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BACKGROUND: Atherosclerosis (AS) is the main pathological basis for the development of cardiovascular diseases. Vascular inflammation is an important factor in the formation of AS, and macrophage pyroptosis plays a key role in AS due to its unique inflammatory response. Guizhitongluo Tablet (GZTLT) has shown clinically effective in treating patients with AS, but its mechanism is elusive. PURPOSE: This study was to determine the effects of GZTLT on atherosclerotic vascular inflammation and pyroptosis and to understand its underlying mechanism. MATERIALS AND METHODS: The active constituents of GZTLT were analysed by means of UPLC-HRMS. In vivo experiments were performed using ApoE-/- mice fed a high fat diet for 8 weeks, followed by treatment with varying concentrations of GZTLT orally by gavage and GsMTx4 (GS) intraperitoneally and followed for another 8 weeks. Oil red O, Haematoxylin-eosin (HE) and Masson staining were employed to examine the lipid content, plaque size, and collagen fibre content of the mouse aorta. Immunofluorescence staining was utilised to identify macrophage infiltration, as well as the expression of Piezo1 and NLRP3 proteins in aortic plaques. The levels of aortic inflammatory factors were determined using RT-PCR and ELISA. In vitro, foam cell formation in bone marrow-derived macrophages (BMDMs) was observed using Oil Red O staining. Intracellular Ca2+ measurements were performed to detect the calcium influx in BMDMs, and the expression of NLRP3 and its related proteins were detected by Western blot. RESULTS: The UPLC-HRMS analysis revealed 31 major components of GZTLT. Our data showed that GZTLT inhibited aortic plaque formation in mice and increased plaque collagen fibre content to stabilise plaques. In addition, GZTLT could restrain the expression of serum lipid levels and suppress macrophage foam cell formation. Further studies found that GZTLT inhibited macrophage infiltration in aortic plaques and suppressed the expression of inflammatory factors. It is noteworthy that GZTLT can restrain Piezo1 expression and reduce Ca2+ influx in BMDMs. Additionally, we found that GZTLT could regulate NLRP3 activation and pyroptosis by inhibiting Piezo1. CONCLUSION: The present study suggests that GZTLT inhibits vascular inflammation and macrophage pyroptosis through the Piezo1/NLRP3 signaling pathway, thereby delaying AS development. Our finding provides a potential target for AS treatment and drug discovery.
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OBJECTIVE: We aimed to assess the secular trends in cardiovascular health (CVH) among U.S. adults with different glycemic statuses based on the Life's Essential 8 (LE8). METHODS: This cross-sectional study used nationally representative data from 6 cycles of the National Health and Nutrition Examination Surveys between 2007 and 2018. Survey-weighted linear models were used to assess time trends in LE8 scores. Stratified analyses and sensitivity analyses were conducted to validate the stability of the results. RESULTS: A total of 23,616 participants were included in this study. From 2007 to 2018, there was no significant improvement in overall CVH and the proportion of ideal CVH among participants with diabetes and prediabetes. We observed an opposite trend between health behavior and health factors in the diabetes group, mainly in increasing physical activity scores and sleep scores (P for trend<0.001), and declining BMI scores [difference, -6.81 (95% CI, -12.82 to -0.80)] and blood glucose scores [difference, -6.41 (95% CI, -9.86 to -2.96)]. Dietary health remained at a consistently low level among participants with different glycemic status. The blood lipid scores in the prediabetes group improved but were still at a lower level than other groups. Education/income differences persist in the CVH of participants with diabetes or prediabetes, especially in health behavior factors. Sensitivity analyses of the absolute difference and change in proportion showed a consistent trend. CONCLUSIONS: Trends in CVH among participants with diabetes or prediabetes were suboptimal from 2007 to 2018, with persistent education/income disparities.
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Glucemia , Enfermedades Cardiovasculares , Encuestas Nutricionales , Humanos , Masculino , Femenino , Estudios Transversales , Persona de Mediana Edad , Estados Unidos/epidemiología , Enfermedades Cardiovasculares/epidemiología , Adulto , Glucemia/análisis , Conductas Relacionadas con la Salud , Estado Prediabético/epidemiología , Ejercicio Físico , Diabetes Mellitus/epidemiología , AncianoRESUMEN
BACKGROUND: Gut bacteria, which serve as essential modulators, exert a significant impact on insect physiology and behavior and have substantial application potential in pest management. The dynamics of gut bacteria and their impact on Phortica okadai behavior remain unclear. METHODS: In this study, the dynamics of gut bacteria at different developmental stages in P. okadai were analyzed using 16S ribosomal RNA (rRNA) gene sequencing, and the species and abundance of gut bacteria that affect host behavior were examined via behavioral experiments. RESULTS: A total of 19 phyla, 29 classes, 74 orders, 101 species, and 169 genera were identified. The results of the behavioral experiments indicated that the species Lactiplantibacillus argentoratensis, Acetobacter tropicalis, Leuconostoc citreum, and Levilactobacillus brevis effectively influenced the feeding preference of P. okadai, and the single-bacterium-seeded P. okadai exhibited feeding preferences distinct from those of the germ-free (GF) and wild-type P. okadai. CONCLUSIONS: The species and relative abundance of gut bacteria together positively impact P. okadai behavior. Lactiplantibacillus argentoratensis, as the most attractive bacteria to P. okadai, presents opportunities for novel pest control strategies targeting this vector and agricultural pest.
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Bacterias , Microbioma Gastrointestinal , ARN Ribosómico 16S , Animales , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , ARN Ribosómico 16S/genética , Conducta Animal , Conducta Alimentaria , Tephritidae/microbiología , Tephritidae/fisiologíaRESUMEN
BACKGROUND: Myocardial infarction (MI) poses a global public health challenge, often associated with elevated mortality rates and a grim prognosis. A crucial aspect of the inflammatory injury and healing process post-MI involves the dynamic differentiation of macrophages. A promising strategy to alleviate myocardial damage after MI is by modulating the inflammatory response and orchestrating the shift from pro-inflammatory (M1) to anti-inflammatory (M2) macrophages, aiming to achieve a reduced M1/M2 ratio. Nuanxinkang (NXK), a simplified herbal decoction, has demonstrated noteworthy cardioprotective, inflammation-regulating, and myocardial energy metabolism-regulating properties. METHODS: In this study, we constructed an MI model by ligating coronary arteries to investigate the efficacy of NXK in improving ventricular remodeling and cardiac function. Mice were administered NXK (1.65 g/kg/d) or an equivalent volume of regular saline via gavage for 28 consecutive days, commencing the day after surgery. Then, we conducted echocardiography to assess the cardiac function, Masson staining to illustrate the extent of myocardial fibrosis, TUNEL staining to reveal myocardial apoptosis, and flow cytometry to analyze the polarization of M1 and M2 macrophages in the hearts. Besides, a lipopolysaccharide (LPS)-induced pro-inflammatory macrophage (M1) polarization model was implemented in RAW264.7 cells to elucidate the underlying mechanism of NXK in regulating macrophage polarization. RAW264.7 cells were pre-treated with or without NXK-containing serum. Oxidative stress was detected by MitoSox staining, followed by Seahorse energy metabolism assay to evaluate alterations in mitochondrial metabolic patterns and ATP production. Both In vivo and in vitro, HIF-1α and PDK1 were detected by fluorescent quantitative PCR and Western blotting. RESULTS: In vivo, MI mice exhibited a decline in cardiac function, adverse ventricular remodeling, and an increase in glycolysis, coupled with M1-dominant polarization mediated by the HIF-1α/PDK1 axis. Notably, robust responses were evident with high-dose NXK treatment (1.65 g/kg/day), leading to a significant enhancement in cardiac function, inhibition of cardiac remodeling, and partial suppression of macrophage glycolysis and the inflammatory phenotype in MI mice. This effect was achieved through the modulation of the HIF-1α/PDK1 axis. In vitro, elevated levels of mitochondrial ROS production and glycolysis were observed in LPS-induced macrophages. Conversely, treatment with NXK notably reduced the oxidative stress damage induced by LPS and enhanced oxidative phosphorylation (OXPHOS). Furthermore, NXK demonstrated the ability to modify the energy metabolism and inflammatory characteristics of macrophages by modulating the HIF-1α/PDK1 axis. The influence of NXK on this axis was partially counteracted by the HIF-1α agonist DMOG. And NXK downregulated PDK1 expression, curtailed glycolysis, and reversed LPS-induced M1 polarization in macrophages, similar to the PDK1 inhibitor DCA. CONCLUSION: In conclusion, NXK protects against MI-induced cardiac remodeling by inducing metabolic reprogramming and phenotypic differentiation of macrophages, achieved through the modulation of the HIF-1α/PDK1 axis. This provides a novel and promising strategy for the treatment of MI.
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To explore the population structures and dynamics of Rhododendron shrub communities at different stages of succession in northwest Guizhou, China, this study examined the populations of Rhododendron annae and Rhododendron irroratum shrub with two different stages. A space-for-time substitution was employed to establish the diameter class/height structures, static life tables, and survival/mortality rate/disappearance rate curves of both Rhododendron populations with different orders of succession. Their structural and quantitative dynamics were analyzed, and their development trends were predicted. The results showed that, quantitatively, the populations of R. annae and R. irroratum in the two Rhododendron communities with different orders of succession were dominated by age classes one, two, and three as well as height classes i, ii, and iii. The number of Rhododendron plants at the three age classes and the three height classes accounted for 97.61-100% of the total. The quantitative dynamic indices of R. annae and R. irroratum were both greater than 0, with and without considering external interference. In terms of age class and height structures, both Rhododendron populations were expanding populations, presenting "inverted-J-shaped" and irregular pyramid patterns. There was a sufficient number of young individuals, but few or no old individuals. Both survival curves of the populations of R. annae and R. irroratum in the two Rhododendron communities with different orders of succession belonged to the Deevy-II type. In the late stage of succession, the mortality curves and disappearance curves of both Rhododendron populations in these communities presented a trend of increasing first and then decreasing with increasing age class. This result indicates that at each age class, R. annae and R. irroratum showed a trend of gradual increase after two, four, and six years. In brief, the populations of R. annae and R. irroratum have rich reserves of seedlings and saplings, but high mortality and disappearance rates. In this context, it is necessary to reduce human interference and implement targeted conservation measures to promote the natural renewal of Rhododendron populations.
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ABSTRACT: Platelet α-granules are rich in transforming growth factor ß1 (TGF-ß1), which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and rebalancing T-cell subsets. Mechanistically, transcriptome analysis confirmed the participation of TGF-ß/Smad pathways in TPO-RA-corrected MDSCs, which was offset by Smad2/3 knockdown. In platelet TGF-ß1-deficient mice, TPO-RA-induced amplification and enhanced suppressive capacity of MDSCs was waived. Furthermore, our retrospective data revealed that patients with ITP achieving complete platelet response showed superior long-term outcomes compared with those who only reach partial response. In conclusion, we demonstrate that platelet TGF-ß1 induces the expansion and functional reprogramming of MDSCs via the TGF-ß/Smad pathway. These data indicate that platelet recovery not only serves as an end point of treatment response but also paves the way for immune homeostasis in immune-mediated thrombocytopenia.
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Plaquetas , Células Supresoras de Origen Mieloide , Púrpura Trombocitopénica Idiopática , Factor de Crecimiento Transformador beta1 , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Plaquetas/metabolismo , Plaquetas/inmunología , Reprogramación Celular , Ratones SCID , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/patología , Púrpura Trombocitopénica Idiopática/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Xinyang tablet (XYT) has been used for heart failure (HF) for over twenty years in clinical practice, but the underlying molecular mechanism remains poorly understood. AIMS OF THE STUDY: In the present study, we aimed to explore the protective effects of XYT in HF in vivo and in vitro. MATERIALS AND METHODS: Transverse aortic constriction was performed in vivo to establish a mouse model of cardiac pressure overload. Echocardiography, tissue staining, and real-time quantitative PCR (qPCR) were examined to evaluate the protective effects of XYT on cardiac function and structure. Adenosine 5'-triphosphate production, reactive oxygen species staining, and measurement of malondialdehyde and superoxide dismutase was used to detect mitochondrial damage. Mitochondrial ultrastructure was observed by transmission electron microscope. Immunofluorescence staining, qPCR, and Western blotting were performed to evaluate the effect of XYT on the mitochondrial unfolded protein response and mitophagy, and to identify its potential pharmacological mechanism. In vitro, HL-1 cells and neonatal mouse cardiomyocytes were stimulated with Angiotensin II to establish the cell model. Western blotting, qPCR, immunofluorescence staining, and flow cytometry were utilized to determine the effects of XYT on cardiomyocytes. HL-1 cells overexpressing receptor-interacting serum/three-protein kinase 3 (RIPK3) were generated by transfection of RIPK3-overexpressing lentiviral vectors. Cells were then co-treated with XYT to determine the molecular mechanisms. RESULTS: In the present study, XYT was found to exerta protective effect on cardiac function and structure in the pressure overload mice. And it was also found XYT reduced mitochondrial damage by enhancing mitochondrial unfolded protein response and restoring mitophagy. Further studies showed that XYT achieved its cardioprotective role through regulating the RIPK3/FUN14 domain containing 1 (FUNDC1) signaling. Moreover, the overexpression of RIPK3 successfully reversed the XYT-induced protective effects and significantly attenuated the positive effects on the mitochondrial unfolded protein response and mitophagy. CONCLUSIONS: Our findings indicated that XYT prevented pressure overload-induced HF through regulating the RIPK3/FUNDC1-mediated mitochondrial unfolded protein response and mitophagy. The information gained from this study provides a potential strategy for attenuating mitochondrial damage in the context of pressure overload-induced heart failure using XYT.
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Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Ratones Endogámicos C57BL , Mitofagia , Miocitos Cardíacos , Respuesta de Proteína Desplegada , Animales , Mitofagia/efectos de los fármacos , Respuesta de Proteína Desplegada/efectos de los fármacos , Ratones , Masculino , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/ultraestructura , Comprimidos , Línea Celular , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismoRESUMEN
Atherosclerosis is characterised by lipid accumulation and formation of foam cells in arterial walls. Dysregulated autophagy is a crucial factor in atherosclerosis development. The significance of microRNA (miR)-125b-1-3p in cardiovascular disease is well-established; however, its precise role in regulating autophagy and impact on atherosclerosis in vascular smooth muscle cells (VSMCs) remain unclear. Here, we observed reduced autophagic activity and decreased miR-125b expression during atherosclerosis progression. miR-125b-1-3p overexpression significantly reduced atherosclerotic plaque development in mice; it also led to decreased lipid uptake and deposition in VSMCs, enhanced autophagy, and suppression of smooth muscle cell phenotypic changes in-vitro. An interaction between miR-125b-1-3p and the RRAGD/mTOR/ULK1 pathway was revealed, elucidating its role in promoting autophagy. Therefore, miR-125b-1-3p plays a pivotal role in enhancing autophagic processes, inhibiting foam cell formation in VSMCs and mitigating atherosclerosis progression, partly through RRAGD/mTOR/ULK1 signaling axis modulation. Thus, miR-125b-1-3p is a promising target for preventive and therapeutic strategies for atherosclerosis.
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Aterosclerosis , MicroARNs , Animales , Ratones , Aterosclerosis/genética , Aterosclerosis/metabolismo , Autofagia/genética , Proliferación Celular/fisiología , Lípidos , MicroARNs/genética , MicroARNs/metabolismo , Miocitos del Músculo Liso/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
INTRODUCTION: The study focuses on the long-term prognosis of myocardial infarction (MI) influenced by neutrophil extracellular traps (NETs). It also aims to analyze and validate relative hub genes in this process, in order to further explore new therapeutic targets that can improve the prognosis of MI. MATERIALS AND METHODS: We established a MI model in mice by ligating the left anterior descending branch (LAD) and conducted an 8-week continuous observation to study the dynamic changes in the structure and function of the heart in these mice. Meanwhile, we administered Apocynin, an inhibitor of NADPH Oxidase, which has also been shown to inhibit the formation of NETs, to mice undergoing MI surgery in order to compare. This study employed hematoxylin-eosin (HE) staining, echocardiography, immunofluorescence, and real-time quantitative PCR (RT-qPCR) to examine the impact of NETs on the long-term prognosis of MI. Next, datasets related to MI and NETs were downloaded from the GEO database, respectively. The Limma package of R software was used to identify differentially expressed genes (DEGs). After analyzing the "Robust Rank Aggregation (RRA)" package, we conducted a screening for robust differentially expressed genes (DEGs) and performed pathway enrichment analysis using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to determine the functional roles of these robust DEGs. The protein-protein interaction (PPI) network was visualized and hub genes were filtered using Cytoscape. RESULTS: Immunofluorescence and qPCR results showed an increase in the expression of Myeloperoxidase (MPO) at week 1 and week 8 in the hearts of mice after MI. HE staining reveals a series of pathological manifestations in the heart of the MI group during 8â¯weeks, including enlarged size, disordered arrangement of cardiomyocytes, infiltration of inflammatory cells, and excessive deposition of collagen fibers, among others. The utilization of Apocynin could significantly improve these poor performances. The echocardiography displayed the cardiac function of the heart in mice. The MI group has a reduced range of heart movement and decreased ejection ability. Moreover, the ventricular systolic movement was found to be abnormal, and its wall thickening rate decreased over time, indicating a progressive worsening of myocardial ischemia. The Apocynin group, on the contrary, showed fewer abnormal changes in the aforementioned aspects. A total of 81 DEGs and 4 hub genes (FOS, EGR1, PTGS2, and HIST1H4H) were obtained. The results of RT-qPCR demonstrated abnormal expression of these four genes in the MI group, which could be reversed by treatment of Apocynin. CONCLUSION: The NETs formation could be highly related to MI and the long-term prognosis of MI can be significantly influenced by the NETs formation. Four hub genes, namely FOS, EGR1, PTGS2, and HIST1H4H, have the potential to be key genes related to this process. They could also serve as biomarkers for predicting MI prognosis and as targets for gene therapy.
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Trampas Extracelulares , Infarto del Miocardio , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Animales , Trampas Extracelulares/metabolismo , Ratones , Pronóstico , Masculino , Mapas de Interacción de Proteínas/genética , Modelos Animales de Enfermedad , Redes Reguladoras de Genes , Neutrófilos/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Acetofenonas/farmacología , Ratones Endogámicos C57BL , Ontología de GenesRESUMEN
OBJECTIVE: To analyze the risk factors affecting psychiatric behavior and study the psychobehavioral conditions of children with epilepsy. METHOD: We randomly selected and enrolled 294 children with epilepsy who visited and were hospitalized in the pediatric clinic of Hebei General Hospital between January 2017 and January 2022, as the study participants. We comprehensively assessed their cognitive functions using the Gesell development schedule or Wechsler Intelligence Scales. The participants were divided into the study group (n = 123) with cognitive impairment and the control group (n = 171) with normal cognitive functions, for analysis. RESULTS: There were statistically significant differences between the two groups in disease course, frequency of epilepsy, status epilepticus, and the number of antiseizure medications (ASMs) used (P < 0.05), while there were no statistically significant differences in age, gender, age of onset, form of onset, interictal epileptiform discharge, history of febrile convulsion, and the time from onset to initial visit (P > 0.05). Based on multivariate logistic regression analysis, the course of disease, frequency of onset, status epilepticus and number of ASMs used were identified as high-risk factors for cognitive impairment in children with epilepsy. Similarly, early onset, long course of disease, known etiology, and combination of multiple drugs have a negative impact on behavioral problems, school education, and social adaptability. CONCLUSION: The course of disease, the frequency of onset, status epilepticus, and the number of ASMs used are high-risk factors for cognitive impairment in children with epilepsy, which can be prevented and controlled early. When selecting ASMs, their advantages and disadvantages should be weighed. Moreover, the availability of alternative treatment options must be considered. With the help of genomic technology, the causes of epilepsy should be identified as early as possible, and precision medicine and gene therapy for children with epilepsy should be actively developed.
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Trastornos del Conocimiento , Epilepsia , Estado Epiléptico , Niño , Humanos , Cognición , Trastornos del Conocimiento/epidemiología , Comorbilidad , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Epilepsia/psicología , Estado Epiléptico/complicaciones , Masculino , FemeninoRESUMEN
Heart failure (HF) is a complex chronic condition characterized by structural and functional impairments. The differentiation of endothelial cells into myofibroblasts (EndoMT) in response to cardiac fibrosis is controversial, and the relative contribution of endothelial plasticity remains to be explored. Single-cell RNA sequencing was used to identify endothelial cells undergoing fibrotic differentiation within 2 weeks of transverse aortic constriction (TAC). This subset of endothelial cells transiently expressed fibrotic genes but had low expression of alpha-smooth muscle actin, indicating a non-canonical EndoMT, which we named a transient fibrotic-like phenotype (EndoFP). The role of EndoFP in pathological cardiac remodeling may be correlated with increased levels of osteopontin. Cardiomyocytes and fibroblasts co-cultured with EndoFP exhibited heightened pro-hypertrophic and pro-fibrotic effects. Mechanistically, we found that the upregulated expression of insulin-like growth factor-binding protein 5 may be a key mediator of EndoFP-induced cardiac dysfunction. Furthermore, our findings suggested that Rab5a is a novel regulatory gene involved in the EndoFP process. Our study suggests that the specific endothelial subset identified in TAC-induced pressure overload plays a critical role in the cellular interactions that lead to cardiac fibrosis and hypertrophy. Additionally, our findings provide insight into the mechanisms underlying EndoFP, making it a potential therapeutic target for early heart failure.
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Cardiomiopatías , Cardiopatías , Insuficiencia Cardíaca , Animales , Ratones , Miocitos Cardíacos , Células Endoteliales/patología , Cardiopatías/metabolismo , Insuficiencia Cardíaca/patología , Cardiomiopatías/metabolismo , Fibrosis , Fibroblastos/metabolismo , Remodelación Ventricular , Ratones Endogámicos C57BLRESUMEN
Cardiorenal syndrome type 4 (CRS4), a progressive deterioration of cardiac function secondary to chronic kidney disease (CKD), is a leading cause of death in patients with CKD. In this study, we aimed to investigate the cardioprotective effect of emodin on CRS4. C57BL/6 mice with 5/6 nephrectomy and HL-1 cells stimulated with 5% CKD mouse serum were used for in vivo and in vitro experiments. To assess the cardioprotective potential of emodin, we employed a comprehensive array of methodologies, including echocardiography, tissue staining, immunofluorescence staining, biochemical detection, flow cytometry, real-time quantitative PCR, and western blot analysis. Our results showed that emodin exerted protective effects on the function and structure of the residual kidney. Emodin also reduced pathologic changes in the cardiac morphology and function of these mice. These effects may have been related to emodin-mediated suppression of reactive oxygen species production, reduction of mitochondrial oxidative damage, and increase of oxidative metabolism via restoration of PGC1α expression and that of its target genes. In contrast, inhibition of PGC1α expression significantly reversed emodin-mediated cardioprotection in vivo. In conclusion, emodin protects the heart from 5/6 nephrectomy-induced mitochondrial damage via activation of the PGC1α signaling. The findings obtained in our study can be used to develop effective therapeutic strategies for patients with CRS4.
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Síndrome Cardiorrenal , Emodina , Insuficiencia Renal Crónica , Humanos , Ratones , Animales , Emodina/farmacología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Apoptosis , Ratones Endogámicos C57BLRESUMEN
Targeting macrophages can facilitate the site-specific repair of critical bone defects. Herein, a composite hydrogel, gelatin-Bletilla striata polysaccharide-mesoporous bioactive glass hydrogel (GBMgel), is constructed via the self-assembly of mesoporous bioactive glass on polysaccharide structures, through the Schiff base reaction. GBMgel can efficiently capture macrophages and drive the recruitment of seed stem cells and vascular budding required for regeneration in the early stages of bone injury, and the observed sustained release of inorganic silicon ions further enhances bone matrix deposition, mineralization, and vascular maturation. Moreover, the use of macrophage-depleted rat calvarial defect models further confirms that GBMgel, with ligand-selective macrophage targeting, increases the bone regeneration area and the proportion of mature bone. Mechanistic studies reveal that GBMgel upregulates the TLR4/NF-κB and MAPK macrophage pathways in the early stages and the JAK/STAT3 pathway in the later stages; thus initiating macrophage polarization at different time points. In conclusion, this study is based on the endogenous self-healing properties of bone macrophages, which enhances stem cell homing, and provides a research and theoretical basis upon which bone tissue can be reshaped and regenerated using the body's immune power, providing a new strategy for the treatment of critical bone defects.
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Regeneración Ósea , Hidrogeles , Macrófagos , Animales , Regeneración Ósea/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratas , Ratas Sprague-Dawley , Ratones , Células Madre/citología , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Células RAW 264.7 , Ligandos , Masculino , Gelatina/química , Cráneo/efectos de los fármacos , Cráneo/patología , Cráneo/lesiones , Polisacáridos/química , Polisacáridos/farmacologíaRESUMEN
OBJECTIVE: To investigate the association between DII with all-cause and cardiovascular disease (CVD) mortality among older adults in the U. S METHODS: This prospective cohort study included older adults with complete DII data and mortality data from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. Mortality outcomes were linked to National Death Index records through 31 December 2019. The multivariate Cox proportional hazards models were performed to evaluate the association between DII and mortality. Restricted cubic spline analyses were used to examine the nonlinear association of DII with all-cause and CVD mortality. RESULTS: During the median follow-up date of 6.7 years, 4446 all-cause deaths were documented among 10,827 representative older adults, including 1230 CVD deaths. After multivariate adjustment, linear relationships between DII with all-cause mortality (P non-linear = 0.17) and non-linear relationship between DII with CVD mortality (P non-linear = 0.04) were observed. Compared to participants with the lowest quartile of DII scores (-5.28 to≤0.43), the multivariate-adjusted HRs and 95 %CI for participants with higher DII scores were 1.19 (Q2, 95 %CI: 1.08-1.31), 1.28 (Q3, 95 %CI: 1.14-1.44), 1.30 (Q4, 95 %CI: 1.17-1.44) for all-cause mortality (P trend <0.001) and 1.19 (Q2, 95 %CI: 0.99-1.43), 1.34 (Q3, 95 %CI: 1.10-1.62), 1.30 (Q4, 95 %CI: 1.06-1.58) for CVD mortality (P trend < 0.01), respectively. CONCLUSIONS: In the representative sample of older adults in the U.S, higher DII scores were associated with increased risks of all-cause and CVD mortality.
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Enfermedades Cardiovasculares , Humanos , Adulto , Persona de Mediana Edad , Anciano , Enfermedades Cardiovasculares/etiología , Encuestas Nutricionales , Factores de Riesgo , Estudios Longitudinales , Estudios Prospectivos , Estudios de Seguimiento , Dieta , Estudios de CohortesRESUMEN
BACKGROUND: Ambient PM2.5 pollution (APMP2.5) was the leading environmental risk factor for cardiovascular diseases (CVDs) worldwide. An up-to-date comprehensive study is needed to provide global epidemiological patterns. METHODS: Detailed data on CVDs burden attributable to APMP2.5 were obtained from the Global Burden of Disease Study (GBD) 2019. We calculated the estimated annual percentage change (EAPC) to assess temporal trends in age-standardized rates of deaths and disability-adjusted life years (DALYs) over 30 years. RESULTS: Globally, CVDs attributable to APMP2.5 resulted in 2.48 million deaths and 60.91 million DALYs, with an increase of 122%, respectively from 1990 to 2019. In general, men suffered markedly higher burden than women, but the gap will likely turn narrow. As for age distribution, CVDs deaths and DALYs attributable to APMP2.5 mainly occurred in the elder group (>70 years). Low- and middle-income regions endured the higher CVDs burden due to the higher exposure to APMP2.5, and the gap may potentially expand further compared with high-income regions. For regions, the highest age-standardized rates of APMP2.5-related CVDs deaths and DALYs were observed mainly in Central Asia, while the lowest was observed in Australasia. At the national level, countries with the largest ASDR decline were clustered in western Europe, while Equatorial Guinea, Timor-Leste and Bhutan exhibited relatively rapid increases over this period. CONCLUSIONS: The global CVDs burden attributable to APMP2.5 has contributed to the heterogeneity of spatial and temporal distribution. APMP2.5-related CVDs deaths have largely shifted from higher SDI regions to those with a lower SDI. Globally, APMP2.5-attributable CVDs pose a significant threat to public health and diseases burden has increased over time, particularly in male, old-aged populations. The governments and health systems should take measures to reduce air pollution to impede this rising trend.
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Contaminación del Aire , Enfermedades Cardiovasculares , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Carga Global de Enfermedades , Años de Vida Ajustados por Calidad de Vida , Contaminación del Aire/efectos adversos , Salud Global , Material Particulado/toxicidadRESUMEN
OBJECTIVE: Xinyang Tablet (XYT) has emerged as a potential intervention to counter sepsis-induced myocardial dysfunction (SMID) by influencing macrophage autophagy and M2 polarization. This study aimed to unravel the underlying mechanism of XYT in sepsis-induced myocardial dysfunction (SIMD). METHODS: A microarray analysis was employed to explore sepsis-related changes, and bioinformatics analysis was used to predict lncRNAs binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). This studio utilized SIMD mouse models induced by lipopolysaccharide (LPS) injection, followed by treatments involving varied doses of XYT, digoxin (positive control), or si-LncSICRNT1. After seven days, evaluations encompassing mouse hair/mental state/diet/weight were measured, and cardiac function via echocardiography were conducted. Myocardial tissue changes were observed using hematoxylin-eosin staining. Additionally, bone marrow-derived macrophages (BMDMs) subjected to LPS for M1 polarization were treated with oe-LncSICRNT1, si-TRAF6 and their negative control, XYT, or autophagy inhibitor 3-Methyladenine (3-MA) (positive control). RT-qPCR and Western blot analyses were employed to assess LncSICRNT1, TRAF6, Beclin-1, LC3II/LC3I, and p62 levels. Immunohistochemistry and flow cytometry were used for M1/M2 polarization markers, while enzyme-linked immunosorbent assay (ELISA) gauged inflammatory factor levels. Interaction between TRAF6 and LncSICRNT1 was probed using RNA pull-down and RNA immunoprecipitation (RIP) assays. RESULTS: Chip analysis obtained 1463 differentially expressed lncRNAs, including LINC01550 (LncSICRNT1). Further prediction indicated that LncSICRNT1 was highly likely to directly bind to TRAF6. XYT treatment in LPS-induced SIMD mice led to notable enhancements in sleep/hair/diet/activity, increased weight/left ventricular end-diastolic diameter (LVEDd)/LV ejection fraction (LVEF)/LV fraction shortening (LVFS). These improvements were associated with elevated LncSICRNT1 expression and decreased TRAF6 protein levels, culminating in reduced myocardial inflammatory responses and improved cardiac function. Notably, XYT was found to suppress macrophage M1 polarization, while enhancing M2 polarization, ultimately benefitting cardiac function via LncSICRNT1 modulation. Furthermore, the study revealed LncSICRNT1 modulated Beclin-1 ubiquitination and restrained macrophage autophagy by targeting TRAF6 expression. CONCLUSION: The study highlights XYT's potential to ameliorate LPS-induced SIMD by elevating LncSICRNT1 expression, influencing TRAF6 expression, and regulating Beclin-1 ubiquitination. These actions collectively inhibit macrophage autophagy and foster M1/M2 polarization, contributing to cardiac function improvement.
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Myocardial fibrosis (MF) is the characteristic pathological feature of various cardiovascular diseases that lead to heart failure (HF) or even fatal outcomes. Alternatively, activated macrophages are involved in the development of fibrosis and tissue remodeling. Although the receptor for advanced glycation end products (RAGE) is involved in MF, its potential role in regulating macrophage function in cardiac fibrosis has not been fully investigated. We aimed to determine the role of macrophage RAGE in transverse aortic constriction (TAC)-induced MF. In this study, we found that RAGE expression was markedly increased in the infiltrated alternatively activated macrophages within mice hearts after TAC. RAGE knockout mice showed less infiltration of alternatively activated macrophages and attenuated cardiac hypertrophy and fibrosis compared to the wild-type mice. Our data suggest that mice with macrophage-specific genetic deletion of RAGE were protected from interstitial fibrosis and cardiac dysfunction when subjected to pressure overload, which led to a decreased proportion of alternatively activated macrophages in heart tissues. Our in vitro experiments demonstrated that RAGE deficiency inhibited the differentiation into alternatively activated macrophages by suppressing autophagy activation. In the co-culture system, in vitro polarization of RAW264.7 macrophages toward an alternatively activated phenotype stimulated the expression of α-smooth muscle actin and collagen in cardiac fibroblasts. However, the knockdown of RAGE and inhibition of autophagy in macrophages showed reduced fibroblast-to-myofibroblast transition (FMT). Collectively, our results suggest that RAGE plays an important role in the recruitment and activation of alternatively activated macrophages by regulating autophagy, which contributes to MF. Thus, blockage of RAGE signaling may be an attractive therapeutic target for the treatment of hypertensive heart disease.
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Cardiopatías , Insuficiencia Cardíaca , Animales , Ratones , Autofagia , Fibrosis , Cardiopatías/metabolismo , Insuficiencia Cardíaca/metabolismo , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Miocardio/metabolismo , Receptor para Productos Finales de Glicación Avanzada/genética , Receptor para Productos Finales de Glicación Avanzada/metabolismoRESUMEN
BACKGROUND AND AIMS: NAFLD comprises a spectrum of liver disorders with the initial abnormal accumulation of lipids in hepatocytes called NAFL, progressing to the more serious NASH in a subset of individuals. Our previous study revealed that global flavin-containing monooxygenase 2 (FMO2) knockout causes higher liver weight in rats. However, the role of FMO2 in NAFLD remains unclear. Herein, we aimed to determine the function and mechanism of FMO2 in liver steatosis and steatohepatitis. APPROACH AND RESULTS: The expression of FMO2 was significantly downregulated in patients with NAFL/NASH and mouse models. Both global and hepatocyte-specific knockout of FMO2 resulted in increased lipogenesis and severe hepatic steatosis, inflammation, and fibrosis, whereas FMO2 overexpression in mice improved NAFL/NASH. RNA sequencing showed that hepatic FMO2 deficiency is associated with impaired lipogenesis in response to metabolic challenges. Mechanistically, FMO2 directly interacts with SREBP1 at amino acids 217-296 competitively with SREBP cleavage-activating protein (SCAP) and inhibits SREBP1 translocation from the endoplasmic reticulum (ER) to the Golgi apparatus and its subsequent activation, thus suppressing de novo lipogenesis (DNL) and improving NAFL/NASH. CONCLUSIONS: In hepatocytes, FMO2 is a novel molecule that protects against the progression of NAFL/NASH independent of enzyme activity. FMO2 impairs lipogenesis in high-fat diet-induced or choline-deficient, methionine-deficient, amino acid-defined high-fat diet-induced steatosis, inflammation, and fibrosis by directly binding to SREBP1 and preventing its organelle translocation and subsequent activation. FMO2 thus is a promising molecule for targeting the activation of SREBP1 and for the treatment of NAFL/NASH.
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This study analysed the data from the NHANES (1999-2018) to examine how different sources of carbohydrate intake affected the all-cause and cardiovascular mortality of 11,302 chronic kidney disease (CKD) patients. The data were adjusted for other factors using various methods. The results showed that CKD patients (stages 1-2 and 3-5) who consumed more carbohydrates from whole grains, fruits, vegetables and less carbohydrates from fruit juice or sauces had lower mortality rates. Replacing fat intake with carbohydrates from whole grains (HR = 0.86[0.78-0.95]), fruits (raw) (HR = 0.79[0.70-0.88]) and non-starchy vegetables (HR = 0.82[0.70-0.96]), but not protein intake, was linked to lower all-cause mortality. The fibre content in carbohydrates might partly account for the benefits of selected carbohydrate intake. This study provided practical recommendations for optimising the carbohydrate sources in CKD patients.
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Enfermedades Cardiovasculares , Insuficiencia Renal Crónica , Humanos , Encuestas Nutricionales , Verduras , Insuficiencia Renal Crónica/complicaciones , Enfermedades Cardiovasculares/etiología , CarbohidratosRESUMEN
As the most abundant internal mRNA modification, N6-methyladenosine (m6A) RNA methylation has been found to influence many biological events including bone mesenchymal stem cells (BMSCs) osteogenic differentiation. YTH N6-methyladenosine RNA binding protein C2 ï¼YTHDC2ï¼ is an m6A reading protein with the ability to mediate the decay of combined methylated mRNA, however its role in BMSCs osteogenic differentiation remains unknown. In this study, we first found an increase of RUNX family transcription factor 2 ï¼RUNX2ï¼ expression and a decrease of YTHDC2 expression during the process of BMSCs osteogenic differentiation. Furthermore, we transfected BMSCs with YTHDC2 interference fragment, resulting in an increased content of RUNX2 mRNA and protein inside BMSCs. Finally, through RNA Immunoprecipitation experiments, we confirmed that YTHDC2 protein can bind to RUNX2 mRNA and accelerate its decomposition. Moreover, the immunofluorescence staining also showed a negative correlation between YTHDC2 and RUNX2. In conclusion, during BMSCs osteogenic differentiation, YTHDC2 protein showed decreased expression, resulting in a higher level of RUNX2 (mRNA and protein) expression inside cells, indicating YTHDC2 as a promising molecular target for the regulation of BMSCs osteogenic differentiation.