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Purpose: This study aimed to determine the optimal cutoff points for age and tumor size of patients with intrahepatic cholangiocarcinoma (ICC) and to establish and verify a predictive nomogram of overall survival at 1, 3, and 5 years. Methods: From the SEER (Surveillance, Epidemiology, and End Results) database, 1,325 ICC patients were selected and randomly divided into training and testing cohorts at a 7:3 ratio. Using the X-tile software, age and tumor size were classified into 3 subgroups: ≤61, 62-74, and ≥75 years and ≤35, 36-55, and ≥56 mm. Subsequently, univariate and multivariate Cox regression analyses were performed using the R software in the training cohort to determine independent risk factors, compile the prediction nomogram, and verify it with the testing cohort findings. Results: The C-indexes of the new prediction nomograms in the training and testing cohorts were 0.738 (95% confidence interval [CI], 0.718-0.758) and 0.750 (95% CI, 0.72-0.78), respectively. Furthermore, the areas under the 1-, 3-, and 5-year receiver operating characteristic (ROC) curves based on the nomogram were 0.792, 0.853, and 0.838, respectively, higher than the ROC based on the 7th and 8th editions of the American Joint Cancer Commission (AJCC) staging system. Conclusion: This study established and verified a prognostic nomogram that improved the accuracy of the 1-, 3-, and 5-year survival predictions for ICC patients, compared with that based on the 7th and 8th editions of the AJCC staging system, and can help clinicians make personalized survival predictions.
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The difference in the survival of obese patients and normal-weight/lean patients with diabetic MAFLD remains unclear. Therefore, we aimed to describe the long-term survival of individuals with diabetic MAFLD and overweight/obesity (OT2M), diabetic MAFLD with lean/normal weight (LT2M), MAFLD with overweight/obesity and without T2DM (OM), and MAFLD with lean/normal weight and without T2DM (LM). Using the NHANESIII database, participants with MAFLD were divided into four groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cardiovascular disease (CVD)-related, and cancer-related mortalities for different MAFLD subtypes were evaluated using Cox proportional hazards models. Of the 3539 participants, 1618 participants (42.61%) died during a mean follow-up period of 274.41 ± 2.35 months. LT2M and OT2M had higher risks of all-cause mortality (adjusted HR, 2.14; 95% CI 1.82-2.51; p < 0.0001; adjusted HR, 2.24; 95% CI 1.32-3.81; p = 0.003) and CVD-related mortality (adjusted HR, 3.25; 95% CI 1.72-6.14; p < 0.0001; adjusted HR, 3.36; 95% CI 2.52-4.47; p < 0.0001) than did OM. All-cause and CVD mortality rates in LT2M and OT2M patients were higher than those in OM patients. Patients with concurrent T2DM and MAFLD should be screened, regardless of the presence of obesity.
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Diabetes Mellitus Tipo 2 , Obesidad , Humanos , Masculino , Femenino , Obesidad/complicaciones , Obesidad/mortalidad , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/mortalidad , Adulto , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/etiología , Enfermedad del Hígado Graso no Alcohólico/mortalidad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Modelos de Riesgos Proporcionales , Anciano , Factores de RiesgoRESUMEN
OBJECTIVES: Controlled attenuation parameter (CAP) is a noninvasive and quantitative method to evaluate hepatic steatosis, which is not well evaluated in children. The aim of this study was to examine the diagnostic value of CAP for hepatic steatosis in children with obesity based on MR proton density fat fraction (PDFF). METHODS: About 108 pediatric patients with nonalcoholic fatty liver disease (NAFLD) who were assessed for PDFF, CAP, and other laboratory results were enrolled. In this study, pediatric patients were separated for the obese group (n=80) and the severe obese group (n=28). Hepatic steatosis grades (0-3) were classified according to PDFF using cutoff values of 6.4â¯, 17.4, and 22.1â¯%. RESULTS: There are significant differences in CAP between the obese and severe obese groups (p<0.05). CAP showed a good correlation with PDFF in pediatric patients with NAFLD for diagnosing hepatic steatosis using a cutoff value of 265â¯dB/m (p<0.001). Meanwhile, ALT significantly outperforms CAP in receiver-operating curve (ROC) analysis for diagnosing hepatic steatosis grades. The diagnostic accuracy of CAP for steatosis is 77.8â¯%, and the diagnostic accuracy of ALT for steatosis is 83.3â¯%. CONCLUSIONS: While CAP holds promise as a diagnostic tool for pediatric NAFLD, its diagnostic performance warrants some caution. The potential of CAP is evident; however, ALT emerges as a simpler and more accurate measure for detecting hepatic steatosis in children. Further research is essential to determine the optimal role of CAP in pediatric NAFLD diagnosis and management.
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Imagen por Resonancia Magnética , Enfermedad del Hígado Graso no Alcohólico , Obesidad Infantil , Humanos , Niño , Masculino , Femenino , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/patología , Imagen por Resonancia Magnética/métodos , Obesidad Infantil/complicaciones , Obesidad Infantil/diagnóstico por imagen , Adolescente , Curva ROC , Pronóstico , Estudios de SeguimientoRESUMEN
Cardiac hypertrophy is a key factor driving heart failure (HF), yet its pathogenesis remains incompletely elucidated. Mettl1-catalyzed RNA N7-methylguanosine (m7G) modification has been implicated in ischemic cardiac injury and fibrosis. This study aims to elucidate the role of Mettl1 and the mechanism underlying non-ischemic cardiac hypertrophy and HF. It is found that Mettl1 is upregulated in human failing hearts and hypertrophic murine hearts following transverse aortic constriction (TAC) and Angiotensin II (Ang II) infusion. YY1 acts as a transcriptional factor for Mettl1 during cardiac hypertrophy. Mettl1 knockout alleviates cardiac hypertrophy and dysfunction upon pressure overload from TAC or Ang II stimulation. Conversely, cardiac-specific overexpression of Mettl1 results in cardiac remodeling. Mechanically, Mettl1 increases SRSF9 expression by inducing m7G modification of SRSF9 mRNA, facilitating alternative splicing and stabilization of NFATc4, thereby promoting cardiac hypertrophy. Moreover, the knockdown of SRSF9 protects against TAC- or Mettl1-induced cardiac hypertrophic phenotypes in vivo and in vitro. The study identifies Mettl1 as a crucial regulator of cardiac hypertrophy, providing a novel therapeutic target for HF.
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Cardiomegalia , Modelos Animales de Enfermedad , Animales , Cardiomegalia/genética , Cardiomegalia/metabolismo , Ratones , Factores de Empalme Serina-Arginina/metabolismo , Factores de Empalme Serina-Arginina/genética , Humanos , Metiltransferasas/metabolismo , Metiltransferasas/genética , Masculino , Factores de Transcripción NFATC/metabolismo , Factores de Transcripción NFATC/genética , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Ferroptosis is a nonapoptotic form of regulated cell death that has been reported to play a central role in cardiac ischemiaâreperfusion (I/R) injury. N-acetyltransferase 10 (NAT10) contributes to cardiomyocyte apoptosis by functioning as an RNA ac4c acetyltransferase, but its role in cardiomyocyte ferroptosis during I/R injury has not been determined. This study aimed to elucidate the role of NAT10 in cardiac ferroptosis as well as the underlying mechanism. The mRNA and protein levels of NAT10 were increased in mouse hearts after I/R and in cardiomyocytes that were exposed to hypoxia/reoxygenation. P53 acted as an endogenous activator of NAT10 during I/R in a transcription-dependent manner. Cardiac overexpression of NAT10 caused cardiomyocyte ferroptosis to exacerbate I/R injury, while cardiomyocyte-specific knockout of NAT10 or pharmacological inhibition of NAT10 with Remodelin had the opposite effects. The inhibition of cardiomyocyte ferroptosis by Fer-1 exerted superior cardioprotective effects against the NAT10-induced exacerbation of post-I/R cardiac damage than the inhibition of apoptosis by emricasan. Mechanistically, NAT10 induced the ac4C modification of Mybbp1a, increasing its stability, which in turn activated p53 and subsequently repressed the transcription of the anti-ferroptotic gene SLC7A11. Moreover, knockdown of Mybbp1a partially abolished the detrimental effects of NAT10 overexpression on cardiomyocyte ferroptosis and cardiac I/R injury. Collectively, our study revealed that p53 and NAT10 interdependently cooperate to form a positive feedback loop that promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury, suggesting that targeting the NAT10/Mybbp1a/p53 axis may be a novel approach for treating cardiac I/R.
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Ferroptosis , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Proteína p53 Supresora de Tumor , Animales , Humanos , Masculino , Ratones , Acetiltransferasas/metabolismo , Acetiltransferasas/genética , Apoptosis , Modelos Animales de Enfermedad , Retroalimentación Fisiológica , Ferroptosis/genética , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease that seriously threatens the quality of life of the elderly. Its pathogenesis has not yet been fully elucidated. Ferroptosis, a cell death caused by excessive accumulation of iron-dependent lipid peroxides, has been implicated in the pathogenesis of AD. Uncontrolled lipid peroxidation is the core process of ferroptosis, and inhibiting lipid peroxidation of ferroptosis may be an important therapeutic target for AD. Based on previous studies, we mixed standards of icariin, astragaloside IV, and puerarin, named the standard mixture YHG, and investigated the effect of YHG on ferroptosis -lipid peroxidation in APP/PS1 mice. DFX, a ferroptosis inhibitor, was used as a control drug. In this study, APP/PS1 mice were used as an AD animal model, and behavioral experiments, iron level detection, Transmission electron microscopy (TEM) observation, lipid peroxidation level detection, antioxidant capacity detection, immunofluorescence, Western blot and real-time qPCR were performed. It was found that YHG could reduce body weight, significantly improve abnormal behaviors and the ultrastructure of hippocampal neurons in APP/PS1 mice. The results of biochemical tests showed that YHG reduced the contents of iron, malondialdehyde (MDA) and lipid peroxide (LPO) in brain tissue and serum, and increased the levels of superoxide dismutase (SOD) and reduced glutathione (GSH). Immunofluorescence, WesternBlot and real-time qPCR results showed that YHG could promote the expression of solute carrier family 7 member 11 (SLC7A11), solute carrier family 3 member 2 (SLC3A2) and glutathione peroxidase 4(GPX4). Inhibited the expression of long-chain acyllipid coenzyme a synthetase 4(ACSL4) and lysophosphatidyltransferase 3 (LPCAT3). This study suggests that the mechanism by which YHG improves cognitive dysfunction in APP/PS1 mice may be related to the inhibition of ferroptosis-lipid peroxidation.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Ferroptosis , Flavonoides , Isoflavonas , Enfermedades Neurodegenerativas , Saponinas , Triterpenos , Humanos , Anciano , Animales , Ratones , Peroxidación de Lípido , Calidad de Vida , Peróxidos Lipídicos , Enfermedad de Alzheimer/tratamiento farmacológico , Hierro , 1-Acilglicerofosfocolina O-AciltransferasaRESUMEN
Malignant ventricular arrhythmia (VA) after myocardial infarction (MI) is mainly caused by myocardial electrophysiological remodeling. Brahma-related gene 1 (BRG1) is an ATPase catalytic subunit that belongs to a family of chromatin remodeling complexes called Switch/Sucrose Non-Fermentable Chromatin (SWI/SNF). BRG1 has been reported as a molecular chaperone, interacting with various transcription factors or proteins to regulate transcription in cardiac diseases. In this study, we investigated the potential role of BRG1 in ion channel remodeling and VA after ischemic infarction. Myocardial infarction (MI) mice were established by ligating the left anterior descending (LAD) coronary artery, and electrocardiogram (ECG) was monitored. Epicardial conduction of MI mouse heart was characterized in Langendorff-perfused hearts using epicardial optical voltage mapping. Patch-clamping analysis was conducted in single ventricular cardiomyocytes isolated from the mice. We showed that BRG1 expression in the border zone was progressively increased in the first week following MI. Cardiac-specific deletion of BRG1 by tail vein injection of AAV9-BRG1-shRNA significantly ameliorated susceptibility to electrical-induced VA and shortened QTc intervals in MI mice. BRG1 knockdown significantly enhanced conduction velocity (CV) and reversed the prolonged action potential duration in MI mouse heart. Moreover, BRG1 knockdown improved the decreased densities of Na+ current (INa) and transient outward potassium current (Ito), as well as the expression of Nav1.5 and Kv4.3 in the border zone of MI mouse hearts and in hypoxia-treated neonatal mouse ventricular cardiomyocytes. We revealed that MI increased the binding among BRG1, T-cell factor 4 (TCF4) and ß-catenin, forming a transcription complex, which suppressed the transcription activity of SCN5A and KCND3, thereby influencing the incidence of VA post-MI.
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Infarto del Miocardio , Ratones , Animales , Infarto del Miocardio/metabolismo , Arritmias Cardíacas/genética , Miocardio/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Miocitos Cardíacos/metabolismoRESUMEN
BACKGROUND: Increasing evidence suggests that long noncoding RNAs play significant roles in vascular biology and disease development. One such long noncoding RNA, PSMB8-AS1, has been implicated in the development of tumors. Nevertheless, the precise role of PSMB8-AS1 in cardiovascular diseases, particularly atherosclerosis, has not been thoroughly elucidated. Thus, the primary aim of this investigation is to assess the influence of PSMB8-AS1 on vascular inflammation and the initiation of atherosclerosis. METHODS: We generated PSMB8-AS1 knockin and Apoe (Apolipoprotein E) knockout mice (Apoe-/-PSMB8-AS1KI) and global Apoe and proteasome subunit-ß type-9 (Psmb9) double knockout mice (Apoe-/-Psmb9-/-). To explore the roles of PSMB8-AS1 and Psmb9 in atherosclerosis, we fed the mice with a Western diet for 12 weeks. RESULTS: Long noncoding RNA PSMB8-AS1 is significantly elevated in human atherosclerotic plaques. Strikingly, Apoe-/-PSMB8-AS1KI mice exhibited increased atherosclerosis development, plaque vulnerability, and vascular inflammation compared with Apoe-/- mice. Moreover, the levels of VCAM1 (vascular adhesion molecule 1) and ICAM1 (intracellular adhesion molecule 1) were significantly upregulated in atherosclerotic lesions and serum of Apoe-/-PSMB8-AS1KI mice. Consistently, in vitro gain- and loss-of-function studies demonstrated that PSMB8-AS1 induced monocyte/macrophage adhesion to endothelial cells and increased VCAM1 and ICAM1 levels in a PSMB9-dependent manner. Mechanistic studies revealed that PSMB8-AS1 induced PSMB9 transcription by recruiting the transcription factor NONO (non-POU domain-containing octamer-binding protein) and binding to the PSMB9 promoter. PSMB9 (proteasome subunit-ß type-9) elevated VCAM1 and ICAM1 expression via the upregulation of ZEB1 (zinc finger E-box-binding homeobox 1). Psmb9 deficiency decreased atherosclerotic lesion size, plaque vulnerability, and vascular inflammation in Apoe-/- mice in vivo. Importantly, endothelial overexpression of PSMB8-AS1-increased atherosclerosis and vascular inflammation were attenuated by Psmb9 knockout. CONCLUSIONS: PSMB8-AS1 promotes vascular inflammation and atherosclerosis via the NONO/PSMB9/ZEB1 axis. Our findings support the development of new long noncoding RNA-based strategies to counteract atherosclerotic cardiovascular disease.
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Aterosclerosis , Placa Aterosclerótica , ARN Largo no Codificante , Animales , Humanos , Ratones , Apolipoproteínas E/genética , Aterosclerosis/metabolismo , Células Endoteliales/metabolismo , Inflamación/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica/patología , Complejo de la Endopetidasa Proteasomal/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Cardiovascular diseases have been closely linked to abnormal epigenetic regulation. In the context of epigenetic regulation, BRG1, a pivotal SWI/SNF chromatin remodeling enzyme, emerges as a key epigenetic regulator with significant impact on the development and progression of cardiovascular disorders. From the perspective of epigenetic regulation of cardiovascular diseases, BRG1 emerges as a pivotal SWI/SNF chromatin remodeling enzyme, functioning as a key epigenetic regulator. It exerts substantial influence on the development and progression of cardiovascular disorders by exerting precise control over gene expression and protein levels. Therefore, a comprehensive understanding of BRG1's epigenetic regulatory role in cardiovascular disease is essential for unraveling its underlying pathophysiological mechanisms. This paper summarizes and discusses the function of BRG1 in the epigenetic regulation of cardiovascular diseases.
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Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/genética , Epigénesis Genética , CromatinaRESUMEN
Background: PFI-3 is a small-molecule inhibitor that targets the bromodomains (BRDs) of Brahma-related gene 1 (BRG1). This monomeric compound, which has high selectivity and potent cellular effects, has recently been developed. Although PFI-3 has been reported as a potential therapeutic agent targeting thrombomodulin, its role in the regulation of vascular function remains unknown. Therefore, we aimed to investigate the impact of PFI-3 on arterial vessel tone. Methods: A microvascular tension measurement device (DMT) was utilized to identify alterations in vascular tension within the mesenteric artery. To detect variations in cytosolic [Ca2+]i, a Fluo-3/AM fluorescent probe and fluorescence microscope were employed. Additionally, whole-cell patch clamp techniques were utilized to evaluate the activity of L-type voltage-dependent calcium channels (VDCCs) in cultured arterial smooth muscle cells (A10 cells). Results: PFI-3 exerted a dose-dependent relaxation effect on rat mesenteric arteries with both intact and denuded endothelium after phenylephrine (PE)- and high-K+-induced constriction. PFI-3-induced vasorelaxation was not affected by the presence of L-NAME/ODQ or K+ channel blockers (Gli/TEA). PFI-3 abolished Ca2+-induced contraction on endothelium-denuded mesenteric arteries preincubated by PE in Ca2+-free solution. Incubation with TG had no impact on PFI-3-induced vasorelaxation pre-contracted by PE. PFI-3 reduced Ca2+-induced contraction on endothelium-denuded mesenteric arteries pre-incubated by KCl (60 mM) in Ca2+-free solution. PFI-3 declined extracellular calcium influx in A10 cells detected by Fluo-3/AM fluorescent probe and fluorescence microscope. Furthermore, we observed that PFI-3 decreased the current densities of L-type VDCC by whole-cell patch clamp techniques. Conclusions: PFI-3 blunted PE and high K+-induced vasoconstriction independent of endothelium on rat mesenteric artery. The vasodilatory effect of PFI-3 may be attributed to its inhibition of VDCCs and receptor-operated calcium channels (ROCCs) on vascular smooth muscle cells (VSMCs).
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Calcio , Colorantes Fluorescentes , Animales , Ratas , Calcio/metabolismo , Canales de Calcio Tipo L/farmacología , Colorantes Fluorescentes/farmacología , Arterias MesentéricasRESUMEN
Long non-coding RNAs (lncRNAs) are emerging as important players in gene regulation and cardiovascular diseases. However, the roles of lncRNAs in atherosclerosis are poorly understood. In the present study, we found that the levels of NIPA1-SO were decreased while those of NIPA1 were increased in human atherosclerotic plaques. Furthermore, NIPA1-SO negatively regulated NIPA1 expression in human umbilical vein endothelial cells (HUVECs). Mechanistically, NIPA1-SO interacted with the transcription factor FUBP1 and the NIPA1 gene. The effect of NIPA1-SO on NIPA1 protein levels was reversed by the knockdown of FUBP1. NIPA1-SO overexpression increased, whilst NIPA1-SO knockdown decreased BMPR2 levels; these effects were enhanced by the knockdown of NIPA1. The overexpression of NIPA1-SO reduced while NIPA1-SO knockdown increased monocyte adhesion to HUVECs; these effects were diminished by the knockdown of BMPR2. The lentivirus-mediated-overexpression of NIPA1-SO or gene-targeted knockout of NIPA1 in low-density lipoprotein receptor-deficient mice reduced monocyte-endothelium adhesion and atherosclerotic lesion formation. Collectively, these findings revealed a novel anti-atherosclerotic role for the lncRNA NIPA1-SO and highlighted its inhibitory effects on vascular inflammation and intracellular cholesterol accumulation by binding to FUBP1 and consequently repressing NIPA1 expression.
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Aterosclerosis , Placa Aterosclerótica , ARN Largo no Codificante , Humanos , Animales , Ratones , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/farmacología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Proteínas de la Membrana/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/farmacología , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/farmacologíaRESUMEN
BACKGROUND: With the gradual adoption of new metabolic-associated fatty liver disease (MAFLD) definitions in clinical practice, the relationship between MAFLD and cardiovascular disease (CVD) risk remains unclear. Similarly, clinical differences between MAFLD and nonalcoholic fatty liver disease (NAFLD), and the relationship between MAFLD and CVD risk are unclear. METHODS: We conducted a retrospective study using the 1988-1994 National Health and Nutrition Examination Surveys (NHANES III) database, including 11,673 individuals. Multivariate logistic regression analysis was performed to test relationships between MAFLD and the 10-year CVD risk. RESULTS: MAFLD was more significant than NAFLD in medium/high 10-year CVD risk (according to Framingham risk score) (1064 (29.92%) vs. 1022 (26.37%), P < 0.005). MAFLD patients were stratified according to NAFLD fibrosis scores (NFS's). In univariate regression analysis, when compared with non-MAFLD patients, unadjusted-OR values for MAFLD with different liver fibrosis stages, which were tiered by NFS (NFS < -1.455,-1.455 ≤ NFS < 0.676, and NFS ≥ 0.676) in the medium 10-year CVD risk (according to Framingham scores) were 1.175 (95% CI 1.030-1.341), 3.961 (3.449-4.549), and 5.477 (4.100-7.315), and the unadjusted or values of different MAFLD groups in the high 10-year CVD risk were 1.407 (95% CI 1.080-1.833), 5.725 (4.500-7.284), and 5.330 (3.132-9.068). Then, after adjusting for age, sex, race, alcohol consumption, and smoking, or adjusting for age, race, alcohol consumption, smoking, type 2 diabetes mellitus (T2DM), and other confounding factors, the incidence of medium and high 10-year CVD risk was statistically significant (P < 0.05). CONCLUSIONS: We showed that patients with MAFLD had a higher 10-year CVD risk when compared with patients with NAFLD. Increased MAFLD hepatic fibrosis scores were associated with a 10-year CVD risk.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Encuestas Nutricionales , Estudios RetrospectivosRESUMEN
BACKGROUND: The study aimed to investigate the potential risk factors for the placenta accreta spectrum (PAS), determine the predictive value of a diagnostic model, and evaluate the effects of octamethylcyclotetrasiloxane (OMCTS) on trophoblast proliferation and migration. METHODS: This case-control study included 244 pregnant women with PAS and 327 normal pregnant women who visited Guangzhou Women and Children's Medical Centre, China, from January 2014 to December 2017. Blood was collected from 42 women with PAS and 77 controls, and plasma specimens were analyzed by gas chromatography-time-of-flight mass spectrometry. In addition, the proliferation and migration of trophoblast cells were examined after treatment with OMCTS. RESULTS: We found an association between the risk of PAS and clinical factors related to fasting blood glucose levels (BS0, OR = 5.78), as well as factors related to endometrial injury [history of cesarean section (OR = 179.59), uterine scarring (OR = 68.37), and history of abortion (OR = 5.66)]. Equally important, pregnant women with PAS had significantly higher plasma OMCTS concentrations than controls. In vitro, we found that OMCTS could promote the proliferation and migration of HTR8/SVneo cells. The model of combining clinical factors and OMCTS had a good performance in PAS prediction (AUC = 0.97, 95% CI 0.78-0.93). CONCLUSIONS: The early diagnosis of PAS in pregnant women requires assessing risk factors, metabolic status, and BS0 levels before 20 weeks of gestation. OMCTS may be related to the development of PAS by promoting trophoblast cell proliferation and migration.
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Placenta Accreta , Placenta Previa , Estudios de Casos y Controles , Cesárea , Niño , Femenino , Humanos , Placenta , Placenta Accreta/terapia , Embarazo , Estudios Retrospectivos , Factores de Riesgo , SiloxanosRESUMEN
Alzheimer's disease(AD) patients in China have been surging, and the resultant medical burden and care demand have a huge impact on the development of individuals, families, and the society. The active component compound of Epimedii Folium, Astragali Radix, and Puerariae Lobatae Radix(YHG) can regulate the expression of iron metabolism-related proteins to inhibit brain iron overload and relieve hypofunction of central nervous system in AD patients. Hepcidin is an important target regulating iron metabolism. This study investigated the effect of YHG on the expression of a disintegrin and metalloprotease-17(ADAM17), a key enzyme in the hydrolysis of ß amyloid precursor protein(APP) in HT22 cells, by mediating hepcidin. To be specific, HT22 cells were cultured in vitro, followed by liposome-mediated siRNA transfection to silence the expression of hepcidin. Real-time PCR and Western blot were performed to examine the silencing result and the effect of YHG on hepcidin in AD cell model. HT22 cells were randomized into 7 groups: control group, Aß25-35 induction(Aß) group, hepcidin-siRNA(siRNA) group, Aß25-35 + hepcidin-siRNA(Aß + siRNA) group, Aß25-35+YHG(Aß+YHG) group, hepcidin-siRNA+YHG(siRNA+YHG) group, Aß25-35+hepcidin-siRNA+YHG(Aß+siRNA+YHG) group. The expression of ADAM17 mRNA in cells was detected by real-time PCR, and the expression of ADAM17 protein by immunofluorescence and Western blot. Immunofluorescence showed that the ADAM17 protein expression was lower in the Aß group, siRNA group, and Aß+siRNA group than in the control group(P<0.05) and the expression was lower in the Aß+siRNA group(P<0.05) and higher in the Aß+YHG group(P<0.05) than in the Aß group. Moreover, the ADAM17 protein expression was lower in the Aß+siRNA group(P<0.05) and higher in the siRNA+YHG group(P< 0.05) than in the siRNA group. The expression was higher in the Aß+siRNA+YHG group than in the Aß+siRNA group(P<0.05). The results of Western blot and real-time PCR were consistent with those of immunofluorescence. The experiment showed that YHG induced hepcidin to up-regulate the expression of ADAM17 in AD cell model and promote the activation of non-starch metabolic pathways, which might be the internal mechanism of YHG in preventing and treating AD.
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Enfermedad de Alzheimer , Medicamentos Herbarios Chinos , Pueraria , Proteína ADAM17 , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Medicamentos Herbarios Chinos/farmacología , Hepcidinas/genética , HumanosRESUMEN
BACKGROUND AND AIMS: Pyroptosis is a relatively newly discovered form of programmed cell death that plays an important role in the development of atherosclerosis. Many studies have reported that lncRNAs participated in the regulation of atherosclerosis development. However, the regulatory mechanism of lncRNAs in pyroptosis must be studied further. METHODS: In a previous study, microarray analysis was used to detect the lncRNA expression profile in three human advanced atherosclerotic plaques and three normal arterial intimae. In the present research, in vitro assays were performed to investigate the role of lncRNA RP11-490M8.1 on pyroptosis. The relative gene mRNA and lncRNA expression levels were tested by quantitative real-time PCR, and protein levels were evaluated by western blot analysis. The RNA hybrid structure was analyzed using the DINAMelt server. RESULTS: The lncRNA RP11-490M8.1 was significantly downregulated in atherosclerotic plaques and serum. Lipopolysaccharide (LPS) markedly reduced the expression of lncRNA RP11-490M8.1 and induced pyroptosis by increasingthe mRNA and protein levels of NLRP3, caspase-1, ASC, IL-1ß, and IL-18 in HUVECs. The promotion effects ofLPS on pyroptosis were markedly suppressed by overexpression of lncRNA RP11-490M8.1. In addition, LPS increased the mRNA and protein levels ofTLR4 and NF-κB, which was also markedly offsetby overexpression of lncRNA RP11-490M8.1. CONCLUSIONS: These findings indicated that lncRNA RP11-490M8.1 inhibited LPS-induced pyroptosis via the TLR4/NF-κB pathway. Thus, lncRNA RP11-490M8.1 may provide a therapeutic target to ameliorate atherosclerosis.
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Células Endoteliales de la Vena Umbilical Humana , FN-kappa B , Piroptosis , ARN Largo no Codificante , Receptor Toll-Like 4 , Aterosclerosis/genética , Proteínas Adaptadoras de Señalización CARD/genética , Caspasa 1/genética , Células Cultivadas , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inflamasomas/genética , Inflamasomas/metabolismo , Interleucina-18/genética , Interleucina-1beta/genética , Lipopolisacáridos/farmacología , FN-kappa B/genética , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis/efectos de los fármacos , ARN Mensajero , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
OBJECTIVE: Noncoding RNAs are emerging as important players in gene regulation and cardiovascular diseases. Their roles in the pathogenesis of atherosclerosis are not fully understood. The purpose of this study was to determine the role played by a previously uncharacterized long noncoding RNA, RP11-728F11.4, in the development of atherosclerosis and the mechanisms by which it acts. Approach and Results: Expression microarray analysis revealed that atherosclerotic plaques had increased expression of RP11-728F11.4 as well as the cognate gene FXYD6 (FXYD domain containing ion transport regulator 6), which encodes a modulator of Na+/K+-ATPase. In vitro experiments showed that RP11-728F11.4 interacted with the RNA-binding protein EWSR1 (Ewings sarcoma RNA binding protein-1) and upregulated FXYD6 expression. Lentivirus-induced overexpression of RP11-728F11.4 in cultured monocytes-derived macrophages resulted in higher Na+/K+-ATPase activity, intracellular cholesterol accumulation, and increased proinflammatory cytokine production. The effects of RP11-728F11.4 were enhanced by siRNA-mediated knockdown of EWSR1 and reduced by downregulation of FXYD domain containing ion transport regulator 6. In vivo experiments in apoE knockout mice fed a Western diet demonstrated that RP11-728F11.4 increased proinflammatory cytokine production and augmented atherosclerotic lesions. CONCLUSIONS: RP11-728F11.4 promotes atherosclerosis, with an influence on cholesterol homeostasis and proinflammatory molecule production, thus representing a potential therapeutic target. Graphic Abstract: A graphic abstract is available for this article.
Asunto(s)
Aterosclerosis/genética , ARN Largo no Codificante/genética , Animales , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Células Cultivadas , Colesterol/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Canales Iónicos/genética , Canales Iónicos/metabolismo , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Persona de Mediana Edad , Placa Aterosclerótica/etiología , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , ARN Largo no Codificante/metabolismo , Proteína EWS de Unión a ARN/antagonistas & inhibidores , Proteína EWS de Unión a ARN/genética , Proteína EWS de Unión a ARN/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Regulación hacia ArribaRESUMEN
Background: Ischemia/reperfusion (I/R) caused by ischemic stroke treatments leads to brain injury, and autophagy plays a role in the pathology. Astragaloside IV is a potential neuroprotectant, but its underlying mechanism on cerebral I/R injury needs to be explored. The objective of this study is to investigate the neuroprotective mechanism of Astragaloside IV against cerebral I/R injury. Methods: Middle cerebral artery occlusion method (MCAO) and oxygen and glucose deprivation/reoxygenation (OGD/R) method were used to simulate cerebral I/R injury in Sprague-Dawley (SD) rats and HT22 cells, respectively. The neurological score, 2,3,5-Triphe-nyltetrazolium chloride (TTC) staining, and transmission electron microscope were used to detect cerebral damage in SD rats. Cell viability and cytotoxicity assay were tested in vitro. Fluorescent staining and flow cytometry were applied to detect the level of apoptosis. Western blotting was conducted to examine the expression of proteins associated with autophagy. Results: This study found that Astragaloside IV could decrease the neurological score, reduce the infarct volume in the brain, and alleviate cerebral I/R injury in MCAO rats. Astragaloside IV promoted cell viability and balanced Bcl-2 and Bax expression in vitro, reduced the rate of apoptosis, decreased the expression of P62, and increased the expression of LC3II/LC3I in HT22 cells after OGD/R. Conclusions: These data suggested that Astragaloside IV plays a neuroprotective role by down-regulating apoptosis by promoting the degree of autophagy.
Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Saponinas/uso terapéutico , Triterpenos/uso terapéutico , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Masculino , Ratones , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Sprague-Dawley , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND: The aim of this study was to assess the value of serum procalcitonin (PCT) levels as a diagnostic marker for septic arthritis (SA) via meta-analysis. METHODS: We searched PubMed, Embase and the Cochrane Library, as well as the reference lists of relevant articles, for studies published up to May 21, 2015 and did not impose language restrictions. We selected original studies reporting the usefulness of PCT or C-reactive protein (CRP) as a diagnostic marker for SA. We summarized test performance characteristics with the use of forest plots, hierarchical summary receiver operating characteristic curves, and bivariate random effects models. Prespecified subgroup analyses and meta-regression analyses were also performed. RESULTS: This meta-analysis comprised 10 studies including 838 patients. The overall sensitivity of serum PCT levels for the diagnosis of SA in these studies was 0.54 (95% CI, 0.41-0.66), and the specificity of PCT was 0.95 (95% CI, 0.87-0.98). The positive likelihood ratio (LR) was 10.97 (95% CI, 4.65-25.89); the negative LR was 0.49 (95% CI, 0.38-0.62); and the area under ROC curve (AUROC) was 0.82 (95% CI, 0.78-0.85). Six studies also examined the usefulness of CRP levels as a marker for the diagnosis of SA. The sensitivity and specificity of CRP were 0.45 (95% CI, 0.35-0.55) and 0.079 (95% CI, 0.0.021-0.25), respectively, and the positive LR, negative LR and AUROC curve were 0.48 (95% CI, 0.39-0.61), 6.79 (95% CI, 2.04-23.81), and 0.30 (95% CI, 0.26-0.34), respectively. CONCLUSION: PCT is more valuable than CRP for distinguishing SA from non-SA.
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Artritis Infecciosa/sangre , Calcitonina/sangre , Adulto , Área Bajo la Curva , Artritis Infecciosa/diagnóstico , Biomarcadores/sangre , Péptido Relacionado con Gen de Calcitonina , Niño , China , Humanos , Precursores de Proteínas/sangreRESUMEN
Abnormally increased levels of iron in the brain trigger cascade amplification in Alzheimer's disease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese herbs epimedium herb, milkvetch root and kudzuvine root could relieve the abnormal expression of iron metabolism-related protein in Alzheimer's disease patients. An APPswe /PS1ΔE9 double transgenic mouse model of Alzheimer's disease was used. The intragastric administration of compounds from epimedium herb, milkvetch root and kudzuvine root improved pathological alterations such as neuronal edema, increased the number of neurons, downregulated divalent metal transporter 1 expression, upregulated ferroportin 1 expression, and inhibited iron overload in the cerebral cortex of mice with Alzheimer's disease. These compounds reduced iron overload-induced impairment of the central nervous system, indicating a new strategy for developing novel drugs for the treatment of Alzheimer's disease.
RESUMEN
Alzheimer's disease (AD) is a neurodegenerative brain disorder and the most common cause of dementia. New treatments for AD are required due to its increasing prevalence in aging populations. The present study evaluated the effects of the active components of Epimedium, Astragalus and Radix Puerariae on learning and memory impairment, ß-amyloid (Aß) reduction and brain iron load in an APPswe/PS1ΔE9 transgenic mouse model of AD. Increasing evidence indicates that a disturbance of normal iron homeostasis may contribute to the pathology of AD. However, the underlying mechanisms resulting in abnormal iron load in the AD brain remain unclear. It has been hypothesized that the brain iron load is influenced by the deregulation of certain proteins associated with brain iron metabolism, including divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1). The present study investigated the effects of the active components of Epimedium, Astragalus and Radix Puerariae on the expression levels of DMT1 and FPN1. The treatment with the active components reduced cognitive deficits, inhibited Aß plaque accumulation, reversed Aß burden and reduced the brain iron load in AD model mice. A significant increase was observed in the levels of DMT1-iron-responsive element (IRE) and DMT1-nonIRE in the hippocampus of the AD mouse brain, which was reduced by treatment with the active components. In addition, the levels of FPN1 were significantly reduced in the hippocampus of the AD mouse brain compared with those of control mice, and these levels were increased following treatment with the active components. Thus, the present study indicated that the active components of Epimedium, Astragalus and Radix Puerariae may exert a neuroprotective effect against AD by reducing iron overload in the AD brain and may provide a novel approach for the development of drugs for the treatment of AD.