Whole genome methylation combined with RNA-seq reveals the protective effects of Gualou-Xiebai herb pair in foam cells through DNA methylation mediated PI3K-AKT signaling pathway.

DNA methylation, including aberrant hypomethylation and hypermethylation, plays a significant role in atherosclerosis (AS); therefore, targeting the unbalanced methylation in AS is a potential treatment strategy. Gualou-xiebai herb pair (GXHP), a classic herb combination, have been used for the treatment of atherosclerotic-associated diseases in traditional Chinese medicine. However, the effects and underlying mechanism of GXHP on AS remain nebulous. In this study, the CCK-8 method was applied to determine the non-toxic treatment concentrations for GXHP. The formation of foam cells played a critical role in AS, so the foam cells model was established after RAW264.7 cells were treated with ox-LDL. The contents of total cholesterol (TC) and free cholesterol (FC) were determined by Gas chromatography-mass spectrometry (GC-MS). Enzyme-linked immunosorbent assay (ELISA) was used to check the expressions of inflammatory factors including IL-1ß, TNF-α, and VCAM-1. Methyl-capture sequencing (MC-seq) and RNA-seq were applied to observe the changes in genome-wide DNA methylation and gene expression, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to analyze differentially methylated genes (DMGs) and differentially expressed genes (DEGs). The targeted signaling pathway was selected and verified using western blotting (WB). The results showed that the lipids and inflammatory factors in foam cells significantly increased. GXHP significantly reduced the expression of TC, FC, and inflammatory factors. MC-seq and RNA-seq showed that GXHP not only corrected the aberrant DNA hypermethylation, but also DNA hypomethylation, thus restored the aberrant DEGs in foam cells induced by ox-LDL. GXHP treatment may target the PI3K-Akt signaling pathway. GXHP reduced the protein levels of phosphorylated(p)-PI3K and p-AKT in foam cells. Our data suggest that treatment with GXHP showed protective effects against AS through the inhibition of DNA methylation mediated PI3K-AKT signaling pathway, suggesting GXHP as a novel methylation-based agent.

Potential Benefits of Selenium Supplementation in Reducing Insulin Resistance in Patients with Cardiometabolic Diseases: A Systematic Review and Meta-Analysis.

BACKGROUND: Selenium is a trace element that has been reported to be effective in regulating glucose and lipid metabolism. However, there is conflicting evidence from different clinical trials of selenium supplementation in treating cardiometabolic diseases (CMDs). OBJECTIVE: This meta-analysis aimed to identify the effects of selenium supplementation on insulin resistance, glucose homeostasis, and lipid profiles in patients with CMDs. METHODS: Randomized controlled trials (RCTs) of selenium supplementation for treating CMDs were screened in five electronic databases. Insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (FPG), and glycosylated hemoglobin A1C (HbA1c) were defined as the primary outcome markers, and lipid profiles were considered the secondary outcome markers. RESULTS: Ten studies involving 526 participants were included in the meta-analysis. The results suggested that selenium supplementation significantly reduced serum insulin levels (standardized men difference [SMD]: -0.53; 95% confidence interval [CI] [-0.84, -0.21], p = 0.001, I2 = 68%) and HOMA-IR (SMD: -0.50, 95% CI [-0.86, -0.14], p = 0.006, I2 = 75%) and increased high-density lipoprotein cholesterol (HDL-C) levels (SMD: 0.97; 95% CI [0.26, 1.68], p = 0.007, I2 = 92%), but had no significant effect on FPG, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C). CONCLUSION: Current evidence supports the beneficial effects of selenium supplementation on reducing insulin levels, HOMA-IR, and increasing HDL-C levels. Selenium supplementation may be an effective strategy for reducing insulin resistance in patients with CMDs. However, more high-quality clinical studies are needed to improve the certainty of our estimates.

Qing-Xin-Jie-Yu Granule alleviates atherosclerosis by reshaping gut microbiota and metabolic homeostasis of ApoE-/- mice.

BACKGROUND: Atherosclerosis (AS) is a key pathological factor in cardiovascular disease (CVD) and is characterized by high mortality and morbidity worldwide. Metabolic disorders, including pathoglycemia and dyslipidemia that lead to chronic inflammation, represent the prominent pathological characteristics of atherosclerotic CVD, Qing-Xin-Jie-Yu Granule (QXJYG) is a Chinese traditional decoction that has been clinically proven to be effective for patients with CVD. However, the underlying mechanisms have not been completely elucidated. PURPOSE: To investigate the protective effects of QXJYG against AS and its potential mechanisms. METHODS: QXJYG was orally administered at doses of 1.664 and 4.992 g·kg-1·d-1 in a high-fat diet (HFD)-induced AS model using ApoE-/- mice. Histopathological and immunohistochemical analyses, ELISA, untargeted and targeted metabolomics analysis, 16S rRNA analysis, and RT-qPCR were performed to identify the therapeutic effects and mechanisms of QXJYG in treating HFD-induced AS. RESULTS: QXJYG retarded HFD-induced weight gain and reduced the increased serum levels of total cholesterol, triglycerides, and low-density lipoprotein-cholesterol, whereas high-dose QXJYG increased the serum level of high-density lipoprotein-cholesterol in HFD-fed ApoE-/- mice. Meanwhile, QXJYG reduced the serum levels, as well as aortas mRNA levels of the inflammatory cytokines, IL-1ß and IL-6, which indicates that QXJYG is effective against metaflammation. Mechanistically, QXJYG reshaped the gut microbiota and its associated bile acids (BAs) metabolomic phenotype, partly by increasing the levels of BA synthesis enzymes, hepatic CYP7A1, and CYP27A1, while decreasing ileal FGF15 and ß-Klotho mRNA expression, favoring facilitated de novo BAs synthesis and thereby driving cholesterol catabolic excretion. CONCLUSION: Our findings indicate that QXJYG is effective against HFD-triggered chronic inflammation, and contributes to the alleviation of AS development, and the antiatherogenic properties of QXJYG may be partly due to the remodeling of the gut microbiota and BA metabolism. Although the results are encouraging, further clinical studies of anti-AS herbal medicines are required to elucidate the full potential of the gut microbiota and BA metabolism.

Adjuvant Effects of Health Education of Chinese Medicine for Chronic Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To evaluate the adjuvant effects of health education of Chinese medicine (HECM) for patients with three types of common noncommunicable diseases (NCD-hypertension, diabetes, and coronary heart disease (CHD)). METHODS: The protocol of this review was registered in the PROSPERO website (CRD42017058325). Six databases were searched till Sep. 30, 2019. Randomized controlled trials (RCTs) comparing HECM plus conventional therapy with conventional therapy were retrieved. Participants were diagnosed as one of the 3 above NCDs. HECM is regarded as lectures and classes about diet therapy, exercise therapy, emotion balance, and other knowledge according to Chinese medicine theory. The control rate of the disease was defined as a primary outcome in this review. Outcomes were synthesized using meta-analyses where reporting was sufficiently homogeneous or alternatively synthesized in a systematic review. RESULTS: In total, 12 trials with 1142 patients were included in this review. Since all the trials may have unclear or high risk of bias, only low quality evidence could be found for supporting the adjunctive effect of HECM in treating hypertension, diabetes, and CHD, to reduce the control rate (risk ratio -1.58), the blood pressure level (mean difference -9.38 mmHg), the fasting plasma glucose level (mean difference -1.26 mmol/L), and the symptoms of angina. CONCLUSION: The adjunctive effect of HECM on increasing the control rate of hypertension, improving the symptoms of diabetes and CHD, was only supported by low-quality evidence in this review. More rigorous trials with larger sample sizes and higher quality are warranted to provide a high quality of evidence.

Expecting the holistic regulation from Chinese medicine based on the "solar system" hypothesis of ischemic heart disease.

Stenosis of the coronary artery has been considered as an essential component of ischemic heart disease (IHD). Consequently, revascularization [e.g., percutaneous coronary intervention (PCI) and coronary artery bypass] has been the primary therapeutic approach to IHD. Such strategy has indeed revolutionized the management of IHD patients. However, not all patients with myocardial ischemia have visible coronary stenosis. Moreover, cardiovascular events occur in nearly 20% patients with stable coronary artery disease who have undergone PCI. The recently proposed "solar system" hypothesis of IHD postulates that coronary stenosis is only one (albeit important) of its features. Mechanistic contribution and clinical implication of multiple pathophysiological processes beyond coronary stenosis are highlighted in this hypothesis. On the basis of a holistic regulation and individualized medicine, Chinese medicine (CM) has been used in the real-world setting to manage a variety of diseases, including IHD, for more than two thousands years. In this article, we summarize the evidence of CM that supports the "solar system" IHD hypothesis, and argue for a comprehensive approach to IHD. At the theoretical level, the central features of this approach include a holistic view of disease and human subjects, as well as individualized medicine. At the practical level, this approach emphasizes anoxia-tolerance and self-healing.

Systematic review on randomized controlled trials of coronary heart disease complicated with depression treated with Chinese herbal medicines.

OBJECTIVES: This systemic review evaluated the efficacy and safety of Chinese herbal medicines (CHMs) in patients with coronary heart disease (CHD) complicated with depression. METHODS: All databases were retrieved till September 30, 2014. Randomized controlled trials (RCTs) comparing CHMs with placebo or conventional Western medicine were retrieved. Data extraction, analyses and quality assessment were performed according to the Cochrane standards. RevMan 5.3 was used to synthesize the results. RESULTS: Thirteen RCTs enrolling 1,095 patients were included. Subgroup analysis was used to assess data. In reducing the degree of depression, CHMs showed no statistic difference in the 4th week [mean difference (MD)=-1.06; 95% confidence interval (CI)-2.38 to 0.26; n=501; I(2)=73%], but it was associated with a statistically significant difference in the 8th week (MD=-1.00; 95% CI-1.64 to-0.36; n=436; I(2)=48%). Meanwhile, the combination therapy (CHMs together with antidepressants) showed significant statistic differences both in the 4th week (MD=-1.99; 95% CI-3.80 to-0.18; n=90) and in the 8th week (MD=-5.61; 95% CI-6.26 to-4.97; n=242; I(2)=87%). In CHD-related clinical evaluation, 3 trials reported the intervention group was superior to the control group. Four trials showed adverse events in the intervention group was less than that in the control group. CONCLUSIONS: CHMs showed potentially benefits on patients with CHD complicated with depression. Moreover, the effect of CHMs may be similar to or better than antidepressant in certain fields but with less side effects. However, because of small sample size and potential bias of most trials, this result should be interpreted with caution. More rigorous trials with larger sample size and higher quality are warranted to give high quality of evidence to support the use of CHMs for CHD complicated with depression.

[Practical Diagnostic Criterion of Blood Stasis Syndrome: Introduction, Reliability, and Validity].

OBJECTIVE: To introduce practical diagnostic criterion of blood stasis syndrome (BSS), and to evaluate its reliability and validity. METHODS: By referring to three diagnostic criteria of BSS [practical diagnostic criterion of BSS (criterion A), diagnostic criterion of BSS in 1986 (criterion B), Consensus of Integrative Medicine on BSS Diagnosis in 2011 (criterion C)], 712 patients from different departments of Xiyuan Hospital were recruited. The reliability of criterion A and its consistency with the other two criteria were assessed using Kappa coefficient. A Bayesian approach was also employed to assess the sensitivity and specificity of criterion A. RESULTS: According to the consistency check, criterion A presented good consistency when used by different researchers (the diagnostic accordance rate was 91. 96%, Kappa =0. 82, P <0.001). Meanwhile, there was an acceptable diagnostic consistency among the three diagnostic criteria. Bayesian estimation suggested that criterion A had higher sensitivity but similar specificity, as compared with criterion B or criterion C. Compared with criterion B [the median of sensitivity and specificity were 0. 762 (95% Cl: 0. 731 -0. 790) and 0. 902 (95% Cl: 0. 858 -0. 936) respectively, the median of sensitivity and specificity of criterion A were 0. 911 (95% CI: 0. 888 - 0. 930) and 0. 875 (95% CI: 0. 826 - 0. 915) respectively. Estimating the difference between criterion A and B, the median of sensitivity and specificity were 0. 149 (95% CI: 0. 112 -0.184) and -0. 026 (95% CI:-0. 085 -0. 033) respectively. Compared with criterion C [the median of sensitivity and specificity were 0. 831 (95% Cl: 0. 804 -0. 857) and 0. 892 (95% CI: 0. 848 - 0. 926) respectively], the median of sensitivity and specificity of criterion A were 0. 912 (95% CI: 0. 889 -0. 932) and 0. 880 (95%CI: 0. 833 - 0.919) respectively. Estimating the difference between criterion A and C, the median of sensitivity and specificity were 0. 081 (95% CI: 0.047 - 0.114) and -0.011 (95%CI: -0.070 -0.046) respectively. CONCLUSION: Compared with criterion B and C, criterion A not only had better reliability, but also could significantly improve the sensitivity without obviously lowering the specificity.