Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis

Homocysteine (Hcy) is an intermediate amino acid formed during the conversion from methionine to cysteine. When the fasting plasma Hcy level is higher than 15 μmol/L, it is considered as hyperhomocysteinemia (HHcy). The vascular endothelium is an important barrier to vascular homeostasis, and its impairment is the initiation of atherosclerosis (AS). HHcy is an important risk factor for AS, which can promote the development of AS and the occurrence of cardiovascular events, and Hcy damage to the endothelium is considered to play a very important role. However, the mechanism by which Hcy damages the endothelium is still not fully understood. This review summarizes the mechanism of Hcy-induced endothelial injury and the treatment methods to alleviate the Hcy induced endothelial dysfunction, in order to provide new thoughts for the diagnosis and treatment of Hcy-induced endothelial injury and subsequent AS-related diseases

MiR-206 may regulate mitochondrial ROS contribute to the progression of Myocardial infarction via TREM1

Abstract Myocardial infarction (MI) is a leading cause of mortality. To better understand its molecular and cellular mechanisms, we used bioinformatic tools and molecular experiments to explore the pathogenesis and prognostic markers. Differential gene expression analysis was conducted using GSE60993 and GSE66360 datasets. Hub genes were identified through pathway enrichment analysis and PPI network construction, and four hub genes (AQP9, MMP9, FPR1, and TREM1) were evaluated for their predictive performance using AUC and qRT-PCR. miR-206 was identified as a potential regulator of TREM1. Finally, miR-206 was found to induce EC senescence and ER stress through upregulating mitochondrial ROS levels via TREM1. These findings may contribute to understanding the pathogenesis of MI and identifying potential prognostic markers

miR-125b acts as anti-fibrotic therapeutic target through regulating Gli3 in vivo and in vitro

Introduction and objectives: Liver fibrosis is a major characteristic of most chronic liver diseases which leads to accumulation of extracellular matrix (ECM) proteins. Hedgehog (Hh) pathway activated by Gli genes participated in the pathogenesis of liver fibrosis. However, the regulatory role of miR-125b in liver fibrosis via targeting Gli genes remains unknown. Materials and methods: RT-qPCR and western blot were employed to the expression levels of mRNA and protein, respectively. The fibrosis level of liver tissue was determined by Masson's trichrome staining. The interaction between miR-125b and Gli3 was tested by luciferase reporter assay. In addition, LX2 cells were activated and CCl4-induced rat model was used in this study. Results: miR-125b was significantly declined in serum samples of the clinical liver fibrosis patient, activated LX2 cells and the liver tissues of the CCl4-induced rat model. Furthermore, in cellular level, the alpha-smooth muscle actin (α-SMA) and Albumin expressions were ascending and descending in LX2 cells, respectively, with the decline of miR-125b. However, when transfecting with miR-125b mimic, the expressions of α-SMA and Albumin was reversed and Gli3 expression was notably repressed in LX2 cells. The target interaction between miR-125b and Gli3 was determined by dual-luciferase assays. It was further discovered that the changes of α-SMA, Albumin, and Gli3 were similar to the expression trend in LX2 cells with miR-125b mimic transfection. Conclusion: These results suggested that miR-125b might be protective against liver fibrosis via regulating Gli3 and it might be a promising target in the development of novel therapies to treat pathological fibrotic disorders

Additional file 3 of MiR-206 may regulate mitochondrial ROS contribute to the progression of Myocardial infarction via TREM1

Additional file 3: Supplementary Figure 1. PCA plot of samples in different groups. Supplementary Figure 2. The original Gels of Fig. 5I were presented. Supplementary Figure 3. The original Gels of Fig. 5N and O were presented

Additional file 1 of MiR-206 may regulate mitochondrial ROS contribute to the progression of Myocardial infarction via TREM1

Additional file 1. Table S1. qPCR primers used in this study

Additional file 2 of MiR-206 may regulate mitochondrial ROS contribute to the progression of Myocardial infarction via TREM1

Additional file 2. Table S2. The information of 10 hub genes identified in this study

Refined Baohe formula protects against 5-fluorouracil-induced intestinal mucositis by modulating AKT pathway in CT-26 tumor-bearing mice

Background: 5-Fluorouracil (5-FU) is one of the most commonly prescribed anticancer agents. However, intestinal mucositis is a well-known adverse event, which limits its therapeutic use. Refined Baohe formula (RBF) is derived from Baohe Pills with a potent gastrointestinal protective effect. However, the effects of RBF on 5-FU-induced intestinal mucositis remain unknown. Thus, this study investigated the effects and mechanism of RBF on 5-FU-induced intestinal mucositis in a CT-26 xenograft mice colorectal cancer (CRC) model. Methods: The composition of the RBF preparation was analyzed by high-pressure liquid chromatography. CT-26 cells bearing mice were intraperitoneally administered 150 mg/kg of 5-FU on day 1 to construct a 5-FU-induced intestinal injury model. Mice in the 5-FU + RBF group were intragastrically administrated with RBF (12.4 g/kg) for 4 days. Tumor volume and weight were determined, body weight and diarrhea scores were monitored, leukocytes were calculated, and hematoxylin-eosin staining, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick end labeling were performed to investigate the therapeutic efficiency and underlying mechanisms of RBF on 5-FU-induced intestinal mucositis mice. Results: RBF didn`t affect the effect of tumor suppression, while attenuated diarrhea associated with 5-FU-induced intestinal mucositis and significantly reduced leucocyte toxicity. Additionally, RBF significantly promoted cell proliferation and inhibited cell apoptosis, and up-regulated CDK4, c-Myc, and B-cell lymphoma-2 expression, while down-regulated Bax expression, as well as enhanced both p-AKT and AKT expression in intestinal crypts of 5-FU-treated mice. Conclusions: RBF attenuated 5-FU-induced intestinal mucositis by inhibiting apoptosis and promoting cell proliferation by modulating the AKT pathway and its downstream effectors in a CT-26 xenograft mouse CRC model

Qingda granule attenuates cardiac fibrosis via suppression of the TGF-β1/Smad2/3 signaling pathway in vitro and in vivo

Cardiac fibrosis plays an important role in hypertension-related contractile dysfunction and heart failure. Qingda granule (QDG), derived from the Qingxuan Jiangya decoction, has been used clinically for more than 60 years to treat hypertension. However, the effect of QDG on hypertensive cardiac fibrosis remains largely unknown. The objective of this study was to investigate the effect of QDG on cardiac fibrosis and explore the underlying mechanism in vivo and in vitro. For in vivo experiments, 30 male spontaneously hypertensive rats were randomly divided into groups that received no QDG or one of three doses (0.45, 0.9 or 1.8 g/kg/day). Positive-control animals received valsartan (VAL, 7.2 mg/kg/day). Treatments were administered by gavage for 10 weeks. All three doses of QDG and VAL led to significantly lower blood pressure than in SHR animals. Besides, all three doses of QDG and VAL attenuated pathological changes in SHR animals. However, only intermediate, high concentrations of QDG and VAL led to significantly lower left ventricle ejection fraction and left ventricle fractional shortening than in SHR animals. Therefore, the minimum and effective QDG dose (intermediate concentration of QDG) was selected for subsequent animal experiments in this study. Our results showed that intermediate concentration of QDG also significantly mitigated the increases in levels of α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), collagen III, transforming growth factor-β1 (TGF-β1) and in the ratio of phospho-Smad2/3 to total Smad2/3 protein in cardiac tissue, based on immunohistochemistry, Western blotting, and Masson staining. For in vitro experiments, primary cardiac fibroblasts were stimulated with 100 nM angiotensin II in the presence or absence of QDG. And we tested different concentrations of QDG (3.125, 6.25, 12.5, 25, 50 μg/mL) in the cell viability experiment. Our results showed that 3.125, 6.25 and 12.5 μg/mL of QDG treatment for 24 h didn’t affect the cell viability of cardiac fibroblasts. Consistently, QDG at 6.25 or 12.5 μg/mL significantly reduced cell viability and down-regulated α-SMA in primary cardiac fibroblasts were stimulated with 100 nM angiotensin II. Therefore, QDG at 12.5 μg/mL was chosen for the following cell experiment. Our results showed that QDG at 12.5 μg/mL alleviated the increase of PCNA, collagen Ⅲ, TGF-β1 expression, and the ratio of phospho-Smad2/3 to total Smad2/3 protein. Our studies in vitro and in vivo suggest that QDG reduces blood pressure and cardiac fibrosis as well as protecting cardiac function, and that it exerts these effects in part by suppressing TGF-β1/Smad2/3 signaling

Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese

Gout is one of the most common types of inflammatory arthritis, caused by the deposition of monosodium urate crystals in and around the joints. Previous genome-wide association studies (GWASs) have identified many genetic loci associated with raised serum urate concentrations. However, hyperuricemia alone is not sufficient for the development of gout arthritis. Here we conduct a multistage GWAS in Han Chinese using 4,275 male gout patients and 6,272 normal male controls (1,255 cases and 1,848 controls were genome-wide genotyped), with an additional 1,644 hyperuricemic controls. We discover three new risk loci, 17q23.2 (rs11653176, P=1.36 × 10(-13), BCAS3), 9p24.2 (rs12236871, P=1.48 × 10(-10), RFX3) and 11p15.5 (rs179785, P=1.28 × 10(-8), KCNQ1), which contain inflammatory candidate genes. Our results suggest that these loci are most likely related to the progression from hyperuricemia to inflammatory gout, which will provide new insights into the pathogenesis of gout arthritis