20, 30 mg/kg bwt, respectively daily by oral gavage for 21 days then injected with ISO dose of 85 mg/kg bwt subcutaneously for 2 successive days. Isoproterenol administration in rats elevated the activities of Creatine kinase-MB (CK-MB), aspartate transaminase (AST), lactate dehydrogenase (LDH), and other serum cardiac biomarkers Troponin-I activities, oxidative stress biomarkers, malondialdehyde(MDA), Nuclear factor-kappa B (NF-KB), while it decreased Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), Nuclear factor erythroid-2-related factor 2 (Nfe212), mitochondrial transcriptional factor A (mt TFA), mitochondrial DNA copy number and glutathione system parameters. However, Astaxanthin decreased the activities of serum AST, LDH, CK-MB, and Troponin I that elevated by ISO. In addition, it increased glutathione peroxidase and reductase activities, total glutathione and reduced GSH content, and GSH/GSSG ratio, mtDNA copy number, PGC-1α expression and Tfam expression that improved mitochondrial biogenesis while it decreased GSSG and MDA contents and NF-KB level in the cardiac tissues. This study indicated that astaxanthin relieved isoproterenol induced myocardial infarction via scavenging free radicals and reducing oxidative damage and apoptosis in cardiac tissue.
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Antioxidantes , Isoproterenol , Infarto del Miocardio , Xantófilas , Animales , Xantófilas/farmacología , Isoproterenol/toxicidad , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Ratas , Masculino , Antioxidantes/farmacología , Antioxidantes/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacosRESUMEN
This study aimed to investigate the cardioprotective effect of quinacrine in an in vivo model of myocardial ischemia/reperfusion injury. A 30-min regional myocardial ischemia followed by a 2-h reperfusion was modeled in anesthetized Wistar rats. Starting at the last minute of ischemia and during the first 9 min of reperfusion the rats in the control (n=8) and experimental (n=9) groups were injected with 0.9% NaCl and quinacrine solution (5 mg/kg), respectively. The area at risk and infarct size were evaluated by "double staining" with Evans blue and triphenyltetrazolium chloride. To assess vascular permeability in the area at risk zone, indocyanine green (ICG) and thioflavin S (ThS) were injected intravenously at the 90th and 120th minutes of reperfusion, respectively, to assess the no-reflow zone. The images of ICG and ThS fluorescence in transverse sections of rat hearts were obtained using a FLUM multispectral fluorescence organoscope. HR tended to decrease by 13% after intravenous administration of quinacrine and then recovered within 50 min. Quinacrine reduced the size of the necrotic zone (p=0.01), vascular permeability in the necrosis region, and the no-reflow area (p=0.027); at the same time, the area at risk did not significantly differ between the groups. Intravenous administration of quinacrine at the beginning of reperfusion of the rat myocardium reduces no-reflow phenomenon and infarct size.
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Cardiotónicos , Daño por Reperfusión Miocárdica , Quinacrina , Ratas Wistar , Animales , Quinacrina/farmacología , Quinacrina/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/patología , Ratas , Masculino , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Modelos Animales de Enfermedad , Permeabilidad Capilar/efectos de los fármacos , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Miocardio/patologíaRESUMEN
Myocardial infarction (MI) has a 5-year mortality rate of more than 50% due to the lack of effective treatments. Interactions between cardiomyocytes and the MI microenvironment (MIM) can determine the progression and fate of infarcted myocardial tissue. Here, a specially designed Melanin-based composite nanomedicines (MCN) is developed to effectively treat MI by reprogramming the MIM. MCN is a nanocomposite composed of polydopamine (P), Prussian blue (PB) and cerium oxide (CexOy) with a Mayuan-like structure, which reprogramming the MIM by the efficient conversion of detrimental substances (H+, reactive oxygen species, and hypoxia) into beneficial status (O2 and H2O). In coronary artery ligation and ischemia reperfusion models of male mice, intravenously injecting MCN specifically targets the damaged area, resulting in restoration of cardiac function. With its promising therapeutic effects, MCN constitutes a new agent for MI treatment and demonstrates potential for clinical application.
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Cerio , Indoles , Melaninas , Infarto del Miocardio , Nanomedicina , Polímeros , Animales , Melaninas/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Masculino , Ratones , Nanomedicina/métodos , Indoles/química , Polímeros/química , Cerio/química , Cerio/farmacología , Cerio/administración & dosificación , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Nanocompuestos/química , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos C57BL , Microambiente Celular/efectos de los fármacos , FerrocianurosRESUMEN
BACKGROUND: Ischemia reperfusion (IR) causes impaired myocardial function, and autophagy activation ameliorates myocardial IR injury. Isoliquiritigenin (ISO) has been found to protect myocardial tissues via AMPK, with exerting anti-tumor property through autophagy activation. This study aims to investigate ISO capacity to attenuate myocardial IR through autophagy activation mediated by AMPK/mTOR/ULK1 signaling. METHODS: ISO effects were explored by SD rats and H9c2 cells. IR rats and IR-induced H9c2 cell models were established by ligating left anterior descending (LAD) coronary artery and hypoxia/re-oxygenation, respectively, followed by low, medium and high dosages of ISO intervention (Rats: 10, 20, and 40 mg/kg; H9c2 cells: 1, 10, and 100 µmol/L). Myocardial tissue injury in rats was assessed by myocardial function-related index, HE staining, Masson trichrome staining, TTC staining, and ELISA. Autophagy of H9c2 cells was detected by transmission electron microscopy (TEM) and immunofluorescence. Autophagy-related and AMPK/mTOR/ULK1 pathway-related protein expressions were detected with western blot. RESULTS: ISO treatment caused myocardial function improvement, and inhibition of myocardial inflammatory infiltration, fibrosis, infarct area, oxidative stress, CK-MB, cTnI, and cTnT expression in IR rats. In IR-modeled H9c2 cells, ISO treatment lowered apoptosis rate and activated autophagy and LC3 fluorescence expression. In vivo and in vitro, ISO intervention exhibited enhanced Beclin1, LC3II/LC3I, and p-AMPK/AMPK levels, whereas inhibited P62, p-mTOR/mTOR and p-ULK1(S757)/ULK1 protein expression, activating autophagy and protecting myocardial tissues from IR injury. CONCLUSION: ISO treatment may induce autophagy by regulating AMPK/mTOR/ULK1 signaling, thereby improving myocardial IR injury, as a potential candidate for treatment of myocardial IR injury.