RESUMEN

Mesenchymal stem cells (MSCs) are expected to be useful therapeutics in osteoarthritis (OA), the most common joint disorder characterized by cartilage degradation. However, evidence is limited with regard to cartilage repair in clinical trials because of the uncontrolled differentiation and weak cartilage-targeting ability of MSCs after injection. To overcome these drawbacks, here we synthesized CuO@MSN nanoparticles (NPs) to deliver Sox9 plasmid DNA (favoring chondrogenesis) and recombinant protein Bmp7 (inhibiting hypertrophy). After taking up CuO@MSN/Sox9/Bmp7 (CSB NPs), the expressions of chondrogenic markers were enhanced while hypertrophic markers were decreased in response to these CSB-engineered MSCs. Moreover, a cartilage-targeted peptide (designated as peptide W) was conjugated onto the surface of MSCs via a click chemistry reaction, thereby prolonging the residence time of MSCs in both the knee joint cavity of mice and human-derived cartilage. In a surgery-induced OA mouse model, the NP and peptide dual-modified W-CSB-MSCs showed an enhancing therapeutic effect on cartilage repair in knee joints compared with other engineered MSCs after intra-articular injection. Most importantly, W-CSB-MSCs accelerated cartilage regeneration in damaged cartilage explants derived from OA patients. Thus, this new peptide and NPs dual engineering strategy shows potential for clinical applications to boost cartilage repair in OA using MSC therapy.

Asunto(s)

Diferenciación Celular , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Nanopartículas , Osteoartritis , Péptidos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Animales , Osteoartritis/terapia , Osteoartritis/patología , Nanopartículas/química , Humanos , Diferenciación Celular/efectos de los fármacos , Péptidos/química , Trasplante de Células Madre Mesenquimatosas/métodos , Condrogénesis/efectos de los fármacos , Ratones , Factor de Transcripción SOX9/metabolismo , Factor de Transcripción SOX9/genética , Cartílago Articular/patología , Cartílago Articular/efectos de los fármacos , Proteína Morfogenética Ósea 7/química , Proteína Morfogenética Ósea 7/farmacología , Ingeniería de Tejidos/métodos , Regeneración/efectos de los fármacos

RESUMEN

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.

Asunto(s)

Apoptosis , Cardiomegalia , Cardiotónicos , Modelos Animales de Enfermedad , Hipertiroidismo , Mitofagia , Tiroxina , Vitamina D , Animales , Hipertiroidismo/complicaciones , Hipertiroidismo/metabolismo , Hipertiroidismo/tratamiento farmacológico , Mitofagia/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratas , Tiroxina/farmacología , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Vitamina D/farmacología , Masculino , Cardiotónicos/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Miocardio/metabolismo , Miocardio/patología , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Malondialdehído/metabolismo , Hormonas Tiroideas/metabolismo

RESUMEN

Cardiac functional, morphological, and histological analysis, coupled with liquid chromatography and mass spectrometry, of two transgenic mouse models with cardiomyocyte-specific overexpression of insulin-like growth factor 1 receptor (IGF1R) or a dominant-negative PI3K mutant (DCM-dnPI3K) revealed distinctive functional and molecular profiles during physiological (driven by IGF1R overexpression) and pathological (driven by dn-PI3K overexpression) atrial remodeling. The current study confirmed previously reported findings, including ventricular dilatation and enhanced systolic function with no evidence of arrhythmia in IGF1R model, as well as ventricular hypertrophy and decreased systolic function with intermittent atrial fibrillation in DCM-dnPI3K model. Novel findings obtained from the left atrial (LA) characterization of female mice revealed that physiological atrial enlargement resulted from increased atrial myocyte size and was associated with preserved atrial function, as determined by maintained LA ejection fraction (EF). The proteomic profile of IGF1R transgenic (Tg) mice was enriched for metabolic remodeling and showed a protein expression pattern similar to that of healthy human atria; on the other hand, pathological atrial enlargement resulted from increased atrial fibrosis with normal myocyte size and was associated with impaired atrial function due to a reduced LA EF. The proteomic profile of DCM-dnPI3K mice was enriched to both metabolic and structural remodeling and showed a protein expression pattern similar to that of human AF atria.

Asunto(s)

Remodelación Atrial , Atrios Cardíacos , Ratones Transgénicos , Miocitos Cardíacos , Medicina de Precisión , Receptor IGF Tipo 1 , Animales , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Atrios Cardíacos/metabolismo , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/patología , Femenino , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Humanos , Proteómica/métodos , Fibrosis , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Fibrilación Atrial/genética , Modelos Animales de Enfermedad , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Cardiomegalia/patología , Cardiomegalia/genética , Masculino , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Función del Atrio Izquierdo

RESUMEN

Cisplatin is a potent chemotherapy medication that is used to treat various types of cancer. However, it can cause nephrotoxic side effects, which lead to acute kidney injury (AKI) and subsequent chronic kidney disease (CKD). Although a clinically relevant in vitro model of CKD induced by repeated administration of low-dose cisplatin (RAC) has been established, its underlying mechanisms remain poorly understood. Here, we compared single administration of high-dose cisplatin (SAC) to repeated administration of low-dose cisplatin (RAC) in myofibroblast transformation and cellular morphology in a normal rat kidney fibroblast NRK-49F cell line. RAC instead of SAC transformed the fibroblasts into myofibroblasts as determined by α-smooth muscle actin, enlarged cell size as represented by F-actin staining, and increased cell flattening as expressed by the semidiameter ratio of attached cells to floated cells. Those phenomena, as well as cellular senescence, were significantly detected from the time right before the second administration of cisplatin. Interestingly, inhibition of the interaction between Yes-associated protein (YAP) and the transcriptional enhanced associated domain (TEAD) using Verteporfin remarkedly reduced cell size, cellular senescence, and myofibroblast transformation during RAC. These findings collectively suggest that YAP activation is indispensable for cellular hypertrophy, senescence, and myofibroblast transformation during RAC in kidney fibroblasts.

Asunto(s)

Cisplatino , Fibroblastos , Riñón , Miofibroblastos , Proteínas Señalizadoras YAP , Cisplatino/farmacología , Animales , Proteínas Señalizadoras YAP/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/efectos de los fármacos , Miofibroblastos/patología , Ratas , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Línea Celular , Senescencia Celular/efectos de los fármacos , Verteporfina/farmacología , Factores de Transcripción de Dominio TEA , Proteínas Adaptadoras Transductoras de Señales/metabolismo

RESUMEN

Lymphatic vessels of the heart undergo dynamic remodeling in response to physiological and pathological cardiovascular events such as development, adult cardiac maintenance and injury repair. During pregnancy, the cardiovascular system undergoes physiological changes to meet the increased demand of blood supply to the fetus. These extensive physiologic changes make pregnancy and delivery a high-risk period in a woman's life. However, whether and how cardiac lymphatics change during pregnancy is largely undefined. Therefore, we used whole mount immunofluorescent labeling and quantitative morphometric analysis to characterize the changes in cardiac lymphatic vasculature during pregnancy using two genetically distinct inbred mouse strains, C57BL/6J and BALB/cJ. Compared to age-matched, non-pregnant C57BL/6J control mice, the hearts of C57BL/6J dams in late-pregnancy (gestation day 17.5 (G17.5)) undergo physiologic hypertrophy. However, there were no significant changes in the cardiac lymphatic vasculature. In contrast, BALB/cJ mice do not exhibit pregnancy-induced cardiac hypertrophy at G17.5 compared to age-matched, non-pregnant mice. Yet interestingly, the cardiac lymphatic vasculature of pregnant BALB/cJ dams undergoes extensive morphological changes, including decreased lymphatic length, number of endpoints, and vessel branchpoint junctions on the ventral side of the heart. These findings underscore the complexity of genetic and physiologic factors that contribute to the heterotypic remodeling of cardiac lymphatics during late pregnancy.

RESUMEN

Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53-75 and 85-107) directly interacts with the C-terminal region of TAK1 (amino acids 1-300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.

Asunto(s)

Cardiomegalia , Quinasas Quinasa Quinasa PAM , Proteínas de la Membrana , Miocitos Cardíacos , Animales , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Ratones , Ratones Endogámicos C57BL , Masculino , Progresión de la Enfermedad , Humanos , Fenilefrina/farmacología , Sistema de Señalización de MAP Quinasas , Estrés Oxidativo

RESUMEN

This case report concerns a 48-year-old man with a history of ischemic stroke at the age of 41 who reported cardiac hypertrophy, registered in his twenties when explained by increased physical activity. Family history was positive for a mother with permanent atrial fibrillation from her mid-thirties. At the age of 44, he had a first episode of persistent atrial fibrillation, accompanied by left atrial thrombosis while on a direct oral anticoagulant. He presented at our clinic at the age of 45 with another episode of persistent atrial fibrillation and decompensated heart failure. Echocardiography revealed a dilated left atrium, reduced left ventricular ejection fraction, and an asymmetric left ventricular hypertrophy. Cardiac magnetic resonance was positive for a cardiomyopathy with diffuse fibrosis, while slow-flow phenomenon was present on coronary angiography. Genetic testing by whole-exome sequencing revealed three variants in the patient, c.309C > A, p.His103Gln in the ACTC1 gene, c.116T > G, p.Leu39Ter in the PLN gene, and c.5827C > T, p.His1943Tyr in the SCN5A gene, the first two associated with hypertrophic cardiomyopathy and the latter possibly with familial atrial fibrillation. This case illustrates the need for advanced diagnostics in unexplained left ventricular hypertrophy, as hypertrophic cardiomyopathy is often overlooked, leading to potentially debilitating health consequences.

Asunto(s)

Fibrilación Atrial , Cardiomiopatía Hipertrófica , Hipertrofia Ventricular Izquierda , Humanos , Fibrilación Atrial/genética , Fibrilación Atrial/diagnóstico , Masculino , Persona de Mediana Edad , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/complicaciones , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/diagnóstico , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/diagnóstico , Ecocardiografía , Canal de Sodio Activado por Voltaje NAV1.5/genética

RESUMEN

Hypertrophic cardiomyopathy encompasses a broad spectrum of muscular diseases that involve not only the interventricular septum and the left ventricular outflow tract but also the papillary muscles and the mitral valve apparatus. This article presents the successful surgical treatment of two patients with generalized hypertrophic cardiomyopathy with hypertrophy of the papillary muscles without severe septal hypertrophy: one with a history of unsuccessful chemical ablation and coronary disease following an interventional event, and another young patient without a history of chronic degenerative diseases who developed hypertrophic cardiomyopathy during her third pregnancy. Both patients with left ventricular outflow tract gradients greater than 55 mmHg and those who underwent surgical treatment had a gradient of less than 10 mmHg.

RESUMEN

Pathological cardiac remodeling predisposes individuals to developing heart failure. Here, we investigated two co-regulated long non-coding RNAs (lncRNAs), termed Gadlor1 and Gadlor2, which are upregulated in failing hearts of patients and mice. Cardiac overexpression of Gadlor1 and Gadlor2 aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. Compound Gadlor1/2 knockout (KO) mice showed markedly reduced myocardial hypertrophy, fibrosis, and dysfunction, while exhibiting increased angiogenesis during short and prolonged periods of pressure overload. Paradoxically, Gadlor1/2 KO mice suffered from sudden death during prolonged overload, possibly due to cardiac arrhythmia. Gadlor1 and Gadlor2, which are mainly expressed in endothelial cells (ECs) in the heart, where they inhibit pro-angiogenic gene expression, are strongly secreted within extracellular vesicles (EVs). These EVs transfer Gadlor lncRNAs to cardiomyocytes, where they bind and activate calmodulin-dependent kinase II, and impact pro-hypertrophic gene expression and calcium homeostasis. Therefore, we reveal a crucial lncRNA-based mechanism of EC-cardiomyocyte crosstalk during heart failure, which could be specifically modified in the future for therapeutic purposes.

RESUMEN

Background: The traditional classification of left ventricular hypertrophy (LVH), which relies on left ventricular geometry, fails to correlate with outcomes among patients with increased LV mass (LVM). Objectives: To identify unique clinical phenotypes of increased LVM patients using unsupervised cluster analysis, and to explore their association with clinical outcomes. Methods: Among the UK Biobank participants, increased LVM was defined as LVM index ≥72 g/m2 for men, and LVM index ≥55 g/m2 for women. Baseline demographic, clinical, and laboratory data were collected from the database. Using Ward's minimum variance method, patients were clustered based on 27 variables. The primary outcome was a composite of all-cause mortality with heart failure (HF) admissions, ventricular arrhythmia, and atrial fibrillation (AF). Cox proportional hazard model and Kaplan-Meier survival analysis were applied. Results: Increased LVM was found in 4,255 individuals, with an average age of 64 ± 7 years. Of these patients, 2,447 (58%) were women. Through cluster analysis, four distinct subgroups were identified. Over a median follow-up period of 5 years (IQR: 4-6), 100 patients (2%) died, 118 (2.8%) were admissioned due to HF, 29 (0.7%) were admissioned due to VA, and 208 (5%) were admissioned due to AF. Univariate Cox analysis demonstrated significantly elevated risks of major events for patients in the 2nd (HR = 1.6; 95% CI 1.2-2.16; p < .001), 3rd (HR = 2.04; 95% CI 1.49-2.78; p < .001), and 4th (HR = 2.64; 95% CI 1.92-3.62; p < .001) clusters compared to the 1st cluster. Further exploration of each cluster revealed unique clinical phenotypes: Cluster 2 comprised mostly overweight women with a high prevalence of chronic lung disease; Cluster 3 consisted mostly of men with a heightened burden of comorbidities; and Cluster 4, mostly men, exhibited the most abnormal cardiac measures. Conclusions: Unsupervised cluster analysis identified four outcomes-correlated clusters among patients with increased LVM. This phenotypic classification holds promise in offering valuable insights regarding clinical course and outcomes of patients with increased LVM.

RESUMEN

Background: Sex-specific differences in left ventricular (LV) geometry might help in developing tailored strategies for hypertension management. Objectives: The purpose of the study was to evaluate sex-related differences in LV geometry at baseline and over time in hypertension. Methods: From a prospective registry, we included hypertensives without prevalent cardiovascular disease, incident myocardial infarction, chronic kidney disease > stage III, and with normal LV ejection fraction. LV mass index >115 g/m2 in males and >95 g/m2 in females, identified LV hypertrophy (LVH). Relative wall thickness ≥0.43 defined LV concentric geometry. LVH in presence of concentric geometry was defined as concentric LVH, whereas relative wall thickness <0.43 was categorized as eccentric. Concentric geometry, or LVH, identified LV remodeling. Results: Six thousand four hundred twenty-seven patients (age 53 ± 11 years, 43% females) were included. At baseline, females showed lower prevalence of normal geometric pattern and higher prevalence of LVH than males (50% vs 72%, P < 0.001; 47% vs 23%, P < 0.001, respectively), with a higher prevalence of eccentric LVH (40% vs 18%, P < 0.001). Female sex was independently associated with LV remodeling (OR: 2.36; 95% CI: 2.12-2.62; P < 0.001). At long-term follow-up (mean 6.1 years, IQR: 2.8-8.6 years), prevalence of LV remodeling increased in both sexes, although a normal LV geometry remained less frequent in females than males (43% vs 67%, P < 0.001), with differences persisting in eccentric (41% vs 21%, P < 0.001) and concentric LVH (11% vs 5%, P < 0.001). Conclusions: We found sex-related differences in LV geometry among hypertensives. Females have higher risk of LV remodeling at baseline compared with males, with differences persisting at long-term follow-up.

RESUMEN

Children diagnosed with severe tonsillar hypertrophy display discernible craniofacial features distinct from those with adenoid hypertrophy, prompting illuminating considerations regarding microbiota regulation in this non-inflammatory condition. The present study aimed to characterize the salivary microbial profile in children with tonsillar hypertrophy and explore the potential functionality therein. A total of 112 children, with a mean age of 7.79 ± 2.41 years, were enrolled and divided into the tonsillar hypertrophy (TH) group (n = 46, 8.4 ± 2.5 years old), adenoid hypertrophy (AH) group (n = 21, 7.6 ± 2.8 years old), adenotonsillar hypertrophy (ATH) group (n = 23, 7.2 ± 2.1 years old), and control group (n = 22, 8.6 ± 2.1 years old). Unstimulated saliva samples were collected, and microbial profiles were analyzed by 16S rRNA sequencing of V3-V4 regions. Diversity and composition of salivary microbiome and the correlation with parameters of overnight polysomnography and complete blood count were investigated. As a result, children with tonsillar hypertrophy had significantly higher α-diversity indices (P＜0.05). ß-diversity based on Bray-Curtis distance revealed that the salivary microbiome of the tonsillar hypertrophy group had a slight separation from the other three groups (P＜0.05). The linear discriminant analysis effect size (LEfSe) analysis indicated that Gemella was most closely related to tonsillar hypertrophy, and higher abundance of Gemella, Parvimonas, Dialister, and Lactobacillus may reflect an active state of immune regulation. Meanwhile, children with different degrees of tonsillar hypertrophy shared similar salivary microbiome diversity. This study demonstrated that the salivary microbiome in pediatric tonsillar hypertrophy patients had different signatures, highlighting that the site of upper airway obstruction primarily influences the salivary microbiome rather than hypertrophy severity.IMPORTANCETonsillar hypertrophy is the most frequent cause of upper airway obstruction and one of the primary risk factors for pediatric obstructive sleep apnea (OSA). Studies have discovered that children with isolated tonsillar hypertrophy exhibit different craniofacial morphology features compared with those with isolated adenoid hypertrophy or adenotonsillar hypertrophy. Furthermore, characteristic salivary microbiota from children with OSA compared with healthy children has been identified in our previous research. However, few studies provided insight into the relationship between the different sites of upper airway obstruction resulting from the enlargement of pharyngeal lymphoid tissue at different sites and the alterations in the microbiome. Here, to investigate the differences in the salivary microbiome of children with tonsillar hypertrophy and/or adenoid hypertrophy, we conducted a cross-sectional study and depicted the unique microbiome profile of pediatric tonsillar hypertrophy, which was mainly characterized by a significantly higher abundance of genera belonging to phyla Firmicutes and certain bacteria involving in the immune response in tonsillar hypertrophy, offering novel perspectives for future related research.

RESUMEN

Vitamin D deficiency (VDD) is a widespread global health issue, affecting nearly a billion individuals worldwide, and mounting evidence links it to an increased risk of cardiovascular diseases like hypertension, atherosclerosis, and heart failure. The discovery of vitamin D receptors and metabolizing enzymes in cardiac and vascular cells, coupled with experimental studies, underscores the complex relationship between vitamin D and cardiovascular health. This review aims to synthesize and critically evaluate the preclinical evidence elucidating the role of vitamin D in cardiovascular health. We examined diverse preclinical in vitro (cardiomyocyte cell line) models and in vivo models, including knockout mice, diet-induced deficiency, and disease-specific animal models (hypertension, hypertrophy and myocardial infarction). These studies reveal that vitamin D modulates vascular tone, and prevents fibrosis and hypertrophy through effects on major signal transduction pathways (NF-kB, Nrf2, PI3K/AKT/mTOR, Calcineurin/NFAT, TGF-ß/Smad, AMPK) and influences epigenetic mechanisms governing inflammation, oxidative stress, and pathological remodeling. In vitro studies elucidate vitamin D's capacity to promote cardiomyocyte differentiation and inhibit pathological remodeling. In vivo studies further uncovered detrimental cardiac effects of VDD, while supplementation with vitamin D in cardiovascular disease (CVD) models demonstrated its protective effects by decreasing inflammation, attenuating hypertrophy, reduction in plaque formation, and improving cardiac function. Hence, this comprehensive review emphasizes the critical role of vitamin D in cardiovascular health and its potential as a preventive/therapeutic strategy in CVDs. However, further research is needed to translate these findings into clinical applications as there are discrepancies between preclinical and clinical studies.

RESUMEN

Exercise training leads to physiological cardiac hypertrophy and the protective axis of the renin-angiotensin system composed of angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor seems involved in this process. However, the role of the basal activity of the Mas receptor in exercise-induced physiological cardiac hypertrophy is still unclear. We evaluated the effects of the Mas receptor blockade on the left ventricular structure and function of rats submitted to running training. Rats were assigned to 4 groups: sedentary (S), sedentary + A-779 (Mas receptor antagonist, 120 µg/kg/day, i.p.; SA), trained (60-minute treadmill running sessions, five days a week, 8 weeks; T), and trained + A-779 (TA). Systolic blood pressure was higher in sedentary and trained rats treated with A-779 at the end of the experimental period. The A-779 treatment prevented the left ventricular hypertrophy evoked by physical exercise and increased collagen deposition in sedentary and trained rats. Cardiomyocytes from the SA group presented increased length and thickness of the sarcomeres, elongated mitochondria, glycogen deposits, and enlarged cisterns of the sarcoplasmic reticulum. TA group presented a reduced sarcomere thickness and cytoplasm with a degenerative aspect. These findings show that the basal activity of the Mas receptor is essential for the proper turnover of the extracellular matrix in the myocardium and the maintenance of the sarcomeric structure of cardiomyocytes.

RESUMEN

Background: Botulinum toxin type A (BoNT-A) injection is widely used for masseter hypertrophy. Traditional BoNT-A injection methods often incorporate landmark-guided blind injections, which approximate the shape of the masseter muscle inject across various points. Conversely, ultrasound (US)-guided injection techniques offer real-time visualization and dynamic monitoring, enhancing accuracy. Patients and Methods: 50 patients who underwent BoNT-A injections were included in this trial. One on the face side received a landmark-guided injection, and the other side was treated with a US-guided injection. Initial and post-procedure measurements of muscle thickness at the upper, middle, and lower regions were collected using ultrasound. Results: Both methods led to a significant reduction in muscle thickness one month after injection. In the upper area, the absolute difference in muscle thickness between the two methods was observed as a mean ± standard deviation (SD) value of 0.37 ± 0.0314 (p < 0.0001), indicating a superior effect with US-guided injection. Similarly, in the middle area, the mean ± SD difference was 0.41 ± 0.0608 (p < 0.0001) and in the lower area, the mean ± SD difference was 0.24 ± 0.0134 (p = 0.0004). Conclusions: This study demonstrated that the US-guided single-point injection technique is a more effective and accurate method for BoNT-A injection compared to the conventional method.

RESUMEN

The aim of this study was to investigate the effects of a supplement rich in ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) and antioxidant vitamins on physical performance and body composition following a period of high-intensity functional training (HIFT). Nineteen healthy young adults (nine males, ten females) underwent an 8-week HIFT program (3 days·week-1) where they were randomized 1:1 into either the supplement group (SG)-n = 10, receiving a 20 mL daily dose of a dietary cocktail formula (Neuroaspis™ PLP10) containing a mixture of ω-3 and ω-6 PUFAs (12,150 mg), vitamin A (0.6 mg), vitamin E (22 mg), and γ-tocopherol (760 mg)-or the placebo group (PG)-n = 9, receiving a 20 mL daily dose of virgin olive oil. Body composition, cardiorespiratory fitness, muscle strength, and muscle endurance were assessed before and after the training period. Body mass did not change, but muscle mass increased by 1.7 ± 1.9% or 0.40 ± 0.53 kg in the SG (p = 0.021) and decreased by 1.2 ± 1.6% or 0.28 ± 0.43 kg (p = 0.097) in the PG, compared with baseline. VO2max, vertical jump, squat 1RM, bench press 1RM, and muscle endurance increased similarly in both groups. The effects of HIFT on physical performance parameters, muscle damage, and inflammation indices were not affected by the supplementation. In conclusion, HIFT combined with high doses of ω-3 and ω-6 PUFAs and antioxidant vitamins resulted in a small but significant increase in muscle mass and fat reduction compared with HIFT alone.

Asunto(s)

Antioxidantes , Composición Corporal , Suplementos Dietéticos , Ácidos Grasos Omega-3 , Ácidos Grasos Omega-6 , Humanos , Masculino , Femenino , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-6/administración & dosificación , Antioxidantes/administración & dosificación , Método Doble Ciego , Composición Corporal/efectos de los fármacos , Adulto Joven , Adulto , Fuerza Muscular/efectos de los fármacos , Ejercicio Físico/fisiología , Vitaminas/administración & dosificación , Vitaminas/farmacología , Capacidad Cardiovascular/fisiología , Vitamina E/administración & dosificación , Vitamina E/farmacología , Entrenamiento de Intervalos de Alta Intensidad/métodos

RESUMEN

Cyst nematodes establish permanent feeding structures called syncytia inside the host root vasculature, disrupting the flow of water and minerals. In response, plants form WOX11-mediated adventitious lateral roots at nematode infection sites. WOX11 adventitious lateral rooting modulates tolerance to nematode infections; however, whether this also benefits nematode parasitism remains unknown. Here, we report on bioassays using a 35S::WOX11-SRDX transcriptional repressor mutant to investigate whether WOX11 adventitious lateral rooting promotes syncytium development and thereby female growth and fecundity. Moreover, we chemically inhibited cellulose biosynthesis to verify if WOX11 directly modulates cell wall plasticity in syncytia. Finally, we performed histochemical analyses to test if WOX11 mediates syncytial cell wall plasticity via reactive oxygen species (ROS). Repression of WOX11-mediated transcription specifically enhanced the radial expansion of syncytial elements, increasing both syncytium size and female offspring. The enhanced syncytial hypertrophy observed in the 35S::WOX11-SRDX mutant could be phenocopied by chemical inhibition of cellulose biosynthesis and was associated with elevated levels of ROS at nematode infection sites. We, therefore, conclude that WOX11 restricts radial expansion of nematode-feeding structures and female growth and fecundity, likely by modulating ROS-mediated cell wall plasticity mechanisms. Remarkably, this novel role of WOX11 in plant cell size control is distinct from WOX11 adventitious lateral rooting underlying disease tolerance.

RESUMEN

The liver's unique regenerative capacity, immunotolerant feature, and polyploidy status distinguish it as a metabolic organ unlike any other in the body. Despite aging, the liver generally exhibits fewer pathological abnormalities than other organs (such as the kidney), maintaining its functions near-normal balanced manner. Subtle changes in the liver, including reduced blood flow, detoxification alterations, pseudo-capillarization, and lipofuscin deposition, may occur with chronological age. Research indicates that carefully selected liver grafts from octogenarian donors can perform well post-transplant, emphasizing instances where age doesn't necessarily compromise liver function. Notably, a recent report suggests that the liver is a youthful organ, with hepatocytes averaging an age of only 3 years. Despite the liver's impressive regenerative capabilities and cellular reserve, a lingering question persists: how does the liver maintain its youthful characteristic amidst the chronological aging of the entire organism? The various adaptive mechanism possibly include:(a) cellular hypertrophy to maintain physiological capacity even before proliferation initiates, (b) the "ploidy conveyor" as a genetic adaptation to endure aging-related stress, (c) sustained telomere length indicative of youthfulness (d) active extracellular matrix remodelling for normal cellular functioning, (e) Mitochondria-Endoplasmic Reticulum based metabolic adaptation and (c) cellular plasticity as fitness mechanisms for healthy aging. However, it's crucial to note that aged livers may have compromised regenerative capacity and chronic liver disease is often associated with declining function due to premature hepatocyte senescence. This review delves into varied cellular adaptations sustaining liver homeostasis with chronological aging and briefly explores the role of accelerated hepatocyte aging as a precursor to chronic liver disease.

RESUMEN

Skeletal muscle tissue is in a constant state of turnover, with muscle tissue protein synthesis and breakdown rates ranging between 1-2 % across the day in vivo in humans. Muscle tissue remodeling is largely controlled by the up- and down-regulation of muscle tissue protein synthesis rates. Research studies generally apply stable isotope labeled amino acids to assess muscle protein synthesis rates in vivo in humans. Following labeled amino acid administration in a laboratory setting, muscle tissue samples are collected over several hours to assess the incorporation rate of these labeled amino acids in muscle tissue protein. To allow quantification of bulk muscle protein synthesis rates over more prolonged periods, the use of deuterated water methodology has regained much interest. Ingestion of daily boluses of deuterium oxide (2H2O) results in 2H-enrichment of the body water pool. The available 2H-atoms become incorporated into endogenously synthesized alanine primarily through transamination of pyruvate in the liver. With 2H-alanine widely available to all tissues, it becomes incorporated into de novo synthesized tissue proteins. Assessing the increase in tissue protein-bound 2H-alanine enrichment in muscle biopsy samples over time allows for calculation of muscle protein synthesis rates over several days or even weeks. As the deuterated water method allows for assessment of muscle tissue protein synthesis rates under free living conditions in non-laboratory settings, there is an increasing interest in its application. This manuscript describes the theoretical background of the deuterated water method and offers a comprehensive tutorial to correctly apply the method to determine bulk muscle protein synthesis rates in vivo in humans.

RESUMEN

PRKAG2 cardiomyopathy is a rare genetic disorder that manifests early in life with an autosomal dominant inheritance pattern. It harbors left ventricular hypertrophy (LVH), ventricular pre-excitation and progressively worsening conduction system defects. Its estimated prevalence among patients with LVH ranges from 0.23 to about 1%, but it is likely an underdiagnosed condition. We report the association of the PRKAG2 missense variant c.1006G>A p. (Val336Ile) with LVH, conduction abnormalities (short PR interval and incomplete right bundle branch bock) and early-onset arterial hypertension (AH) in a 44-year-old Caucasian patient. While cardiac magnetic resonance (CMR) showed a mild hypertrophic phenotype with maximal wall thickness of 17 mm in absence of tissue alterations, the electric phenotype was relevant including brady-tachy syndrome and recurrent syncope. The same variant has been detected in the patient's sister and daughter, with LVH + early-onset AH and electrocardiographic (ECG) alterations + lipothymic episodes, respectively. Paying close attention to the coexistence of LVH and ECG alterations in the proband has been helpful in directing genetic tests to exclude primary cardiomyopathy. Hence, identifying the genetic basis in the patient allowed for familial screening as well as a proper follow-up and therapeutic management of the affected members. A review of the PRKAG2 cardiomyopathy literature is provided alongside the case report.

Asunto(s)

Proteínas Quinasas Activadas por AMP , Hipertrofia Ventricular Izquierda , Mutación Missense , Humanos , Adulto , Hipertrofia Ventricular Izquierda/genética , Femenino , Proteínas Quinasas Activadas por AMP/genética , Electrocardiografía , Masculino , Linaje