Increased production of reactive oxygen species (ROS) significantly contributed to the pathogenesis of acute myocardial infarction (AMI). Recent studies suggest that hypoxia upregulated the long ...noncoding RNA taurine upregulated gene 1 (TUG1). In this study, we explored the functional significance and molecular mechanisms of TUG1/miR-132-3p axis in ischemia-challenged cardiomyocytes. In primary cardiomyocytes challenged with H
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, expressions of miR-132-3p, TUG1, and other target proteins were measured by RT quantitative PCR or Western blot analysis; cell viability by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay; apoptosis by annexin V and propidium iodide staining; the abundance of acetylated H3K9 or histone deacetylase 3 (HDAC3) within the promoter of target genes by chromatin immunoprecipitation; the direct interaction between miR-132-3p and HDAC3 or TUG1 by luciferase reporter assay. The biological significance of miR-132-3p, TUG1, and HDAC3 was assessed using miR-132-3p mimic, siRNA-targeting TUG1 and HDAC3 inhibitor RGF966, respectively, in H
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-challenged cells in vitro or ischemia-reperfusion (I/R)-induced AMI in vivo. miR-132-3p was downregulated, whereas TUG1 upregulated in H
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-challenged cardiomyocytes. Overexpressing miR-132-3p or knocking down TUG1 significantly improved viability, inhibited apoptosis, and reduced ROS production in H
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-stressed cardiomyocytes in vitro and alleviated I/R-induced AMI in vivo. Mechanistically, TUG1 sponged miR-132-3p and upregulated HDAC3, which reduced the acetylation of H3K9 and epigenetically inhibited expressions of antioxidative genes, including Bcl-xL, Prdx2, and Hsp70. The TUG1/miR-132-3p/HDAC3 axis critically regulates ROS production and the pathogenic development of AMI. Targeting TUG1, upregulating miR-132-3p, or inhibiting HDAC3 may benefit AMI treatment.
Increased production of reactive oxygen species (ROS) significantly contributed to the pathogenesis of acute myocardial infarction (AMI). Recent studies suggest that hypoxia upregulated the long noncoding RNA taurine upregulated gene 1 (TUG1). However, the underlying mechanisms remain elusive. In the present study, we reported for the first time that H
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or ischemia-reperfusion-induced TUG1, by sponging microRNA 132-3p, activated histone deacetylase 3, which in turn targeted multiple protective genes, stimulated intracellular ROS accumulation, and aggravated the injury of AMI. Our findings might provide some insight to seek new targets for AMI treatment.
Myocardial ischemia/reperfusion injury (MIRI) causes severe damage in cardiac tissue, thereby resulting in a high rate of mortality. 6-Gingerol (6-G) is reported to play an essential role in ...alleviating MIRI. However, the underlying mechanism remains obscure. This study was intended to explore the potential mechanism by which 6-G functions. Q-PCR was employed to quantify the relative RNA levels of long noncoding RNA (lncRNA) H19 (H19), miR-143, and ATG7, an enzyme essential for autophagy, in HL-1 cells. Western blotting, immunofluorescence, and immunohistochemistry were employed for protein evaluation in cultured cells or mouse tissues. Cell viability, cytotoxicity, and apoptosis were analysed by CCK-8, LDH, and flow cytometry assays, respectively. The binding sites for miR-143 were predicted using starBase software and experimentally validated through a dual-luciferase reporter system. Here, we found that 6-G elevated cellular H19 expression in hypoxia/reoxygenation (H/R)-treated HL-1 cells. Moreover, 6-G increased Bcl-2 expression but reduced cleaved caspase 3 and caspase 9 protein levels. Mechanistically, H19 directly interacted with miR-143 and lowered its cellular abundance by acting as a molecular sponge. Importantly, ATG7 was validated as a regulated gene of miR-143, and the depletion of miR-143 by H19 caused an increased in ATG7 expression, which in turn promoted the autophagy process. Last, mouse experiments highly supported our in vitro findings that 6-G relieves MIRI by enhancing autophagy. The H19/miR-143/ATG7 axis was shown to be critical for the function of 6-G in relieving MIRI.
Long non-coding RNAs (lncRNAs) play a central role in regulating heart diseases. In the present study, we examined the effects of lncRNA taurine up-regulated gene 1 (TUG1) in ischemia/reperfusion ...(I/R)- or hydrogen peroxide-challenged cardiomyocytes, with specific focus on autophagy-induced cell apoptosis.
The expressions of miR-142-3p and TUG1 in H2O2-challenged cardiomyocytes and I/R-injured heart tissue were measured by RT-qPCR. Cell death was measured by trypan blue staining assay. Cell apoptosis was determined by Annexin V/PI staining and TUNEL assay. Autophagy was examined by quantifying cells or tissues containing LC3+ autophagic vacuoles by immunofluorescence, or by measuring the expressions of autophagy-related biomarkers by Western blot. The direct interaction between miR-142-3p and TUG1, high mobility group box 1 protein (HMGB1), or Ras-related C3 botulinum toxin substrate 1 (Rac1) was examined using luciferase reporter assay. The significance of miR-142-3p and TUG1 on cell apoptosis or autophagy was examined using both gain-of-function and loss-of-function approaches. The importance of HMGB1 or Rac1 was assessed using siRNA-mediated gene silencing.
miR-142-3p was down-regulated, while TUG1 up-regulated in H2O2-challenged cardiomyocytes in vitro and I/R-injured heart tissues in vivo. Functionally, inhibition of TUG1 and overexpression of miR-142-3p inhibited cell apoptosis and autophagy in cardiomyocytes. The function of TUG1 were achieved by sponging miR-142-3p and releasing the suppression of the putative targets of miR-142-3p, HMGB1 and Rac1. Both HMGB1 and Rac1 essentially mediated cell apoptosis and autophagy induced by TUG1.
TUG1, by targeting miR-142-3p and up-regulating HMGB1 and Rac1, plays a central role in stimulating autophagic cell apoptosis in ischemia/hypoxia-challenged cardiomyocytes. Down-regulating TUG1 or up-regulating miR-142-3p may ameliorate myocardial injury and protect against acute myocardial infarction.
A simple wet chemical process followed by high temperature calcination has been successfully used to coat Li-ion conductive Li4Ti5O12 on the surface of Ni-rich LiNi0.8Co0.1Mn0.1O2. Physicochemical ...characterization results indicate that a Li4Ti5O12 with a thickness of about 2–3 nm was uniformly distributed on the surface of microspheres, without inducing significant change of the structure and morphology. Electrochemical test results show that proper content of Li4Ti5O12 coating layer can greatly improve the cycling performance and rate capability of Ni-rich LiNi0.8Co0.1Mn0.1O2 for the improved Li+ ions diffusion rate and suppressed side reactions between electrode and electrolyte. Notably, the 1 wt% Li4Ti5O12 coated sample exhibits excellent cycling stability with the capacity retention of 75.86% at 1 C after 170 cycles when cycled between 2.7 and 4.3 V at 25 °C, while that is only 39.40% for bare LiNi0.8Co0.1Mn0.1O2.
Early inflammatory responses post myocardial infarction (MI) is associated with increased myocardial fibrosis and cardiac remodelling. The NLRP3 inflammasome, a key factor in this response, regulates ...the expression of interleukins (IL)‐1β and IL‐18. Inhibiting the inflammatory process may be beneficial for post‐MI recovery. Bufalin effectively inhibits inflammation and fibrosis. The aim of this study was to evaluate the effects of bufalin and MCC950, an NLRP3 inflammasome inhibitor, as potential treatment agents for MI using an experimental mouse model. Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and subsequently treated with bufalin (0.5 mg/kg), MCC950 (10 mg/kg) or saline thrice a week for 2 weeks. After 4 weeks, cardiac function and myocardial fibrosis were evaluated. Myocardial levels of fibrotic markers and inflammatory factors were analysed using western blotting, enzyme‐linked immunosorbent assay, real‐time quantitative polymerase chain reaction and immunofluorescence. In mice with MI, cardiac ultrasonography showed decreased cardiac function and myocardial fibrosis. Bufalin treatment restored left ventricular ejection fraction and fractional shortening and decreased the myocardial infarct size. Moreover, both bufalin and MCC950 preserved cardiac function and relieved myocardial fibrosis, with no significant difference. Hence, the present study findings suggest that bufalin can alleviate fibrosis and improve cardiac function in a mouse model by suppressing NLRP3/IL‐1β signalling post‐MI.
Bufalin reduces myocardial infarction–induced myocardial fibrosis and improves cardiac function. By reducing the expression of NLRP3, Bufalin ameliorates the infiltration of immune cells. As a result, Bufalin restores the mouse cardiac function after MI.
Data on LA/LAA thrombus resolution after rivaroxaban treatment has not been established. The aim of the present study was to compare the efficacy and safety on the resolution of LA/LAA thrombus ...between rivaroxaban and warfarin in nonvalvular atrial fibrillation (AF) patients. 80 AF patients with LA/LAA thrombus between January 2013 and June 2016 were randomized divided into warfarin group (n = 40) and rivaroxaban group (n = 40). Compared to warfarin group, thrombin time (TT; p < 0.0001), plasma prothrombin time (PT; p < 0.0001), and activated partial thromboplastin time (APTT; p = 0.0019) were significantly lower, and fibrinogen (FIB; p < 0.0001) was significantly higher in rivaroxaban group. TEE shown the average length (p < 0.0001), average width (p = 0.0008) and average area (p < 0.0001) of thrombus were significantly lower in rivaroxaban group compared to warfarin group after 6-week treatments. No major or fatal bleeding and ischemic stroke occurred in both two groups. The 20 mg dose Rivaroxaban is more effective than warfarin on the resolution of LA/LAA thrombus in nonvalvular AF patients especially after 6-week treatments. The results suggest that rivaroxaban is a potential option for the treatment of LA/LAA thrombus in patients with nonvalvular AF.
In this study, we aim to investigate the regulation of specific long non-coding RNAs (lncRNAs) on the progression of ischemia/reperfusion (I/R) injury. We identified and characterized the exosomes ...derived from mouse primary aortic endothelial cells. Subsequently, we found that these exosomes expressed typical exosomal markers and high levels of LINC00174, which significantly ameliorated I/R-induced myocardial damage and suppressed the apoptosis, vacuolation, and autophagy of myocardial cells. Mechanistic approaches revealed that LINC00174 directly interacted with SRSF1 to suppress the expression of p53, thus restraining the transcription of myocardin and repressing the activation of the Akt/AMPK pathway that was crucial for autophagy initiation in I/R-induced myocardial damage. Moreover, this molecular mechanism was verified by in vivo study. In summary, exosomal LINC00174 generated from vascular endothelial cells repressed p53-mediated autophagy and apoptosis to mitigate I/R-induced myocardial damage, suggesting that targeting LINC00174 may be a novel strategy to treat I/R-induced myocardial infarction.
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In the present study, Su and colleagues show that exosomal LINC00174 derived from vascular endothelial cells attenuates myocardial ischemia-reperfusion (I/R) injury by suppressing p53-mediated autophagy and apoptosis. This discovery reveals a new regulation mechanism for I/R-induced injury and provides a potential therapeutic strategy to treat I/R-induced myocardial infarction.
In recent years, many cities in the Chinese loess plateau (especially in Shanxi province) have encountered ground subsidence problems due to the construction of underground projects and the ...exploitation of underground resources. With the completion of the world’s largest geotechnical project, called “mountain excavation and city construction,” in a collapsible loess area, the Yan’an city also appeared to have uneven ground subsidence. To obtain the spatial distribution characteristics and the time-series evolution trend of the subsidence, we selected Yan’an New District (YAND) as the specific study area and presented an improved time-series InSAR (TS-InSAR) method for experimental research. Based on 89 Sentinel-1A images collected between December 2017 to December 2020, we conducted comprehensive research and analysis on the spatial and temporal evolution of surface subsidence in YAND. The monitoring results showed that the YAND is relatively stable in general, with deformation rates mainly in the range of −10 to 10 mm/yr. However, three significant subsidence funnels existed in the fill area, with a maximum subsidence rate of 100 mm/yr. From 2017 to 2020, the subsidence funnels enlarged, and their subsidence rates accelerated. Further analysis proved that the main factors induced the severe ground subsidence in the study area, including the compressibility and collapsibility of loess, rapid urban construction, geological environment change, traffic circulation load, and dynamic change of groundwater. The experimental results indicated that the improved TS-InSAR method is adaptive to monitoring uneven subsidence of deep loess area. Moreover, related data and information would provide reference to the large-scale ground deformation monitoring and in similar loess areas.
Induction of tumor vascular normalization is a crucial measure to enhance immunotherapy efficacy. cGAS-STING pathway is vital for anti-tumor immunity, but its role in tumor vasculature is unclear. ...Herein, using preclinical liver cancer models in Cgas/Sting-deficient male mice, we report that the interdependence between tumor cGAS and host STING mediates vascular normalization and anti-tumor immune response. Mechanistically, TET2 mediated IL-2/STAT5A signaling epigenetically upregulates tumor cGAS expression and produces cGAMP. Subsequently, cGAMP is transported via LRRC8C channels to activate STING in endothelial cells, enhancing recruitment and transendothelial migration of lymphocytes. In vivo studies in male mice also reveal that administration of vitamin C, a promising anti-cancer agent, stimulates TET2 activity, induces tumor vascular normalization and enhances the efficacy of anti-PD-L1 therapy alone or in combination with IL-2. Our findings elucidate a crosstalk between tumor and vascular endothelial cells in the tumor immune microenvironment, providing strategies to enhance the efficacy of combinational immunotherapy for liver cancer.
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