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BACKGROUND AND AIMS: Iron deficiency is a major public health concern. We aimed to assess the predictive capability of 4 iron metabolism biomarkers for all-cause and cardiovascular disease-specific mortality in U.S. patients with congestive heart failure (CHF). METHODS AND RESULTS: 1904 CHF patients aged ≥20 years were enrolled from NHANES, 1999-2000 to 2017-2018. All analyses were weighted to provide nationally representative estimates. Among 1905 CHF patients, mean age was 71 years, and 1024 (53.8%), 459 (24.1%), 206 (10.8%), and 216 (11.3%) were Non-Hispanic Black, Non-Hispanic White, Hispanic-Mexican American, and Hispanic-Other Hispanic, respectively. During follow-ups, 1080 deaths occurred. Median follow-up time was 5.08 years. Per-unit increase in natural-logarithmic-transformed iron and transferrin saturation decreased all-cause mortality risk separately by 33.0% (adjusted hazard ratio: 0.670, 95% confidence interval: 0.563 to 0.797, P < 0.001) and 32.6% (0.674, 0.495 to 0.917, 0.013), and per-unit increase in transferrin receptor increased mortality risk by 33.7% (1.337, 1.104 to 1.618, 0.004). Two derivates from 3 significant iron biomarkers were generated - transferrin receptor to natural-logarithmic-transformed iron ratio (TRI) and transferrin receptor to natural-logarithmic-transformed transferrin saturation ratio (TRTS), which were significantly associated with all-cause mortality, with per-unit increase corresponding to 2.692- and 1.655-fold increased all-cause mortality risk (P: 0.003 and 0.023). Only iron and TRTS were associated with the significant risk of cardiovascular disease-specific mortality (P: 0.004 and 0.017). CONCLUSIONS: Our findings identified 3 iron metabolism biomarkers that were individually, significantly, and independently associated with all-cause mortality in patients with CHF, and importantly 2 derivates generated exhibited stronger predictive capability.
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Context: Diabetic cardiomyopathy (DCM) is particularly dangerous in diabetes mellitus (DM). The Shengjie Tongyu decoction (SJTYD) is a well-known, traditional Chinese medicinal formulation that practitioners use to treat myocardial diseases in China; however, its role in DCM remain unclear. Objective: The study intended to investigate: (1) SJTYD's role in the treatment of DCM and its underlying mechanisms, (2) the association of autophagy with DCM, and (3) the involvement of mammalian target of rapamycin (mTOR) signaling in the regulation of DCM. Design: The research team performed an animal study. Setting: The study took place in the Department of Endocrinology in the No. 2 ward-Traditional and Complementary Medicine(TCM) of the China-Japan Friendship Hospital in Beijing, China. Animals: The animals were 60 C57/BL6 mice weighing 200-250 g. Intervention: To determine the role of SJTYD in treating DCM, the research team established a mouse model of DM using streptozotocin (STZ). The team randomly divided the mice into three groups with 20 mice each: (1) a negative control group, which didn't receive injections of STZ or treatment with SJTYD; (2) a model group, the Model group, which received injections of STZ but didn't receive treatment with SJTYD; and (3) an SJTYD group, which received injections of STZ and treatment with SJTYD. Outcome Measures: The research team: (1) conducted a differential analysis to identify the differentially expressed genes; (2) performed deep sequencing of the long noncoding RNAs (lncRNAs) expressed in cardiomyocytes from the control, Model, and SJTYD groups ; (3) performed a bioinformatics analysis; (4) used the ultrasonic and pathological, transmission electron microscopy (TEM) test as well as a Western blot to evaluate cardiac function, myocardial-injury areas, and autophagy in vivo; (5) transfected primary cardiomyocytes treated them with lncRNA H19 and SJTY 3-MA to establish SJTYD subgroups in which the H19 protected against DCM and the 3-MA inhibited autophagy; and (6) carried out immunofluorescence staining and Western blot to test the phosphorylated levels of phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) as well as autophagy levels in vitro. Results: The bioinformatics analysis indicated that SJTYD significantly modulated lncRNA H19 as well as the mTOR pathway. The vevo2100's results indicated the SJTYD reversed the cardiac-dysfunction parameters in DCM. The Masson' staining, TEM, and Western blot demonstrated that the SJTYD could suppress the myocardial-injury areas as well as the numbers of autophagosomes and the expression proteins of autophagy in vivo. The SJTYD promoted the phosphorylated-levels of PI3K, AKT, and mTOR and decreased the levels of autophagy proteins. LC3A-II and Beclin-1; lncRNA H19 amplified the SJTYD's role; and 3-MA reversed those effects, as tested using immunofluorescence and Western blot in primary cardiomyocytes. Conclusions: The SJTYD can protect against diabetic myocardial injury by inhibiting cardiomyocyte autophagy through the activation of lncRNA H19, reactive oxygen species (ROS), and the PI3K/Akt/mTOR signaling pathway. SJTYD may be an effective strategy to ameliorate diabetic myocardial injuries.
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Diabetes Mellitus , Cardiomiopatías Diabéticas , ARN Largo no Codificante , Animales , Ratones , Fosfatidilinositol 3-Quinasas , ARN Largo no Codificante/genética , Cardiomiopatías Diabéticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt , Miocitos Cardíacos , Especies Reactivas de Oxígeno , Fosfatidilinositol 3-Quinasa , Serina-Treonina Quinasas TOR , Autofagia , MamíferosRESUMEN
Hepatocyte nuclear factor 6 (HNF6), as a transcription factor, has been reported to be involved in cell proliferation, carcinogenesis, and tumor metastasis. Here, we demonstrated the role of HNF6 in tumor growth and liver metastasis in colorectal cancer (CRC). Through bioinformatics and clinical samples analysis, we found HNF6 messenger RNA was upregulated both in CRC primary sites and liver metastases, and its high expression indicated poor survival in CRC patients. In vitro studies confirmed that HNF6 promoted cell proliferation and colony formation. What is more, in mouse models, the xenografts grew significantly faster and liver metastasis rate was nearly 45% higher in mice injected with HNF6-overexpressing cells. Further mechanism exploration showed that HNF6 expression affected cell adhesion and conferred resistance to anoikis in CRC cells. Taken together, HNF6 expression was upregulated in CRC and closely correlated with poor survival. HNF6 promoted CRC cell proliferation and tumor growth, and may contribute to liver metastasis via conferring cell resistance to anoikis.
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Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/metabolismo , Factor Nuclear 6 del Hepatocito/metabolismo , Neoplasias Hepáticas/metabolismo , Animales , Anoicis , Adhesión Celular , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 6 del Hepatocito/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal , Carga Tumoral , Regulación hacia ArribaRESUMEN
BACKGROUND: Laparoscopic surgery, fast-track perioperative treatment and XELOX chemotherapy are effective strategies for shortening the duration of hospital stay for cancer patients. This trial aimed to clarify the safety and efficacy of the fast-track multidisciplinary treatment (FTMDT) model compared to conventional surgery combined with chemotherapy in Chinese colorectal cancer patients. METHODS: This trial was a prospective randomized controlled study with a 2 × 2 balanced factorial design and was conducted at six hospitals. Patients in group 1 (FTMDT) received fast-track perioperative treatment and XELOX adjuvant chemotherapy. Patients in group 2 (conventional treatment) received conventional perioperative treatment and mFOLFOX6 adjuvant chemotherapy. Subgroups 1a and 2a had laparoscopic surgery and subgroups 1b and 2b had open surgery. The primary endpoint was total length of hospital stay during treatment. RESULTS: A total of 374 patients were randomly assigned to the four subgroups, and 342 patients were finally analyzed, including 87 patients in subgroup 1a, 85 in subgroup 1b, 86 in subgroup 2a, and 84 in subgroup 2b. The total hospital stay of group 1 was shorter than that of group 2 [13 days, (IQR, 11-17 days) vs. 23.5 days (IQR, 15-42 days), P = 0.0001]. Compared to group 2, group 1 had lower surgical costs, fewer in-hospital complications and faster recovery (all P < 0.05). Subgroup 1a showed faster surgical recovery than that of subgroup 1b (all P < 0.05). There was no difference in 5-year overall survival between groups 1 and 2 [87.1% (95% CI, 80.7-91.5%) vs. 87.1% (95% CI, 80.8-91.4%), P = 0.7420]. CONCLUSIONS: The FTMDT model, which integrates laparoscopic surgery, fast-track treatment, and XELOX chemotherapy, was the superior model for enhancing the recovery of Chinese patients with colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01080547 , registered on March 4, 2010.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/cirugía , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Laparoscopía , Anciano , Capecitabina , Quimioterapia Adyuvante , Neoplasias Colorrectales/patología , Costos y Análisis de Costo , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Humanos , Tiempo de Internación , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/uso terapéutico , Oxaloacetatos , Estudios Prospectivos , Calidad de Vida , Resultado del TratamientoRESUMEN
This study aims to explore the specific mechanism by which miR-155 regulates SHP2 expression in mouse ischemia-reperfusion (I/R) induced necroptosis. Various methods including cardiac ultrasound, TTC staining, Masson staining, TUNEL staining, and Western blotting were used to examine changes in the morphology and function of the rat left ventricle, myocardial fibrosis, as well as the expression of proteins related to tissue and cardiomyocyte necroptosis pathways. In vivo results showed that knockdown (KD) of miR-155 significantly improved cardiac ultrasound parameters (EF, FS, LVAW;d, and LVAW;s), reduced the myocardial infarction area, myocardial fibrosis, and cell apoptosis in I/R mice, upregulated cardiac SHP2 protein expression, and other proteins including p-ERK1/2, NLRP3, GSDMD, caspase-3, caspase-4, and caspase-11 were also significantly decreased. In vitro experiments showed that compared with the SHP2 WT miR-155 KD group, SHP2 protein expression was significantly increased in the SHP2 WT miR-155 KD group, while the expression of other proteins was significantly reduced, consistent with in vivo results. MiR-155 can regulate ERK1/2 and NLRP3 through SHP2. After adding the ERK1/2 inhibitor U0126 to cardiomyocytes from SHP2 KO mice, it was found that the expression of proteins other than SHP2 significantly decreased compared to SHP2 KO cells without the inhibitor. In summary, low expression of miR-155 promoted the expression of SHP2 and improved mouse I/R-induced necroptosis by inhibiting the activation of the ERK1/2 pathway.
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MicroARNs , Infarto del Miocardio , Animales , Ratones , Ratas , Fibrosis , Sistema de Señalización de MAP Quinasas , MicroARNs/metabolismo , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis , Reperfusión , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismoRESUMEN
OBJECTIVE: The study attempted to explore how allicin reduces oxidative stress levels by promoting SHP2 expression to inhibit p-PERK in I/R mice. METHODS: The GEO database and RNA sequencing were used to predict downstream gene. TTC staining was used to visualize the myocardial infarction area. Masson staining was used to assess the level of fibrosis. IF was used to examine the expression of SHP2, CTGF, ROS. RT-PCR analysis was used to quantify the expression of SHP2 mRNA. Western blot was used to detect the protein expression levels of SHP2, p-PERK, MFN1, NLRP3, NOX2, and NOX3. RESULTS: GEO and transcriptomic data revealed low expression of SHP2 in the heart tissues I/R mice. In the I/R mouse model, TTC staining result showed that allicin can reduce the area of myocardial infarction; Masson staining results indicated that allicin can reduce fibrosis; Macrophage transcriptome sequencing found SHP2 is a target gene of allicin; Immunofluorescence showed allicin can increase SHP2; qPCR results showed allicin can raise SHP2 mRNA level; Immunofluorescence indicated that allicin can inhibit ROS in myocardial infarction tissue, but the specific SHP2-KD eliminates changes in ROS. Western blot analysis demonstrated allicin can increase SHP2 protein and reduce the expression of p-PERK, MFN1, NLRP3, NOX2, and NOX3; SHP2-KD eliminates the expression differences in p-PERK, MFN1, NLRP3, NOX2, and NOX3. CONCLUSIONS: Allicin can modulate p-PERK activation by enhancing the expression of SHP2, thereby inhibiting myocardial ischemia-reperfusion-induced oxidative stress in mice.
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Disulfuros , Infarto del Miocardio , Proteína con Dominio Pirina 3 de la Familia NLR , Ácidos Sulfínicos , Ratones , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo , Infarto del Miocardio/tratamiento farmacológico , Fibrosis , ARN Mensajero/metabolismoRESUMEN
Introduction: To better understand the role of immune escape and cancer-associated fibroblasts (CAFs) in colon adenocarcinoma (COAD), an integrative analysis of the tumor microenvironment was performed using a set of 12 immune- and CAF-related genes (ICRGs). Methods: Univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to establish a prognostic signature based on the expression of these 12 genes (S1PR5, AEN, IL20RB, FGF9, OSBPL1A, HSF4, PCAT6, FABP4, KIF15, ZNF792, CD1B and GLP2R). This signature was validated in both internal and external cohorts and was found to have a higher C-index than previous COAD signatures, confirming its robustness and reliability. To make use of this signature in clinical settings, a nomogram incorporating ICRG signatures and key clinical parameters, such as age and T stage, was developed. Finally, the role of S1PR5 in the immune response of COAD was validated through in vitro cytotoxicity experiments. Results: The developed nomogram exhibited slightly improved predictive accuracy compared to the ICRG signature alone, as indicated by the areas under the receiver operating characteristic curves (AUC, nomogram:0.838; ICRGs:0.807). The study also evaluated the relationships between risk scores (RS) based on the expression of the ICRGs and other key immunotherapy variables, including immune checkpoint expression, immunophenoscore (IPS), and microsatellite instability (MSI). Integration of these variables led to more precise prediction of treatment efficacy, enabling personalized immunotherapy for COAD patients. Knocking down S1PR5 can enhance the efficacy of PD-1 monoclonal antibody, promoting the cytotoxicity of T cells against HCT116 cells ((p<0.05). Discussion: These findings indicate that the ICRG signature may be a valuable tool for predicting prognostic risk, evaluating the efficacy of immunotherapy, and tailoring personalized treatment options for patients with COAD.
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Adenocarcinoma , Fibroblastos Asociados al Cáncer , Neoplasias del Colon , Humanos , Pronóstico , Adenocarcinoma/genética , Reproducibilidad de los Resultados , Neoplasias del Colon/genética , Microambiente Tumoral , CinesinasRESUMEN
Immune checkpoint inhibitors (ICIs) offer new options for the treatment of patients with solid cancers worldwide. The majority of colorectal cancers (CRC) are proficient in mismatch-repair (pMMR) genes, harboring fewer tumor antigens and are insensitive to ICIs. These tumors are often found to be immune-deserted. We hypothesized that forcing immune cell infiltration into the tumor microenvironment followed by immune ignition by PD1 blockade may initiate a positive immune cycle that can boost antitumor immunity. Bioinformatics using a public database suggested that IFNγ was a key indicator of immune status and prognosis in CRC. Intratumoral administration of IFNγ increased immune cells infiltration into the tumor, but induced PD-L1 expression. A combined treatment strategy using IFNγ and anti-PD-1 antibody significantly increased T cell killing of tumor cells in vitro and showed synergistic inhibition of tumor growth in a mouse model of CRC. CyTOF found drastic changes in the immune microenvironment upon combined immunotherapy. Treatment with IFNγ and anti-PD1 antibody in CT26 tumors significantly increased infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). IFNγ had a more pronounced effect in decreasing intratumoral M2-like macrophages, while PD1 blockade increased the population of CD8+Ly6C + T cells in the tumor microenvironment, creating a more pro-inflammatory microenvironment. Additionally, PD1 induced increased expression of lymphocyte activating 3 (LAG3) in a significant fraction of CD8+ T cells and Treg cells, indicating potential drug resistance and feedback mechanisms. In conclusion, our work provides preclinical data for the Combined immunotherapy of CRC using intratumoral delivery of IFNγ and systemic anti-PD1 monoclonoal antibody.
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Linfocitos T CD8-positivos , Neoplasias Colorrectales , Animales , Ratones , Humanos , Interferón gamma/metabolismo , Inyecciones Intralesiones , Inmunoterapia , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Microambiente Tumoral , Línea Celular TumoralRESUMEN
In order to explore the computerized tomography (CT) based on three-dimensional reconstruction of coronary artery model, the functional evaluation was made after percutaneous coronary intervention (PCI). In this study, 90 patients with coronary heart disease who received elective PCI were selected. The blood flow reserve fraction (FFR) and SYNTAX score were calculated by three-dimensional reconstruction of CT images, followed up for 2-4 years. According to the SYNTAX score, 0-22 points were defined as the low group (28 cases), 23-32 points as the medium group (33 cases), and 33 points as the high group (29 cases). In this paper, the accuracy, sensitivity, and specificity of CT images of three-dimensional reconstructed coronary artery model are 91%, 73%, and 62%, respectively. The follow-up results showed that the incidence of major adverse cerebrovascular events in the high group was significantly higher than that in the low group and the middle group, and the difference was statistically significant (P < 0.05). Pearson correlation analysis showed that SYNTAX score was related to serum total cholesterol (r = 0.234, P=0.003), triglyceride (r = 0.237, P=0.014), low-density lipoprotein cholesterol (r = 0.285, P=0.004), and ApoB/ApoA1 (R = 0.004). In this study, FFR is calculated by CT images based on three-dimensional reconstruction of coronary artery model, which can provide support for the diagnosis and treatment of coronary heart disease. SYNTAX score can be used as a risk predictor for PCI patients with coronary heart disease.
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Enfermedad de la Arteria Coronaria , Intervención Coronaria Percutánea , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/cirugía , Intervención Coronaria Percutánea/efectos adversos , Resultado del Tratamiento , Tomografía Computarizada por Rayos X , ColesterolRESUMEN
INTRODUCTION: Many causes lead to sympathetic-vagus imbalance, which promotes the development of hypertension and accelerates the process of target organ damage. Many studies have shown that exercise training and heart rate variability (HRV) biofeedback can improve diseases caused by autonomic nerve dysfunction, such as hypertension. Based on these theories and the Yin-Yang balance theory of traditional Chinese medicine and Cannon's homeostasis theory, we have developed an assessment system of autonomic nerve regulation system and a harmony instrument. In this study, we aimed to find a new way to control blood pressure of hypertensive patients via cardiopulmonary resonance indices-based respiratory feedback training. METHODS AND ANALYSIS: This is a prospective, randomised, parallel-controlled clinical trial, which aims to evaluate the effectiveness and safety of biofeedback therapy and exercise rehabilitation combined intervention in hypertension management. 176 healthy individuals will be recruited to get their autonomic nerve function parameters as normal control, while 352 hypertensive patients will be enrolled and randomly divided into a conventional treatment group and an experiment group in a ratio of 1:1. All patients will continue to receive standard hypertension blood pressure treatment, except that patients in the experiment group will have to complete additional daily respiratory training for 6 months. The primary outcome is the difference of clinical systolic blood pressure (SBP) between the two groups after 6 months of intervention. The secondary outcomes include the changes in the mean SBP and diastolic blood pressure (DBP) by 24-hour blood pressure monitoring, home SBP, clinical and home DBP, clinical and home heart rate, the standard-reaching rate of clinic and home SBP and the incidence of composite endpoint events at 6 months. ETHICS AND DISSEMINATION: This study has been approved by the clinical research ethics committee of China-Japan Friendship Hospital (No. 2018-132 K98-2), the results of this study will be disseminated via peer-reviewed publications or conference presentations. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry, ChiCTR1800019457, registered on 12 August 2018.
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Hipertensión , Humanos , Estudios Prospectivos , Hipertensión/tratamiento farmacológico , Presión Sanguínea , Sistema Nervioso Autónomo , Corazón , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies. The mutation, isoform (KRAS, HRAS, and NRAS), position, and type of substitution vary depending on the tissue types. Despite decades of developing RAS-targeted therapies, only small subsets of these inhibitors are clinically effective, such as the allele-specific inhibitors against KRASG12C . Targeting the remaining RAS mutants would require further experimental elucidation of RAS signal transduction, RAS-altered metabolism, and the associated immune microenvironment. This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants, including KRAS allele-specific inhibitors, combination therapies, immunotherapies, and metabolism-associated therapies.
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Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Mutación , Transducción de Señal/genética , Microambiente TumoralRESUMEN
Rigosertib (RGS) is a benzyl styryl sulfone which exhibits impressive cytotoxicity in cancer cells. However, its modulating effect on tumor immune microenvironment remains elusive. In our experiments, compared with immunodeficient mouse model, increased tumor growth arrest and robust anti-tumor immunity were observed in RGS-treated colorectal cancer (CRC) isograft tumors in immunocompetent mice. Intriguingly, RGS markedly down-regulated programmed cell death ligand 1 (PD-L1) expression in both vivo and in vitro. Meanwhile, RGS increased autophagic vacuole number in CRC cells as seen by transmission electron microscopy and immunofluorescence. Moreover, increased LC3-II level and tandem-mRFP- GFP- LC3 labeled vacuole accumulation demonstrated RGS-induced autophagic flux. Mechanistically, it is the activation of AMP-activated protein kinase-UNC-51-like kinase 1 (AMPK-ULK1) axis, rather than the canonical mTOR signaling pathway, that plays a pivotal role in RGS-induced autophagy. AMPK-ULK1 dependent autophagy inhibition, by either short interfering RNA or chemical inhibitors, blocked RGS-induced PD-L1 degradation. Finally, RGS exhibited synergistic anti-tumor activity with cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody in the CRC isograft model. Furthermore, apart from the immunomodulatory effect, we also confirmed the direct cytotoxicity of RGS in inducing mitochondria-related apoptosis. Altogether, considering its PD-L1 inhibitory and cytotoxic effects, RGS could be a promising drug for CRC therapy.
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Proteínas Quinasas Activadas por AMP , Neoplasias Colorrectales , Animales , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia/efectos de los fármacos , Antígeno B7-H1/efectos de los fármacos , Antígeno B7-H1/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Sulfonas/farmacología , Microambiente TumoralRESUMEN
This study aims to investigate the regulatory effect of Xuesaitong (XST) and miR-3158-3p on angiogenesis. All mice were randomly assigned into Sham group, Model group, XST group, XST + miR-3158-3P-overexpression (miRNA-OE) group. XST was found to increase the left ventricular anterior wall thickness at end diastole and end systole (LVAWd and LVAWs), left ventricular internal dimension at end diastole and end systole (LVIDd and LVIDs), fractional shortening (FS), and ejection fraction (EF) and decrease the proportion of fibrotic areas in mice. In contrast to those in Sham group, the protein expressions of Nur77, p-PI3K, HIF-1α, VEGFs, COX-2 in the heart tissues of mice in Model group were elevated and further increased after XST treatment in comparison with those in Model group. Nur77-/- mice were utilized. It was found that XST enhanced cell viability through a methyl thiazolyl tetrazolium assay and facilitated angiogenesis in each group, as assessed by a catheter formation assay. Specifically, XST was shown to promote the formation of blood vessels. Moreover, the protein expression levels of Associated proteins in the heart tissues of Nur77-/- mice were dramatically reduced in mice in Model and XST group compared with those in WT mice. Additionally, the above-mentioned protein expressions in the heart tissues of Nur77-/- mice did not change significantly in mice in Model + miRNA-OE + XST group compared with those in WT mice, suggesting that miR-3158-3p can specifically inhibit the expression of Nur77. In conclusion, XST inhibits miR-3158-3p targeting Nur77 to facilitate myocardial angiogenesis in mice with myocardial infarction.
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Medicamentos Herbarios Chinos , MicroARNs , Infarto del Miocardio , Ratones , Animales , Miocardio/metabolismo , Infarto del Miocardio/metabolismo , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
This study was to analyze the diagnostic value of coronary computed tomography angiography (CCTA) and fractional flow reserve (FFR) based on computer-aided diagnosis (CAD) system for coronary lesions and the possible impact of calcification. 80 patients who underwent CCTA and FFR examination in hospital were selected as the subjects. The FFR value of 0.8 was used as the dividing line and divided into the ischemic group (FFR ≤ 0.8) and nonischemic group (FFR > 0.8). The basic data and imaging characteristics of patients were analyzed. The maximum diameter stenosis rate (MDS %), maximum area stenosis rate (MAS %), and napkin ring sign (NRS) in the ischemic group were significantly lower than those in the nonischemic group (P < 0.05). Remodeling index (RI) and eccentric index (EI) compared with the nonischemic group had no significant difference (P > 0.05). The total plaque volume (TPV), total plaque burden (TPB), calcified plaque volume (CPV), lipid plaque volume (LPV), and lipid plaque burden (LPB) in the ischemic group were significantly different from those in the non-ischemic group (P < 0.05). MAS % had the largest area under curve (AUC) for the diagnosis of coronary myocardial ischemia (0.74), followed by MDS % (0.69) and LPV (0.68). CT-FFR had high diagnostic sensitivity, specificity, accuracy, truncation value, and AUC area data for patients in the ischemic group and nonischemic group. The diagnostic sensitivity, specificity, accuracy, cutoff value, and AUC area data of CT-FFR were higher in the ischemic group (89.93%, 92.07%, 95.84%, 60.51%, 0.932) and nonischemic group (93.75%, 90.88%, 96.24%, 58.22%, 0.944), but there were no significant differences between the two groups (P > 0.05). In summary, CT-FFR based on CAD system has high accuracy in evaluating myocardial ischemia caused by coronary artery stenosis, and within a certain range of calcification scores, calcification does not affect the diagnostic accuracy of CT-FFR.
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Calcinosis/diagnóstico por imagen , Angiografía por Tomografía Computarizada/estadística & datos numéricos , Angiografía Coronaria/estadística & datos numéricos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Reserva del Flujo Fraccional Miocárdico/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Biología Computacional , Enfermedad de la Arteria Coronaria/fisiopatología , Estenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/fisiopatología , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/fisiopatología , Diagnóstico por Computador/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/fisiopatología , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/fisiopatologíaRESUMEN
Introduction: Contrast-induced encephalopathy (CIE) is a complication associated with the administration of iodinated contrast, which usually happens minutes to hours after contact with contrast, and fully recovers within 72 h. The clinical manifestations of CIE are diverse, and the pathological mechanism is not explicit. Methods: We report the case of a 66-year-old female who suffered from a delayed CIE following the administration of iodinated contrast agent. Symptoms were severe. Imaging examination, biochemical and etiological detection were performed timely. The course of neurological symptoms was atypical. Her complex complications of hypothyroidism and cerebrovascular abnormalities contributed to more challenges, which were also clues to the diagnosis. With prompt and active treatment, the patient recovered fully over 10 days. Discussion: The diagnosis standard of CIE highly depends on the association with the contact of contrast and the exclusion of other nervous system diseases. Complicated clinical circumstances and individual specificity can lead to different clinical manifestations of CIE, making it even more difficult to diagnose and treat. Prompt and dynamic imaging examination would provide great value in the diagnosis and evaluation of CIE. Timely diagnosis and intervention may be the key to its satisfying prognosis.
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OBJECTIVE: Extensive studies have shown that ERS may be implicated in the pathogenesis of DCM. We explored the therapeutic effects of lncRNAH19 on DCM and its effect on ERS-associated cardiomyocyte apoptosis. METHODS: C57/BL-6j mice were randomly divided into 3 groups: non-DM group (controls), DM group (DCM), and lncRNAH19 overexpression group (DCM+H19 group). The effect of H19 on cardiac function was detected. The effect of H19 on cardiomyocyte apoptosis and cardiac fibrosis in DM was examined. Differentially expressed genes (DEGs) and activated pathways were examined by bioinformatics analysis. STRING database was applied to construct a PPI network using Cytoscape software. The expression of p-PERK, p-IRE1, ATF6, CHOP, cleaved caspase-3, -9, -12 and BAX proteins in cardiac tissue was used to determine the ERS-associated apoptotic indicators. We established the HG-stimulated inflammatory cell model. The expression of p-PERK and CHOP in HL-1 cells following HG was determined by immunofluorescence labeling. The effects of H19 on ERS and PI3K/AKT/mTOR pathway were also detected. RESULTS: H19 improved left ventricular dysfunction in DM. H19 could reduce cardiomyocytes apoptosis and improve fibrosis in vivo. H19 could reduce the expression of p-PERK, p-IRE1α, ATF6, CHOP, cleaved caspase-3, cleaved caspase-9, cleaved caspase-12, and BAX proteins in cardiac tissues. Furthermore, H19 repressed oxidative stress, ERS and apoptosis in vitro. Moreover, the effect of H19 on ERS-associated apoptosis might be rescued by LY294002 (the specific inhibitor for PI3K and AKT). CONCLUSION: H19 attenuates DCM in DM and ROS, ERS-induced cardiomyocyte apoptosis, which is associated with the activation of PI3K/AKT/mTOR signaling pathway.
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Diabetes Mellitus , Cardiomiopatías Diabéticas , ARN Largo no Codificante , Animales , Apoptosis , Caspasa 3 , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/metabolismo , Endorribonucleasas , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/farmacología , Serina-Treonina Quinasas TOR , Proteína X Asociada a bcl-2RESUMEN
A simple, cost-effective and lithography-free fabrication of graphene strips for device applications is demonstrated. The graphene thin layers were directly grown on Cu wires, followed by Cu etching and transfer printing to arbitrary substrates by a PDMS stamp. The Cu wires can be arranged on the PDMS stamp in a desired pattern; hence, the substrates can receive graphene strips with the same pattern. Moreover, the preparation of graphene strips does not involve conventional lithography; therefore, the surface of the graphene strip is free of residual photoresists, which may be useful for studies requiring clean graphene surfaces.
RESUMEN
Cardiomyocyte apoptosis is a fundamental pathogenic factor leading to myocardial ischemia/reperfusion (MI/R) injury. The long non-coding RNA (IncRNA) TUG1 regulates apoptosis in various cell types. We report here that TUG1 expression is induced in mouse heart following MI/R injury as well as in cardiomyocytes subjected to simulated ischemia/reperfusion (SI/R) in vitro. Clinically, TUG1 expression is also elevated in plasma from patients with acute myocardial infarction (AMI), which implies its potential application as a disease biomarker. Functionally, TUG1 overexpression promotes, and its knockdown reduces SI/R-induced lactate dehydrogenase (LDH) release and caspase-3 activity in cardiomyocytes in vitro, illustrating that TUG1 exacerbates SI/R-induced apoptosis. Furthermore, in vivo, TUG1 aggravates MI/R injury in a mouse model, and subsequent observations show concurrent increased apoptosis of cardiomyocytes. Hence, this study unveils a clinical relevance and functional role of TUG1 in MI/R injury, and also implicates that targeting TUG1 may have therapeutic effects in treating MI/R injury.
Asunto(s)
Apoptosis/fisiología , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/sangre , Infarto del Miocardio/genética , ARN Largo no Codificante/genéticaRESUMEN
BACKGROUND: The prognosis of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) between patients with diabetes mellitus (DM) and those without DM is unknown. This study aimed to investigate whether DM has adverse effects on CTO PCI patients. METHODS: This single-center retrospective study included consecutive patients who underwent PCI for CTO at the China-Japan Friendship Hospital (Beijing, China) between January 2016 and April 2019. The clinical outcomes during follow-up were compared between patients with DM and those without DM. RESULTS: The analysis included 187 patients (152 males) aged 62.6±11.5 years. A total of 99 participants (52.9%) had DM, which involved a higher body mass index (BMI) and triglyceride level than those without DM (P<0.05). Participants with DM and those without DM had similar PCI success rates (89.9% vs. 95.4%, respectively) and complete revascularization rates (82.8% vs. 84.1%, respectively). There were no significant differences between groups in the rates of all-cause mortality, cardiac death, major adverse cardiovascular events (MACEs), readmission, recurrence of angina, target vessel revascularization (TVR), or myocardial infarction (MI) during a median follow-up of 20.5 months. Multivariable logistic regression revealed that CTO in a coronary branch vessel was associated with higher odds of all-cause death (odds ratio (OR): 53.56; 95% confidence interval (CI): 2.48 to 1,155.41; P<0.05) and failure of PCI for CTO (OR: 5.40; 95% CI: 1.263 to 23.098; P<0.05). Additionally, PCI for single CTO was associated with lower odds of MACEs (OR: 0.300; 95% CI: 0.118 to 0.765; P<0.05). CONCLUSIONS: The performance of PCI for CTO has a high success rate in both patients with DM and those without DM, and clinical outcomes are comparable between groups.
Asunto(s)
Oclusión Coronaria , Diabetes Mellitus , Intervención Coronaria Percutánea , Enfermedad Crónica , Angiografía Coronaria , Oclusión Coronaria/cirugía , Humanos , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVES: Allicin is an allyl 2-propenethiosulfinate or diallyl thiosulfinate acid with cardioprotective effects in myocardial ischemia/reperfusion (MI/R) injury. This study aims to examine the underlying mechanism by which Allicin protects against MI/R. METHODS: C57BL6 mice were subjected to either sham or MI/R surgery, and mice in the Allicin group were injected with Allicin (5 mg/ml) before the induction of ischemia. The cardiac function and histopathology of experimental mice were evaluated by ultrasound quantification and Masson staining. We next measured the capillary angiogenesis of the peri-infarct area by Masson staining and immunohistochemical staining. The miRNA microarray was carried out to examine the expressed miRNAs in MI/R tissues and corresponding normal tissues. Real-time quantitative polymerase chain reaction (q-PCR) was performed to validate the selected miRNA-19α-3p gene expression. Besides, we evaluated the myocardial lactate dehydrogenase and COX-2 by immunofluorescence staining. The western blot analysis was used to evaluate the protein levels of p-AKT, p-PI3K, p-mTOR, COX-2, and VEGF protein in the Allicin and Model group. In vitro study, LPS stimulated Tie2 expressing macrophages were cultured in an ischemic buffer. We evaluated the accumulation of VEGF by fura-2/AM fluorescence. Besides, Western blotting was performed to examine the protein levels of p-PI3K, p-AKT, p-mTOR, VEGF, COX2, and MMP2. The PI3K inhibitor was applied to investigate whether Allicin-induced myocardial ischemia-reperfusion injury protection is mediated via the PI3K/AKT pathway. And the miR-19α-3p mimic/inhibitor were transfected to promote/inhibit the expression of miR-19a-3p for verifying the regulation of miR-19a-3p on PI3K pathway. RESULTS: Allicin pretreatment significantly improved I/R-induced cardiac function damage. Furthermore, Allicin could repress cardiac fibrosis, as evidenced by reduced areas of cardiac fibrosis. Allicin's effect on the MI/R was associated with increased capillary angiogenesis. Microarray analysis exposed that miR-19a-3p down-regulated PIK3CA (PI3K) expression by directly targeting the PIK3CA gene. The regulation of the angiogenesis pathway and gene miRNA-19a-3p might affect the Allicin-induced MI/R protection. Immunofluorescence staining revealed that COX-2 and myocardial lactate dehydrogenase were significantly increased after Allicin treatment. Furthermore, western blot analysis demonstrated that p-AKT, p-PI3K, p-mTOR, COX-2, and VEGF protein levels were also increased in the Allicin group. In vitro study, the protein levels of p-PI3K, p-AKT, p-mTOR, VEGF, COX2, and MMP2 were significantly increased in the Allicin-treated Tie2 expressing macrophages. These effects were partially reversed by PI3K inhibitor (Wortmannin) treatment. MiR-19α-3p plays an important role in myocardial I/R injury. It could regulate the activity of the PI3K-AKT pathway. And inhibition of miR-19a-3p promoted angiogenesis by regulating PI3K/AKT pathway. CONCLUSIONS: Allicin pretreatment protects against myocardial I/R and activating the miR-19a-3p/PI3K/AKT pathway.