Multi-omics analysis identifies potential mechanisms by which high glucose accelerates macrophage foaming.

Atherosclerotic morbidity is significantly higher in the diabetic population. Hyperglycemia, a typical feature of diabetes, has been proven to accelerate foam cell formation. However, the molecular mechanisms behind this process remain unclear. In this study, LPS and IFN-γ were used to convert THP-1-derived macrophages into M1 macrophages, which were then activated with ox-LDL in either high glucose or normal condition. We identified lipids within macrophages by Oil red O staining and total cholesterol detection. The genes involved in lipid absorption, efflux, inflammation, and metabolism were analyzed using qRT-PCR. The mechanisms of high glucose-induced foam cell formation were further investigated through metabolomics and transcriptomics analysis. We discovered that high glucose speed up lipid accumulation in macrophages (both lipid droplets and total cholesterol increased), diminished lipid efflux (ABCG1 down-regulation), and aggravated inflammation (IL1B and TNF up-regulation). Following multi-omics analysis, it was determined that glucose altered the metabolic and transcriptional profiles of macrophages, identifying 392 differently expressed metabolites and 293 differentially expressed genes, respectively. Joint pathway analysis suggested that glucose predominantly disrupted the glycerolipid, glycerophospholipid, and arachidonic acid metabolic pathways in macrophages. High glucose in the glyceride metabolic pathway, for instance, suppressed the transcription of triglyceride hydrolase (LIPG and LPL), causing cells to deposit excess triglycerides into lipid droplets and encouraging foam cell formation. More importantly, high glucose triggered the accumulation of pro-atherosclerotic lipids (7-ketocholesterol, lysophosphatidylcholine, and glycerophosphatidylcholine). In conclusion, this work elucidated mechanisms of glucose-induced foam cell formation via a multi-omics approach.

Discovery and therapeutic implications of bioactive dihydroxylated phenolic acids in patients with severe heart disease and conditions associated with inflammation and hypoxia.

Our initial studies detected elevated levels of 3,4-dihydroxyphenyllactic acid (DHPLA) in urine samples of patients with severe heart disease when compared with healthy subjects. Given the reported anti-inflammatory properties of DHPLA and related dihydroxylated phenolic acids (DPAs), we embarked on an exploratory multi-centre investigation in patients with no urinary tract infections to establish the possible pathophysiological significance and therapeutic implications of these findings. Chinese and Caucasian patients being treated for severe heart disease or those conditions associated with inflammation (WBC ≥ 10 ×109/L or hsCRP ≥ 3.0 mg/L) and/or hypoxia (PaO2 ≤ 75 mmHg) were enrolled; their urine samples were analyzed by HPLC, HPLC-MS, GC-MS and biotransformation assays. DHPLA was detected in urine samples of patients, but undetectable in healthy volunteers. Dynamic monitoring of inpatients undergoing treatment showed their DHPLA levels declined in proportion to their clinical improvement. In DHPLA-positive patients' fecal samples, Proteus vulgaris and P. mirabilis were more abundant than healthy volunteers. In culture, these gut bacteria were capable of reversible interconversion between DOPA and DHPLA. Furthermore, porcine and rodent organs were able to metabolize DOPA to DHPLA and related phenolic acids. The elevated levels of DHPLA in these patients suggest bioactive DPAs are generated de novo as part of a human's defense mechanism against disease. Because DHPLA isolated from Radix Salvia miltiorrhizae has a multitude of pharmacological activities, these data underpin the scientific basis of this medicinal plant's ethnopharmacological applications as well as highlighting the therapeutic potential of endogenous, natural or synthetic DPAs and their derivatives in humans.

Factors Influencing Stent Restenosis After Percutaneous Coronary Intervention in Patients with Coronary Heart Disease: A Clinical Trial Based on 1-Year Follow-Up.

BACKGROUND This study observed the incidence of in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) and discusses the risk factors of ISR based on clinical data, coronary angiography, and stent features, to provide a theoretical basis for the prevention and treatment of ISR. MATERIAL AND METHODS We selected 1132 cases who received stent implantation at the Shaanxi People's Hospital from June 2014 to June 2016 and were followed up by coronary angiography within 1 year. Based on coronary angiography, the cases were divided into ISR and non-ISR groups. ISR was defined as a reduction in lumen diameter by over 50% after PCI. The ISR group consisted of 93 cases and the non-ISR group consisted of 1039 cases. Medical history, biochemical indicators, features of coronary artery lesions, and stent status were analyzed retrospectively. Risk factors of ISR were identified by univariate and multivariate logistic regression analyses. RESULTS Among 1132 cases, 93 cases had ISR, with the overall incidence of 8.21%. Univariate and multivariate logistic regression analyses indicated that postoperative hypersensitive C-reactive protein (hs-CRP) levels (OR=2.309, 1.579-3.375 mg/L), postoperative homocysteine (HCY) levels (OR=2.202, 1.268-3.826 µmol/L), history of diabetes (OR=1.955,1.272-3.003), coronary bifurcation lesions (OR=3.785, 2.246-6.377), and stent length (OR=1.269, 1.179-1.365 mm) were independent risk factors of ISR after PCI (P<0.05). CONCLUSIONS Elevated hs-CRP and HCY levels after PCI, history of diabetes, coronary bifurcation lesions, and greater stent length were associated with a higher risk of ISR. Patients with a higher risk of ISR should receive routine follow-up and intense medication management after PCI to control the risk factors and to reduce ISR.