刘尧
中国医学科学院阜外医院 急症抢救中心
Mounting evidence has shown that circular RNAs (circRNAs) function as key regulators in carcinogenesis and cancer progression, and this study is aimed at investigating the regulatory functions of circRNA TLK1 (circ-TLK1) in hepatocellular carcinoma (HCC). We observed that circ-TLK1 was highly expressed in HCC samples, and its high expression was closely associated with poor clinicopathological variables of HCC patients. The results of functional experiments revealed that knockdown of circ-TLK1 remarkably inhibited the proliferation, migration, invasion, and EMT of HCC cells, while circ-TLK1 overexpression promoted these malignant behaviors. Moreover, we noted that circ-TLK1 was capable of binding to miR-138-5p and upregulating its target gene, SOX4 in HCC. Based on rescue assays, miR-138-5p inhibition partially suppressed the effects of circ-TLK1 knockdown on the malignant behaviors of HCC cells. In short, this study is the first to indicate that circ-TLK1 functions as an oncogene in HCC progression partly through acting as a ceRNA of miR-138-5p, which may be a promising target for HCC therapy.
Journal of oncology 2022
Inhibitors of histone deacetylase enzymes induce various molecular and extracellular effects that lead to their anticancer role. In this study, the result of valproic acid on the expression of genes of extrinsic pathway and intrinsic pathway of apoptosis, cell viability, and apoptosis in liver cancer PLC/PRF5 cell line was designed. For this purpose, PLC/PRF5 liver cancer cells were cultured, and after the overlapping of the cells reached about 80%, the cells were collected with trypsin and after washing, they were cultured on a plate with a concentration of 3 x 105. After 24 hours, the culture medium was treated with a medium containing valproic acid (the control group received only DMSO). 24, 48, and 72 hours after treatment to determine the cell viability, apoptotic cells, gene expression, MTT, flow cytometry, and Real-time techniques. The results showed that valproic acid significantly inhibited cell growth, induced apoptosis, and decreased the expression of Bcl-2 and Bcl-xL genes. Also, it increased the expression of DR4, DR5, FAS, FAS-L, TRAIL, BAX, BAK, and APAF1 genes. In general, valproic acid seems to play its apoptotic role through intrinsic and extrinsic pathways in liver cancer.
Cellular and molecular biology (Noisy-le-Grand, France) 2022
Endothelial-to-mesenchymal transition (EndMT) plays a critical role in the flow-induced vascular remodeling process, such as pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). NBL1 (neuroblastoma suppressor of tumorigenicity 1) is a secreted glycoprotein that has been implicated in CHD-PAH by aggravating the phenotypic transformation of smooth muscle cells. However, the underlying mechanisms regarding the interplay between NBL1 and endothelial cells in CHD-PAH remain to be fully elucidated. Thus, we aimed to identify the potential effect of NBL1 on EndMT using a novel flow-associated PAH model with Nbl1 knockout rats. The phenotype of EndMT was detected using RNA sequencing and further examined using western blotting and immunostaining of pulmonary arteries. Our observations demonstrated that the novel strategy of Nbl1 knockout effectively attenuated flow-associated PAH through downregulation of EndMT to some extent. Mechanistic experiments were established on human pulmonary artery endothelial cells to confirm that EndMT was induced by NBL1 in vitro. After 7 days' stimulation with NBL1, concentrations of EndMT-related biomarkers and downstream transcription factors were quantified using RNA sequencing, western blotting, and immunocytochemistry. Both in vitro and in vivo experiments supported the imbalance of increased TGF-β (transforming growth factor-β) and dysregulation of BMP (bone morphogenetic protein) signaling by NBL1. Blocking the canonical TGF-β pathway efficiently preserved endothelial function upon NBL1 stimulation. These data suggested that NBL1 aggravated flow-associated PAH by inducing EndMT via the TGF-β and BMP signaling pathway. Thus, antagonizing NBL1 and rebalancing TGF-β and BMP signaling may be a suitable therapeutic target for CHD-PAH.
American journal of respiratory cell and molecular biology 2022
BACKGROUND:Patients with transposition of the great arteries are likely to survive surgery despite severe pulmonary artery hypertension. However, the underlying mechanisms remain largely unknown. The present study aimed to test the hypothesis that high blood oxygen saturation may protect the pulmonary artery from remodeling.METHODS:An in vitro pulmonary artery perfusion model was successfully performed by connecting rabbit pulmonary artery to a closed perfusion circuit. Twenty-five rabbits were divided randomly into 5 groups according to exposure conditions: Normal Control (NC) group (unperfused normal pulmonary artery), High Saturation (HS) group (oxygen saturation range: 90-100%), Medium Saturation (MS) group (oxygen saturation: 65-75%); Low Saturation (LS) group (oxygen saturation: 40-50%), and anti-hypoxia inducible factor-1α (anti-HIF-1α) group (oxygen saturation range: 40-50%, and LW6, which is a novel HIF-1α inhibitor; was added). By staining and optical microscopy examination, pathological morphology was analyzed, and the protein expression levels of HIF-1α, angiotensin-II (Ang-II), endothelin-1 (ET-1), Rho-associated protein kinase-1 (Rock-1), and matrix metallopeptidase-2 (MMP-2) were determined by Western blotting.RESULTS:The amounts of elastin, muscle, and collagen and the protein levels of ET-1, HIF-1α, Rock-1, and MMP-2, increased significantly with decreased oxygen saturation in the perfusion circuit. A significant improvement in pathological morphology was observed in the anti-HIF1α group. The expression of HIF-1α, ET-1, Ang-II, Rock-1, and MMP-2 in the anti-HIF1α group was also significantly lower than that in the LS group.CONCLUSIONS:In the closed perfusion model, high blood oxygen saturation alleviated pulmonary vascular structural remodeling. Similar beneficial effects were observed when inhibiting the HIF-1α protein, suggesting a key role for HIF-1α in pulmonary artery remodeling.
Journal of thoracic disease 2021
BACKGROUND:The impact of septal myectomy on diastolic function in patients with obstructive hypertrophic cardiomyopathy is not well studied.METHODS:A transcatheter hemodynamic study was performed before and 3 to 6 months after septal myectomy in 12 patients with obstructive hypertrophic cardiomyopathy (HCM).RESULTS:Postoperative hemodynamic studies were done 4.4±1.2 months after myectomy. The left ventricular outflow tract peak-to-peak gradient decreased from 83.2±43.3 mmHg preoperatively to 11.6±4.3 mmHg after myectomy (P<0.00). The left ventricular diastolic time constant (Tau) was 64.2±26.1 ms before surgery and 42.2±15.7 ms postoperatively (P=0.029). The average left atrial pressure (LAP) decreased from 20.2±7.0 to 12.1±4.5 mmHg after myectomy (P=0.008). Pulmonary artery hypertension was present in 6 patients preoperatively and remained in 2 patients after myectomy. Mean pulmonary artery pressure decreased from 29.3±16.2 to 20±6.7 mmHg after surgery (P=0.05), and the systolic pulmonary artery pressure decreased from 46±26.9 to 30.5±8.3 mmHg (P=0.048). Pulmonary vascular resistance decreased from 5.7±4.1 to 3.6±1.6 wood after surgery (P=0.032).CONCLUSIONS:Septal myectomy improved left ventricular diastolic function and subsequently relieved the right ventricular congestion in patients with obstructive HCM.
Journal of thoracic disease 2021
BACKGROUND:Percutaneous balloon pulmonary valvuloplasty (PBPV) is the procedure of choice for uncomplicated severe or symptomatic pulmonary stenosis. Echocardiography (echo)-guided PBPV can completely avoid the use of radiation and contrast agents compared to fluoroscopy-guided PBPV. Although we have confirmed that echo-guided PBPV is feasible in humans, the poor visibility of the traditional catheter under echo greatly limits the promotion of this new technology.METHODS:We produced a novel double-balloon catheter to make the catheter easy to be detected by echo through adding a guiding balloon at the distal end of the catheter. Echo-guided PBPV was performed on thirty healthy swine using either a novel catheter or a traditional catheter to evaluate the feasibility and safety of the novel double-balloon catheter. The feasibility was evaluated by the success rate of balloon inflation at the pulmonary valve annulus and the operating time. The safety was evaluated by the frequency of balloon slippage and the incidence of complications.RESULTS:There were no significant between-group differences in terms of weight and the ratio of balloon diameter to pulmonary annulus diameter. The success rate was 93.3% and 60% in the novel and traditional groups, respectively. The novel group had significantly (p<0.05) lower mean procedure time (6.33±6.86min vs 24.8±9.79min) and lower frequency of balloon slippage (0.07±0.26 vs 0.53±0.52), arrhythmia (0.07±0.26 vs 0.47±0.52), and tricuspid regurgitation (6.7% vs 40%) than the traditional group. No myocardial hematoma or pericardial tamponade occurred in the novel catheter group.CONCLUSION:Although further studies and improvements are required, the study results indicate that the novel double-balloon catheter for echo-guided PBPV is feasible and safe.
Journal of cardiology 2020
Background Heterozygous mutation in BMP (bone morphogenetic protein) receptor 2 is rare, but BMP cascade suppression is common in congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH); however, the underling mechanism of BMP cascade suppression independent of BMP receptor 2 mutation is unknown. Methods and Results Pulmonary hypertensive status observed in CHD-PAH was surgically reproduced in rats. Gremlin-1 expression was increased, but BMP cascade was suppressed, in lungs from CHD-PAH patients and shunted rats, whereas shunt correction retarded these trends in rats. Immunostaining demonstrated increased gremlin-1 was mainly in the endothelium and media of remodeled pulmonary arteries. However, mechanical stretch time- and amplitude-dependently stimulated gremlin-1 secretion and suppressed BMP cascade in distal pulmonary arterial smooth muscle cells from healthy rats. Under static condition, gremlin-1 significantly promoted the proliferation and inhibited the apoptosis of distal pulmonary arterial smooth muscle cells from healthy rats via BMP cascade. Furthermore, plasma gremlin-1 closely correlated with hemodynamic parameters in CHD-PAH patients and shunted rats. Conclusions Serving as an endogenous antagonist of BMP cascade, the increase of gremlin-1 in CHD-PAH may present a reasonable mechanism explanation for BMP cascade suppression independent of BMP receptor 2 mutation.
Journal of the American Heart Association 2020
Percutaneous balloon aortic valvuloplasty (PBAV), which is used to treat symptomatic aortic stenosis, requires ionizing radiation and contrast agent for imaging guidance. The aim of the study is to evaluate the feasibility and effectiveness of ultrasound-guided PBAV in patients with aortic stenosis. This case series included 30 patients (14 males; mean age, 61.5 ± 4.5 years) with moderate/severe aortic stenosis treated with ultrasound-guided PBAV at the Ultrasound Department, Fuwai Hospital, Beijing, China, between January 2016 and July 2019. Cardiac function (New York Heart Association grade) was assessed before PBAV and 1 month after the procedure. Aortic peak jet velocity, aortic valve orifice area (AVA), mean transvalvular pressure gradient (MTPG), left ventricular end-diastolic diameter (LVDD), left ventricular ejection fraction (LVEF), and left ventricular end-systolic diameter (LVESD) were determined before and immediately after PBAV using Doppler echocardiography. Preprocedural cardiac function was grade I in 3 cases, grade II in 9 cases, grade III in 10 cases, and grade IV in 8 cases. Postprocedural cardiac function was grade I in 22 cases, grade II in 4 cases, and grade III in 4 cases, suggesting that cardiac function was improved by PBAV. Ultrasound-guided PBAV resulted in significant improvements (P < 0.05) in aortic peak jet velocity (3.68 ± 0.811 m/s vs. 4.79 ± 0.63 m/s), MTPG (33.77 ± 13.85 mmHg vs. 54.54 ± 13.81 mmHg), AVA (1.96 ± 0.25 cm2 vs. 0.98 ± 0.12 cm2), LVEDD (51.90 ± 3.21 mm vs. 65.60 ± 6.81 mm), LVEF (63.46 ± 11.29% vs. 56.31 ± 11.04%), and LVESD (35.50 2.62 mm vs. 45.20 ± 2.42 mm). Ultrasound-guided PBAV is feasible and achieves good short-term effects in patients with aortic stenosis.
Journal of interventional cardiology 2020
OBJECTIVES:This study was conducted to investigate the combined use of fenestrated atrial septal occluder (F-ASO) and targeted medical therapy (TMT) in patients with secundum atrial septal defect (ASD) and severe pulmonary arterial hypertension (PAH).BACKGROUND:Treatment of patients with ASD and severe PAH is still challenging.METHODS:After ethical approval was obtained, 56 consecutive patients with ASD with severe PAH were included (7 men, 49 women; median age 50.5 years; mean ASD size 26.9 ± 4.6 mm). After 3 months of TMT, transcatheter closure was performed using F-ASO in patients with ratios of pulmonary to systemic blood flow ≥1.5. TMT was continued post-operatively together with 6 months of dual-antiplatelet therapy. The hemodynamic variables during baseline, TMT alone, and combined treatment with F-ASO were compared.RESULTS:After only TMT, systolic pulmonary arterial pressure (-14.5 mm Hg; p < 0.001), pulmonary vascular resistance (-3.9 Wood units; p < 0.001), and exercise capacity (+72.0 m; p < 0.001) improved. Ratio of pulmonary to systemic blood flow increased by 0.9 (p < 0.001), with adverse cardiac remodeling (right ventricular dimension +3.5 mm; p < 0.001). Closure with F-ASO (median size 34.0 mm) led to further decrease in systolic pulmonary artery pressure (-6.0 mm Hg; p < 0.001). Follow-up (median duration 10 months) revealed further improvement in exercise capacity (+60.5 m; p < 0.001), with favorable cardiac remodeling (right ventricular dimension -9.9 mm; p < 0.001). In addition, all fenestrations were stable (p = 0.699), with negligible shunt (median ratio of pulmonary to systemic blood flow 1.1) and no complications. One year later, pulmonary artery pressure was normalized in 8 of 19 patients, and PAH recurred in 5 patients after discontinuation of TMT.CONCLUSIONS:In patients with ASD and severe PAH, combination of F-ASO and TMT was a safe and effective procedure. Compared with TMT alone, the combined treatment further improved exercise capacity, with favorable cardiac remodeling.
JACC. Cardiovascular interventions 2020
Objective:To assess the effectiveness of a novel ultrasound wire for echo-guiding percutaneous atrial septal defect (ASD) closure in a sheep model.Methods:After right lateral thoracotomy, ASDs were created in 20 sheep by transseptal needle puncture followed by balloon dilatation. Animals were evenly randomized into 2 groups to undergo ASD closure using echography as the only imaging tool with either COOK wire (control group) or new ultrasound wire (study group). The total procedural time, passing time (time needed for the guide wire to enter the left atrium), frequency of delivery sheath dropping into the right atrium, frequency of arrhythmias, and 1-week rate of complications were compared between the two groups.Results:All animals survived defect creation procedures uneventfully. ASD devices were successfully implanted in all sheep. Compared with the control group, the study group had significantly (P < 0.05) lower mean procedure time (15.36 ± 4.86 versus 25.82 ± 7.85 min), lower mean passing time (2.69 ± 0.82 versus 5.58 ± 3.34 min), lower frequency of the guide wire dropping into the right atrium (0% versus 40%), and lower frequency of atrial (4.41 ± 2.61 versus 9.60 ± 3.68) or ventricular premature contractions (0.75 ± 0.36 versus 1.34 ± 0.68), respectively, without serious complications up to one week.Conclusion:The novel ultrasound specialized guide wire was effective in echo-guiding percutaneous ASD closure.
Journal of healthcare engineering 2018
