Myc is involved in Genistein protecting against LPS-induced myocarditis in vitro through mediating MAPK/JNK signaling pathway.
Myc 通过介导 MAPK/JNK 信号通路参与金雀异黄素在体外保护 LPS 诱导的心肌炎。
- 作者列表："Huang C","Zhang Y","Qi H","Xu X","Yang L","Wang J
BACKGROUND:Genistein is widely used as a pharmacological compound as well as a food additive. However, the pharmaceutical effects of Genistein on myocarditis and its potential mechanisms have not been studied in detail. METHODS:H9c2 cells were continuously stimulated by lipopolysaccharide (LPS) for 12 h to simulate the in vitro model of myocarditis injury. DrugBank, String and GEO dataset were used to investigate specific genes that interacting with Genistein. KEGG and GO enrichment analysis were employed to explore Myc-related signaling pathways. Biological behaviors of H9c2 cells were observed with the support of CCK-8, MTT and flow cytometry. Expression levels of cytokines including TNF-α and ILs were evaluated by enzyme-linked immunosorbent assay. Western blot was applied to detect the expression of Myc and MAPK pathway related proteins. RESULTS:Genistein alleviated the damage of H9c2 cells subjected to LPS from the perspective of elevating cells growth ability, and inhibiting cells apoptosis and inflammatory response. Through bioinformatics analysis, we identified Myc as the potential target of Genistein in myocarditis, and MAPK as the signaling pathway. Significantly, Myc was highly upregulated in myocarditis samples. More importantly, by performing biological experiments, we discovered that Genistein relieved H9c2 cells apoptosis and inflammatory reaction which caused by LPS stimulation through inhibiting Myc expression. Additionally, the marked augmentation of p-P38 MAPK/p-JNK expression in LPS-induced cardiomyocyte model were blocked by Genistein and si-Myc. CONCLUSIONS:Our research revealed that Myc mediated the protective effects of Genistein on H9c2 cells damage caused by LPS partly through modulation of MAPK/JNK signaling pathway.
背景: 染料木素作为一种药理学化合物和食品添加剂被广泛使用。然而，金雀异黄素对心肌炎的药学作用及其潜在机制尚未得到详细研究。 方法: 用脂多糖 (LPS) 持续刺激 H9c2 细胞 12 h，模拟心肌炎损伤的体外模型。DrugBank 、 String 和 GEO 数据集用于研究与染料木黄酮相互作用的特定基因。采用 KEGG 和 GO 富集分析探索 Myc 相关信号通路。在 CCK-8 、 MTT 和流式细胞术的支持下观察 H9c2 细胞的生物学行为。通过酶联免疫吸附试验评估包括 TNF-α 和 ILs 在内的细胞因子的表达水平。应用 Western blot 检测 Myc 和 MAPK 通路相关蛋白的表达。 结果: 金雀异黄素从提高细胞生长能力、抑制细胞凋亡和炎症反应的角度减轻 LPS 对 H9c2 细胞的损伤。通过生物信息学分析，我们确定 Myc 是金雀异黄素在心肌炎中的潜在靶点，MAPK 是信号通路。显著地，Myc 在心肌炎样本中高度上调。更重要的是，通过生物学实验，我们发现染料木黄酮通过抑制 Myc 的表达来缓解 LPS 刺激引起的 H9c2 细胞凋亡和炎症反应。此外，金雀异黄素和 si-Myc 可阻断 LPS 诱导的心肌细胞模型中 p-P38 MAPK/p-JNK 表达的增加。 结论: 我们的研究揭示了 Myc 介导金雀异黄素对 LPS 引起的 H9c2 细胞损伤的保护作用，部分是通过调节 MAPK/JNK 信号通路实现的。
METHODS:Abstract Background Ischemic cardiomyopathy is a high-cost, resource-intensive public health burden that is associated with a 1-year mortality rate of about 16% in western population. Different in patient ethnicity and pattern of practice may impact the clinical outcome. We aim to determine 1-year mortality and to identify factors that significantly predicts 1-year mortality of Thai patients with ischemic cardiomyopathy. Methods This prospective multicenter registry enrolled consecutive Thai patients that were diagnosed with ischemic cardiomyopathy at 9 institutions located across Thailand. Patients with left ventricular function 75% in the left main or proximal left anterior descending artery or coronary angiography, and/or two major epicardial coronary stenoses; 2) prior myocardial infarction; 3) prior revascularization by coronary artery bypass graft or percutaneous coronary intervention; or, 4) magnetic resonance imaging pattern compatible with ischemic cardiomyopathy. Baseline clinical characteristics, coronary and echocardiographic data were recorded. The 1-year clinical outcome was pre-specified. Results Four hundred and nineteen patients were enrolled. Thirty-nine patients (9.9%) had died at 1 year, with 27 experiencing cardiovascular death, and 12 experiencing non-cardiovascular death. A comparison between patients who were alive and patients who were dead at 1 year revealed lower baseline left ventricular ejection fraction (LVEF) (26.7 ± 7.6% vs 30.2 ± 7.8%; p = 0.021), higher left ventricular end-diastolic volume (LVEDV) (185.8 ± 73.2 ml vs 155.6 ± 64.2 ml; p = 0.014), shorter mitral valve deceleration time (142.9 ± 57.5 ml vs 182.4 ± 85.7 ml; p = 0.041), and lower use of statins (94.7% vs 99.7%; p = 0.029) among deceased patients. Patients receiving guideline-recommended β-blockers had lower mortality than patients receiving non-guideline-recommended β-blockers (8.1% vs 18.2%; p = 0.05). Conclusions The results of this study revealed a 9.9% 1-year mortality rate among Thai ischemic cardiomyopathy patients. Doppler echocardiographic parameters significantly associated with 1-year mortality were LVEF, LVEDV, mitral E velocity, and mitral valve deceleration time. The use of non-guideline-recommended β-blockers rather than guideline recommended β-blockers were associated with increased with 1-year mortality. Guidelines recommended β-blockers should be preferred. Trial registration Thai Clinical Trials Registry TCTR20190722002. Registered 22 July 2019. “Retrospectively registered”.
METHODS:Abstract Background Peripartum cardiomyopathy (PPCM) is rare and potentially life-threatening; its etiology remains unclear. Imaging characteristics on cardiovascular magnetic resonance (CMR) and their prognostic significance have rarely been studied. We sought to determine CMR’s prognostic value in PPCM by using T1 and T2 mapping techniques. Methods Data from 21 PPCM patients from our CMR registry database were analyzed. The control group comprised 20 healthy age-matched females. All subjects underwent comprehensive contrast-enhanced CMR. T1 and T2 mapping using modified Look-Locker inversion recovery and T2 prep balanced steady-state free precession sequences, respectively. Ventricular size and function, late gadolinium enhancement (LGE), myocardial T1 value, extracellular volume (ECV), and T2 value were analyzed. Transthoracic echocardiography was performed at baseline and during follow-up. The recovered left ventricular ejection fraction (LVEF) was defined as LVEF ≥50% on echocardiography follow-up after at least 6 months of the diagnosis. Results CMR imaging showed that the PPCM patients had severely impaired LVEF and right ventricular ejection fraction (LVEF: 26.8 ± 10.6%; RVEF: 33.9 ± 14.6%). LGE was seen in eight (38.1%) cases. PPCM patients had significantly higher native T1 and ECV (1345 ± 79 vs. 1212 ± 32 ms, P < 0.001; 33.9 ± 5.2% vs. 27.1 ± 3.1%, P < 0.001; respectively) and higher myocardial T2 value (42.3 ± 3.7 vs. 36.8 ± 2.3 ms, P < 0.001) than did the normal controls. After a median 2.5-year follow-up (range: 8 months-5 years), six patients required readmission for heart failure, two died, and 10 showed left ventricular function recovery. The LVEF-recovered group showed significantly lower ECV (30.7 ± 2.1% vs. 36.8 ± 5.6%, P = 0.005) and T2 (40.6 ± 3.0 vs. 43.9 ± 3.7 ms, P = 0.040) than the unrecovered group. Multivariable logistic regression analysis showed ECV (OR = 0.58 for per 1% increase, P = 0.032) was independently associated with left ventricular recovery in PPCM. Conclusions Compared to normal controls, PPCM patients showed significantly higher native T1, ECV, and T2. Native T1, ECV, and T2 were associated with LVEF recovery in PPCM. Furthermore, ECV could independently predict left ventricular function recovery in PPCM.
METHODS:BACKGROUND:Atrial fibrillation (AF) is the most common arrhythmia in hypertrophic cardiomyopathy (HCM) and is associated with adverse outcomes in HCM patients. Although the left atrial (LA) diameter has consistently been identified as a strong predictor of AF in HCM patients, the relationship between LA dysfunction and AF still remains unclear. The aim of this study is to evaluate the LA function in patients with non-obstructive HCM (NOHCM) utilizing cardiovascular magnetic resonance feature tracking (CMR-FT).,METHODS:Thirty-three patients with NOHCM and 28 healthy controls were studied. The global and regional LA function and left ventricular (LV) function were compared between the two groups. The following LA global functional parameters were quantitively analyzed: reservoir function (total ejection fraction [LA total EF], total strain [ε], peak positive strain rate [SRs]), conduit function (passive ejection fraction [LA passive EF], passive strain [ε], peak early-negative SR [SRe]), and booster pump function (active ejection fraction [LA active EF], active strain [ε], peak late-negative SR [SRa]). The LA wall was automatically divided into 6 segments: anterior, antero-roof, inferior, septal, septal-roof and lateral. Three LA strain parameters (ε, ε, ε) and their corresponding strain rate parameters (SRs, SRe, SRa) during the reservoir, conduit and booster pump LA phases were segmentally measured and analyzed.,RESULTS:The LA reservoir (LA total EF: 57.6 ± 8.2% vs. 63.9 ± 6.4%, p < 0.01; ε: 35.0 ± 12.0% vs. 41.5 ± 11.2%, p = 0.03; SRs: 1.3 ± 0.4 s vs. 1.5 ± 0.4 s, p = 0.02) and conduit function (LA passive EF: 28.7 ± 9.1% vs. 37.1 ± 10.0%, p < 0.01; ε: 18.7 ± 7.9% vs. 25.9 ± 10.0%, p < 0.01; SRe: - 0.8 ± 0.3 s vs. -1.1 ± 0.4 s, p < 0.01) were all impaired in patients with NOHCM when compared with healthy controls, while LA booster pump function was preserved. The LA segmental strain and strain rate analysis demonstrated that the ε, ε, SRe of inferior, SRs, SRe of septal-roof, and SRa of antero-roof walls (all p < 0.05) were all decreased in the NOHCM cohort. Correlations between LA functional parameters and LV conventional function and LA functional parameters and baseline parameters (age, body surface area and NYHA classification) were weak. The two strongest relations were between ε and LA total EF(r = 0.84, p < 0.01), ε and LA active EF (r = 0.83, p < 0.01).,CONCLUSIONS:Compared with healthy controls, patients with NOHCM have LA reservoir and conduit dysfunction, and regional LA deformation before LA enlargement. CMR-FT identifies LA dysfunction and deformation at an early stage.