The coronavirus disease 2019 (COVID-19) pandemic has led to millions of confirmed cases and deaths worldwide and has no approved therapy. Currently, more than 700 drugs are tested in the COVID-19 clinical trials, and full evaluation of their cardiotoxicity risks is in high demand.We mainly focused on hydroxychloroquine (HCQ), one of the most concerned drugs for COVID-19 therapy, and investigated the effects and underlying mechanisms of HCQ on hERG channel via molecular docking simulations. We further applied the HEK293 cell line stably expressing hERG-wild-type channel (hERG-HEK) and HEK293 cells transiently expressing hERG-p.Y652A or hERG-p.F656A mutants to validate our predictions. Western blot analysis was used to determine the hERG channel, and the whole-cell patch clamp was utilized to record hERG current (IhERG).HCQ reduced the mature hERG protein in a time- and concentration-dependent manner. Correspondingly, chronic and acute treatment of HCQ decreased the hERG current. Treatment with brefeldin A (BFA) and HCQ combination reduced hERG protein to a greater extent than BFA alone. Moreover, disruption of the typical hERG binding site (hERG-p.Y652A or hERG-p.F656A) rescued HCQ-mediated hERG protein and IhERG reduction.HCQ can reduce the mature hERG channel expression and IhERG via enhancing channel degradation. The QT prolongation effect of HCQ is mediated by typical hERG binding sites involving residues Tyr652 and Phe656.
Recent research has explored the potential of the demethylating drug 5-azacytidine (Aza) as therapy for a range of diseases. However, the therapeutic efficacy of Aza for patients of atherosclerosis remains unclear. This study investigates the therapeutic application of Aza to atherosclerosis in order to elucidate the underlying mechanisms. We generated induced Tregs (iTregs) from CD4
Flavonoids are a class of secondary plant metabolites that have been shown to have multiple health benefits, including antioxidant and anti-inflammatory. This study was to explore the association between dietary flavonoid consumption and the prevalence of chronic respiratory diseases (CRDs) in adults. The six main types of flavonoids, including isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones, and flavonols, were obtained from the National Health and Nutrition Examination Survey (NHANES) 2007-2010 and 2017-2018 by the two 24-h recall interviews. The prevalence of CRDs, including asthma, emphysema, and chronic bronchitis, was determined through a self-administered questionnaire. The analysis included 15,753 participants aged 18 years or older who had completed a diet history interview. After adjustment for potential confounders, the inverse link was found with total flavonoids, anthocyanidins, flavanones, and flavones, with an OR (95%CI) of 0.86 (0.75-0.98), 0.84 (0.72-0.97), 0.80(0.69-0.92), and 0.85(0.73-0.98) for the highest group compared to the lowest group. WQS regression revealed that the mixture of flavonoids was negatively linked with the prevalence of CRDs (OR = 0.88 [0.82-0.95], P < 0.01), and the largest effect was mainly from flavanones (weight = 0.41). In addition, we found that flavonoid intake was negatively linked with inflammatory markers, and systemic inflammation significantly mediated the associations of flavonoids with CRDs, with a mediation rate of 12.64% for CRP (P < 0.01). Higher flavonoid intake was related with a lower prevalence of CRDs in adults, and this relationship may be mediated through systemic inflammation.
The objective of this study was to investigate the involved mechanisms of advanced glycation end product- (AGE-) exacerbated atherosclerosis (AS).Toll-like receptor 4 (TLR4) inhibitor was administrated to type 2 diabetes mellitus (T2DM) AS rats. Atherosclerotic plaque, M1 macrophage infiltration, and VSMCs phenotypes were evaluated. AGE-exposed primary macrophages were treated with specific siRNAs knocking down receptor for AGEs (RAGE) and TLR4. Phenotypes of M1 macrophage and VSMCs were identified by fluorescent stains. Contact and noncontact coculture models were established. VSMCs and macrophages were cocultured in these models. ELISA was used to detect inflammatory cytokine concentrations. Relative mRNA expression levels were determined by real-time PCR. Relative protein expression and phosphorylation levels were evaluated by Western blots assays.TLR4 inhibitor treatment significantly reduced arterial stenosis, infiltration of M1 polarized macrophages, and contractile-to-synthetic phenotype conversion of VSMCs in DM AS animals. RAGE and TLR4 silencing dramatically reduced AGE-induced macrophage M1 polarization, inflammatory cytokine secretion, and RAGE/TLR4/forkhead box protein C2 (FOXC2)/signaling which inhibited delta-like ligand 4 (Dll4) expression in macrophages. AGE-treated macrophages induced VSMC phenotypic conversion via activating Notch pathway in a contact coculture model rather than a noncontact model. The VSMC phenotypic conversion induction capability of macrophages was attenuated by RAGE and TLR4 silencing.AGEs induced activation of RAGE/TLR4/FOXC2 signaling, which featured macrophage with Dll4 high expression during M1 polarization. These macrophages promoted contractile-synthetic phenotypic conversion of VSMCs through the Dll4/Notch pathway after direct cell-to-cell contacts.
The previous studies have shown that individuals with hypertension and anxiety have a higher mean left ventricular mass index (LVMI) and QTc dispersion. We explored the associations between anxiety and left ventricular hypertrophy (LVH) and between anxiety and transmural dispersion of repolarization (TDR) (as detected by T peak-T end interval/QT interval, Tp-Te/QT ratio) in patients with hypertension.A total of 353 patients with uncomplicated hypertension from the Shaanxi Provincial People's Hospital were enrolled between 2017 and 2021. Anxiety was defined as a Hamilton Anxiety Scale (HAM-A) score ≥ 14. Logistic regression models were used to estimate the association between HAM-A and LVH. The association between HAM-A score and Tp-Te/QT was estimated using linear regression.Participants were divided into two groups based on the presence of anxiety. LVMI was significantly higher in patients with hypertension and anxiety than in those with hypertension without anxiety (no anxiety: 84.36 ± 23.82, anxiety: 105.75 ± 25.45 g/m2, p < 0.001). HAM-A score was positively correlated with LVMI (r = 0.578, p < 0.001) and with Tp-Te/QT (r = 0.252, p < 0.001). Logistic regression models showed that patients with hypertension and anxiety were at higher risk of LVH than were patients with hypertension without anxiety (adjusted OR, 2.44, 95% CI, 1.35-4.43, p = 0.003). The linear regression analysis showed that the HAM-A score was associated with Tp-Te/QT ratio (adjusted β, 0.001, 95% CI, 0.001-0.002, p = 0.013). There was an interaction between sex and anxiety for LVH risk (p for interaction = 0.035) and for increased Tp-Te/QT (p for interaction = 0.014). After stratification by sex, anxiety was associated with increased risk for LVH in men with hypertension (adjusted OR, 5.56, 95% CI, 2.07-14.98, p = 0.001), but not in women (adjusted: OR, 1.44, 95% CI, 0.64-3.26, p = 0.377) with hypertension. The HAM-A score was also positively associated with Tp-Te/QT ratio in male (adjusted β, 0.002, 95% CI, 0.001-0.003, p < 0.001), but not in women (adjusted β, 0.001, 95% CI, -0.0002-0.002, p = 0.165).Our results indicated that anxiety was associated with LVH and with increased TDR in men with hypertension, but not in women with hypertension.
Background: Previous studies showed that hypertensive with anxiety have a higher mean left ventricular mass index (LVMI) and QTc dispersion. This study explores the associations between anxiety and left ventricular hypertrophy (LVH) as well as transmural dispersion of repolarization (TDR) (as detected by T peak-T end interval/QT interval, Tp-Te/QT ratio) in hypertensive patients. Methods: A total of 353 uncomplicated hypertensive patients were enrolled at Shaanxi Provincial People’s Hospital from 2017 to 2021. All enrolled subjects completed the Hamilton Anxiety Scale (HAMA). HAM-A score ≥14 was defined as the presence of anxiety. The association between HAM-A and hypertensive LVH was estimated with logistic regression models. The association between HAM-A score and Tp-Te/QT was estimated with linear regression model (adjusted for age, sex, body mass index, smoking, creatinine, uric acid, triglyceride, total cholesterol, low density lipoprotein cholesterol, and high-density lipoprotein cholesterol). This study was approved by the Ethics Committee of Shaanxi Provincial People’s Hospital and performed in keeping with the requirements of the Declaration of Helsinki. Results: Participants were divided into two groups according to anxiety or not. The LVMI was significantly higher in hypertensive patients with anxiety than hypertensive patients without anxiety (no anxiety: 84.36±23.82, anxiety: 105.75±25.45, g/m 2 , P <0.001). The HAM-A score was positive correlated with LVMI (r=0.578, P <0.001) and Tp-Te/QT (r=0.252, P <0.001). In logistic regression models, hypertensive patients with anxiety had a higher risk of hypertensive LVH than hypertensive patients without anxiety (unadjusted OR, 2.86, 95% CI, 1.65-4.93, P <0.001; adjusted OR, 2.62, 95% CI, 1.49-4.64, P <0.001). Linear regression analysis also showed that HAM-A score was associated with Tp-Te/QT ratio (unadjusted β, 0.002, 95% CI, 0.001-0.002, P <0.001; adjusted β, 0.002, 95% CI, 0.001-0.002, P <0.001). There was an interaction between sex and anxiety in regard to LVH risk ( P for interaction = 0.035) and increased Tp-Te/QT ( P for interaction = 0.014). After stratification by sex, the anxiety group had a higher risk of hypertensive LVH than no anxiety group in male (unadjusted OR, 5.73, 95% CI, 2.43-13.50, P <0.001; adjusted OR, 5.39, 95% CI, 2.13-13.66, P <0.001) but not in female (unadjusted OR, 1.70, 95% CI, 0.82-3.53, P =0.152; adjusted: OR, 1.62, 95% CI, 0.76-3.45, P =0.209) hypertensive patients. HAM-A score was also associated with Tp-Te/QT ratio in male (unadjusted β, 0.003, 95% CI, 0.002-0.004, P <0.001; adjusted β, 0.003, 95% CI, 0.001-0.004, P <0.001) but not in female (unadjusted β, 0.001, 95% CI, -0.0001-0.002, P =0.061; adjusted β, 0.001, 95% CI, -0.0001-0.002, P =0.086). Conclusion: Our data indicated that anxiety is associated with LVH and increased TDR in male but not female hypertensive patients.
Abstract Percutaneous coronary intervention (PCI) is one of the most effective therapies for coronary artery disease, but stent restenosis remains an important clinical challenge. The studies about the independent effect of the number of stents on stent restenosis were limited. The purpose was to identify the independent effect of the number of stents on stent restenosis. A retrospective cohort study of data reuse. From July 2009 to August 2011, a total of 2338 cases met the inclusion and exclusion criteria. The univariate analysis showed that the number of stents was a risk of stent restenosis, the OR value was 1.30 (95% CI:1.15 to 1.47, P < .001). The multi-factor regression analysis also showed that the number of stents was an independent risk of stent restenosis, the adjusted OR value was 1.38 (95% CI: 1.15 to 1.66, P < .001).Compared with 1–2 stents, the adjusted OR values of 3–5 stents and more than 6 stents were respectively 2.20 (95% CI: 1.24 to 3.90, P = .007) and 5.33 (95% CI: 1.89 to 15.08, P = .002), and the trend adjusted OR values was 2.26 (95% CI: 1.43 to 3.59, P < .001).The subgroup analysis of multi-factor regression analysis showed that when patients with the following conditions: 50 < Age, female, non-DES or SES, the risk of stent restenosis increased obviously. The number of stents was an independent risk of stent restenosis in patients undergoing PCI, especially for patients with the following conditions: 2<the number of stents, 50 < age, female, Non-DES (Drug-eluting stents) or SES (sirolimus-eluting stent).
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