Environmental and epigenetic factors often play an important role in polygenic disorders. However, how such factors affect disease-specific tissues at the molecular level remains to be understood. Here, we address this in pulmonary arterial hypertension (PAH). We obtain pulmonary arterial endothelial cells (PAECs) from lungs of patients and controls (n = 19), and perform chromatin, transcriptomic and interaction profiling. Overall, we observe extensive remodeling at active enhancers in PAH PAECs and identify hundreds of differentially active TFs, yet find very little transcriptomic changes in steady-state. We devise a disease-specific enhancer-gene regulatory network and predict that primed enhancers in PAH PAECs are activated by the differentially active TFs, resulting in an aberrant response to endothelial signals, which could lead to disturbed angiogenesis and endothelial-to-mesenchymaltransition. We validate these predictions for a selection of target genes in PAECs stimulated with TGF-β, VEGF or serotonin. Our study highlights the role of chromatin state and enhancers in disease-relevant cell types of PAH.
Glucagon-like peptide 1 (GLP-1) is a metabolic hormone involved in the stimulation of insulin biosynthesis and secretion. It has been recently reported that GLP-1 also exerts cardioprotective effects and facilitates functional recovery after myocardial infarction through GLP-1 receptor-mediated signaling in cardiomyocytes. GLP-1 treatment has been also demonstrated to produce sustained improvement in cardiac function in long-term studies, suggesting the involvement of mechanisms beyond the acute metabolic and cytoprotective effects. For example, the possible interaction of GLP-1 with the cardiac fibroblasts, which are responsible for the postinfarct remodeling and extracellular matrix production, has not been previously explored. Here, we report that cultures of human cardiac fibroblasts treated with GLP-1 peptides display a selective up-regulation in elastin gene expression and a consequent increase in elastic fibers production, in the absence of the classic GLP-1 receptor. Importantly, we provide experimental evidence that this GLP-1-induced elastogenesis is triggered through the cross-activation of the IGF-I receptor. Because GLP-1 does not stimulate deposition of collagen I, nor promote the proliferation or apoptosis of cultured cardiac fibroblasts, we speculate that its elastogenic effect may also contribute to the beneficial remodeling of the human heart after myocardial infarction.
Sepsis is a systemic inflammatory disease with infection, and autophagy has been shown to play an important role in sepsis. This review summarizes the main regulatory mechanisms of autophagy in sepsis and its latest research. Recent studies have shown that autophagy can regulate innate immune processes and acquired immune processes, and the regulation of autophagy in different immune cells is different. Mitophagy can select damaged mitochondria and remove it to deal with oxidative stress damage. The process of mitophagy is regulated by other factors. Non-coding RNA is also an important factor in the regulation of autophagy. In addition, more and more studies in recent years have shown that autophagy plays different roles in different organs. It tends to be protective in the lungs, heart, kidneys, and brain, and tends to be damaging in skeletal muscle. We also mentioned that some drugs can regulate autophagy. The process of modulating autophagy through drug intervention appears to be a new potential hope for the treatment of sepsis.
Background At present, it is unclear which device (uncemented or cemented total hip arthroplasty [UTA or CTA, respectively]) is more suitable for the conversion of a failed proximal femoral nail anti-rotation (PFNA). The aim of this review was to assess the outcomes of failed PFNAs converted to a UTA or CTA device in elderly individuals with intertrochanteric femoral fractures (IFFs). Methods Two hundred fifty-eight elderly individuals (258 hips) with IFFs who underwent a conversion to a UTA or CTA device following failed PFNAs during 2007–2017 were retrospectively identified from the China Southern Medical Centre (CSMC) database. The primary endpoint was the Harris Hip Score (HHS); secondary endpoint was the key orthopaedic complication rate. Results The median follow-up was 65 months (60–69 months). Significant distinctions were observed (87.26 ± 16.62 for UTA vs. 89.32 ± 16.08 for CTA, p = 0.021; 86.61 ± 12.24 for symptomatic UTA vs. 88.68 ± 13.30 for symptomatic CTA, p = 0.026). A significant difference in the overall key orthopaedic complication rate was detected (40.8% [40/98] vs. 19.0% [19/100], p = 0.001). Apparent distinctions were detected in terms of the rate of revision, loosening, and periprosthetic fracture (11.2% for UTA vs 3.0% for CTA, p = 0.025; 13.2% for UTA vs 5.0% for CTA, p = 0.043; 10.2% for UTA vs 3.0% for CTA, p = 0.041, respectively). Conclusion For elderly individuals with IFFs who suffered a failed PFNA, CTA devices may have a noteworthy advantage in regard to the revision rate and the rate of key orthopaedic complications compared with UTA devices, and CTA revision should be performed as soon as possible, regardless of whether these individuals have symptoms.
BackgroundDanlou tablets, a patented Chinese Medicine, have been long approved for the treatment of ischemic heart disease in China. While numerous empirical observations suggested Danlou tablets could decrease frequency and duration of angina pectoris attacks, evidence supporting its efficacy on cardiac remodeling remains inadequate. Therefore, this pilot trial was designed to determine whether Danlou tablets would reduce adverse left ventricular (LV) remodeling in patients with myocardial infarction (MI).Methods and ResultsEligible patients with acute MI were enrolled and randomly assigned to Danlou tablets or placebo groups, superimposed on standard treatment for MI. Then, in addition to assessment of the clinical outcome, the changes in LV volumes were evaluated by a serial echocardiography. In total, 83 patients (Danlou tablets 42 and placebo 41) completed 90 days of treatment and had complete baseline and outcome data. Standard echocardiographic evaluations revealed significant differences in the change of LV end-diastolic volume index (LVEDVi) between group of patients treated with Danlou tablets and the placebo group (−4.49 ± 7.29 vs. −0.34 ± 9.01 mL/m2, P < 0.001). The reduction in LVEDVi was independent of beta-blocker, ACE inhibitors/ARBs use. Furthermore, treatment with Danlou tablets significantly reduced LV end-systolic volume index (−4.09 ± 5.85 vs. −0.54 ± 5.72 mL/m2, P < 0.001) and improved the LV ejection fraction (4.83 ± 9.23 vs. 0.23 ± 8.15 %, P < 0.001), as compared to placebo. Meaningfully, the incidence of the major adverse cardiovascular events was also lower in patients receiving Danlou tablets (P < 0.05).ConclusionSuperimposed on the standard pharmacologic treatment, Danlou tablets significantly reversed post-MI adverse LV remodeling, thereby contributed to the overall positive clinical outcome.Trial registrationclinicaltrials.gov identifier NCT02675322 (February 1, 2016).Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-016-1406-4) contains supplementary material, which is available to authorized users.
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