GLP-1 receptor agonist liraglutide protects cardiomyocytes from IL-1ß-induced metabolic disturbance and mitochondrial dysfunction.

Cardiac inflammation plays a critical role in the development of heart failure. Inflammation-induced oxidative stress contributes to aberrant cardiac metabolism and mitochondrial function. GLP-1 receptor agonists (GLP-1 RAs) are a type of blood glucose-lowering agent typically used in the treatment of type 2 diabetes. Recent studies have convincingly shown that GLP-1 RAs possess beneficial effects in diabetes-related cardiovascular complications. Liraglutide is a commonly used long-acting agonist that shows promising cardioprotective benefits. In this study, we investigated the protective role of Liraglutide in cultured cardiomyocytes. We found that HL-1 cardiomyocytes moderately expressed the GLP-1 receptor, and co-treatment with Liraglutide ameliorated IL-1ß-induced cellular ROS production and NADPH oxidase (NOX)-4 expression. Furthermore, we found that Liraglutide protected cardiomyocytes from IL-1ß-induced decreased mitochondrial membrane potential and reduced ATP production. Seahorse analysis revealed that Liraglutide mitigated IL-1ß-induced reduced basal and maximum respiration rates as well as spare respiration capacity. Additionally, we found that Liraglutide alleviated IL-1ß-induced aberrant triglyceride accumulation and adiponectin secretion. Mechanistically, we showed that Liraglutide ameliorated IL-1ß-induced phosphorylation of AMPK and ACC as well as the reduction in PGC-1α, CPT-1, and DGAT1. Finally, through the study we demonstrated that the blockage of AMPK activity by Compound C abolished the ameliorative effect of Liraglutide on IL-1ß-induced repressed ATP production and triglyceride accumulation, indicating that the action of Liraglutide was dependent on AMPK activation. In conclusion, this study revealed the molecular mechanism of Liraglutide protection in cultured cardiomyocytes. The GLP-1 RA Liraglutide could have therapeutic implications by modulating cardiac inflammation.

Butyrate mitigates TNF-α-induced attachment of monocytes to endothelial cells.

A major cause of late-life health complications is the cardiovascular disease known as atherosclerosis. The process of atherogenesis is marked by endothelial cell dysfunction, the development of atherogenic lesions, and plaque buildup on the intima of the arterial endothelium. This process is fueled primarily by the adhesion of monocytes to endothelial cells via the actions of the cellular adhesion molecules VCAM-1 and E-selectin. When expressed at their basal levels, these molecules are vital to various cellular processes, but when in a state of overproduction, they drive the progression of atherosclerosis by recruiting monocytes to roll along and adhere to the endothelium. TNF-α is theorized to play a causal role in the development of atherosclerosis, but the exact mechanism remains poorly understood. This cytokine is known to upregulate various factors associated with inflammation and oxidative stress, both of which greatly contribute to endothelial dysfunction and atherogenesis. In the present study, we aimed to elucidate the effect of butyrate on these atherogenic processes. Previously not known to have atheroprotective effects, this natural compound shows promise as a treatment for atherosclerosis. In the present study, we found butyrate to exert various anti-inflammatory and downstream regulatory effects. Namely, butyrate ameliorated the overproduction of adhesion molecules, including VCAM-1 and E-selectin, reduced oxidative stress by reducing the levels of ROS and 4-HNE, and suppressed inflammation via inhibition of MCP-1 and IL-8. Additionally, butyrate rescued the reduced expression of the protective factor KLF2, which was mediated through the ERK5 pathway. Thus, butyrate may serve as a promising treatment against atherosclerosis.

The protective effects of GLP-1 receptor agonist lixisenatide on oxygen-glucose deprivation/reperfusion (OGD/R)-induced deregulation of endothelial tube formation.

Acute myocardial infarction (AMI) is a complication of atherosclerosis that takes place in coronary arteries. Cardiac endothelial cells play a significant role in the pathogenesis of AMI. Oxygen-glucose deprivation/reperfusion (OGD/R) is widely used as a model to simulate AMI in vitro. Recently, antidiabetic GLP-1 receptor agonists have been shown to exert pleiotropic effects that modulate cardiovascular complications. In this study, we investigated the vascular effect of lixisenatide. We show that pre-treatment of endothelial cells with lixisenatide protected them from OGD/R-induced cytotoxicity and improved their viability. Pre-treatment with lixisenatide ameliorated OGD/R-induced ROS accumulation and disturbed endothelial tube formation. At the molecular level, lixisenatide mitigated OGD/R-induced reduced eNOS expression and NO production but further promoted the expression of the anti-oxidant regulators Nrf2 and HO-1. Mechanistically, we confirmed that the PI3K/Akt pathway is essential for mediating the effects of lixisenatide, and blockage of PI3K/Akt using the inhibitor LY294002 abolished the ameliorative effect of lixisenatide on ROS production and impaired tube formation. These data indicate that lixisenatide possesses a beneficial effect on the vasculature in a model of ischemia-induced endothelial injury. We conclude that the GLP-1 receptor agonist lixisenatide has pleiotropic properties that can modulate vascular function independent of its anti-glycemic effect.

VWF, CXCL8 and IL6 might be potential druggable genes for acute coronary syndrome (ACS).

OBJECTIVE: Acute coronary syndrome (ACS) is currently a leading cause of morbidity and mortality worldwide. This study aimed to screen critical genes and miRNAs involved in ACS. MATERIALS AND METHODS: Microarray data (access number GSE19339) was downloaded from Gene Expression Omnibus (GEO) database. After data preprocessing, we screened the differentially expressed genes (DEGs) using limma package and subsequently performed enrichment analysis using DAVID tool. The protein-protein interaction (PPI) network and transcription factor (TF)-miRNA-target gene regulatory network were visualized using Cytoscape software. Finally, the drug-gene interactions were predicted using DGIdb database. RESULTS: A total of 425 DEGs were identified in ACS samples compared with healthy control samples. Functional enrichment analysis showed that DEGs were mainly involved in angiogenesis, inflammatory response and PI3K-Akt signaling pathway. IL6 and VEGFA were key nodes in PPI network. In addition, hsa-miR-29, hsa-miR-1, NFIC, NFKB1 and RELA were identified as key factors in TF-miRNA-target gene network. Finally, the prediction results revealed that VWF, CXCL8 and IL6 had higher degree than other genes. CONCLUSION: IL6 and VEGFA might play major roles in ACS progression. Two miRNAs (hsa-miR-29 and hsa-miR-1) and three TFs (NFIC, NFKB1 and RELA) were critical genes involved in pathological process of ACS. VWF, CXCL8 and IL6 might be potential druggable genes for ACS therapy.

miR-223-5p Suppresses Tumor Growth and Metastasis in Non-Small Cell Lung Cancer by Targeting E2F8.

miR-223-5p has been demonstrated to regulate the development and progression of various cancers, such as hepatocellular carcinoma, breast cancer, and gastric carcinoma. However, the role of miR-223-5p in non-small cell lung cancer (NSCLC) requires further investigation. In this study, we found that the expression of miR-223-5p was significantly downregulated in NSCLC tissues and cell lines. Moreover, the expression level of miR-223-5p is negatively correlated with the malignance of NSCLC. We found that overexpression of miR-223-5p remarkably suppressed the proliferation of NSCLC cells in vitro and in vivo. miR-223-5p overexpression also led to reduced migration and invasion in NSCLC cells. Mechanistically, we found that E2F8, a key transcription factor involved in many kinds of biological processes, was a direct target gene of miR-223-5p. Overexpression of miR-223-5p significantly decreased the mRNA and protein levels of E2F8 in NSCLC cells. We also showed that restoration of E2F8 rescued the proliferation, migration, and invasion of miR-223-5p-overexpressing NSCLC cells. Taken together, our findings demonstrated that miR-223-5p suppressed NSCLC progression through targeting E2F8.

Enhanced tendon-bone healing with acidic fibroblast growth factor delivered in collagen in a rabbit anterior cruciate ligament reconstruction model.

BACKGROUND: The objective of the present study was to investigate the effectiveness of acidic fibroblast growth factor delivered in collagen (aFGF/collagen) for promoting tendon-bone interface healing after anterior cruciate ligament (ACL) reconstruction in rabbits. METHODS: ACL reconstructions were performed in the right hind limbs of New Zealand rabbits. Each left long digital extensor tendon was harvested as an autograft, and collagen incorporating different concentrations of aFGF or same amount of collagen alone was applied at the tendon-bone interface after ACL reconstruction. The control group underwent ACL reconstruction only. There were high and low aFGF/collagen groups, collagen alone group, and control group (n = 21 rabbits per group). Histological and biomechanical analyses were performed at 4, 8, and 12 weeks postoperatively to evaluate the effect of aFGF/collagen on tendon-bone interface healing. RESULTS: Results of biomechanical tests showed that at both 8 and 12 weeks postoperatively, the elastic modulus and stiffness in both the high and low aFGF/collagen treatment groups were significantly higher than those in the control group and collagen alone group, with that in the high aFGF/collagen concentration group being the highest. Histological analysis showed that at 8 weeks, tightly organized Sharpey-like fibers were observed in both aFGF/collagen groups with new bone growth into the tendon in the high concentration group. At 12 weeks postoperatively, a fibrocartilage transition zone was observed in the bone tunnels in both aFGF/collagen groups, especially in the high aFGF/collagen group. CONCLUSION: Application of the aFGF/collagen composite could enhance early healing at the tendon-bone interface after ACL reconstruction, especially with the use of a high aFGF/collagen concentration.

Knockdown of Linc00515 Inhibits Multiple Myeloma Autophagy and Chemoresistance by Upregulating miR-140-5p and Downregulating ATG14.

BACKGROUND/AIMS: The purpose of our experiments was to investigate the targeting relationship of linc00515, miR-140-5p and ATG14 and to explore the roles of linc00515, miR-140-5p and ATG14 in autophagy and chemoresistance of melphalan-resistant multiple myeloma cells. METHODS: Plasmids that could interfere with the expression of linc00515 and ATG14 were loaded into myeloma cells, which were cultured with melphalan. MTT assay and flow cytometry analysis were utilized to investigate the effect of linc00515, miR-140-5p and ATG14 on the resistance of myeloma cells. QRT-PCR was used to determine the levels of mRNAs. Western blot was utilized to explore the level of ATG14 and autophagy-related proteins. Dual luciferase assay was utilized to explore the targeting relationship between linc00515, miR-140-5p and ATG14. GFP LC3 fluorescence assay was conducted to study the autophagy of cells. RESULTS: The expression of linc00515 and ATG14 were significantly higher in melphalan-resistant myeloma cells. Knockdown of linc00515 and ATG14 led to decreased autophagy and chemoresistance of melphalan-resistant myeloma cells. The forced expression of miR-140-5p suppressed autophagy and chemoresistance of melphalan-resistant myeloma cells. CONCLUSION: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Association of serum chemerin concentrations with the presence of atrial fibrillation.

Objective Chemerin, a newly discovered adipokine, is correlated with hypertension, diabetes and coronary heart disease. The aim of this study is to investigate the association of serum chemerin concentrations with the presence of atrial fibrillation. Methods Serum chemerin concentrations were determined in 256 patients with atrial fibrillation and 146 healthy subjects. Atrial fibrillation patients were then divided into paroxysmal, persistent and permanent atrial fibrillation. Results Serum chemerin concentrations were significantly higher in atrial fibrillation patients compared with healthy controls. In subgroup studies, patients with permanent atrial fibrillation had higher serum chemerin concentrations than those with persistent and paroxysmal atrial fibrillation. Furthermore, significant higher serum chemerin concentrations were observed in persistent atrial fibrillation patients compared with paroxysmal atrial fibrillation subjects. Serum chemerin concentrations were associated with the presence of atrial fibrillation after logistic regression analysis. Pearson correlation analysis revealed a positive relation of serum chemerin concentrations with body mass index, systolic blood pressure, diastolic blood pressure, triglycerides, low-density lipoprotein cholesterol, blood urea nitrogen, creatinine, C-reactive protein and left atrial diameter. Conclusion Serum chemerin concentrations are associated with the presence of atrial fibrillation and atrial remodelling.

Complete mitochondrial genome sequence of a coronary heart disease model rat strain (Muridae; Rattus).

We sequenced the complete mitochondrial genome sequencing of an important coronary heart disease model inbred rat strain for the first time. The total length of the mitogenome was 16,308 bp with 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes.

Association of IL-6 polymorphisms with chronic obstructive pulmonary disease risk: meta-analysis of genetic association, gene expression and expression quantitative trait locus analysis.

AIM: IL-6 might play an important role in the mechanism of chronic obstructive pulmonary disease (COPD). This study assessed the relationship of rs1800796 and rs1800797 of IL-6 with COPD. MATERIALS & METHODS: We conducted meta-analysis and gene expression analysis using published datasets to examine the associations between IL-6 SNPs and COPD. RESULTS: rs1800796 was significantly associated with COPD, yielding a pooled odds ratio of 0.52 (95% CI: 0.33-0.84; p = 0.007), and showed cis-expression quantitative trait locus associations (p = 0.02148). Differential gene expression analysis found that IL-6 was upregulated in COPD cases compared with controls. The associations of rs1800797 with COPD were not significant. CONCLUSION: The findings showed that rs1800796 was associated with COPD in Europeans and might affect COPD risk through disturbing IL-6 gene expression.

[ARTHROSCOPIC STUDY OF REMNANT-PRESERVED RECONSTRUCTION OF ANTERIOR CRUCIATE LIGAMENT].

OBJECTIVE: To investigate the value of ligament remnant preservation during anterior cruciate ligament (ACL) reconstruction by observing the integrity, the tension, the synovial membrane covering, and the color of the reconstructed ligament under arthroscopy. METHODS: Between January 2011 and December 2013, 122 patients who underwent ACL reconstruction and arthroscopic internal fixation removal at 1 year after reconstruction were included in this study. Of these cases, 61 cases underwent ACL reconstruction using the remnant-preserved technique (preservation group); the other 61 cases underwent ACL reconstruction using non remnant-preserved technique (non preservation group). There was no significant difference in gender, age, injury side, body mass index, type of injury, the time from injury to reconstruction, and the result of KT-2000 examination between 2 groups (P > 0.05). The reconstructed ACL were observed under arthroscopy when internal fixation was removed, and the effectiveness was evaluated according to the criteria of AO Yingfang. RESULTS: In preservation group, the results were excellent in 34 cases, good in 22 cases, fair in 4 cases, and poor in 1 case; and in non preservation group, the results were excellent in 29 cases, good in 20 cases, fair in 10 cases, and poor in 2 cases; and there was no significant difference between 2 groups (Z= -1.320, P=0.187). CONCLUSION: In ACL reconstruction, the remnant-preserved technique is not obviously better than non remnant-preserved technique in the integrity, tension, membrane covering, and color.

Comparison of the operation of arthroscopic tibial inlay and traditional tibial inlay for posterior cruciate ligament reconstruction.

OBJECTIVE: To perform dual-bundle reconstruction of posterior cruciate ligament using full arthroscopic tibial inlay technology with self-designed tibia tunnel drilling system and to compare the effect of arthroscopic tibial inlay versus traditional technique for posterior cruciate ligament reconstruction. MATERIAL AND METHODS: 32 patients were randomly divided into experiment group (improved tibial inlay, n = 17) and control group (traditional tibial inlay, n = 15). Self-designed tibia tunnel drill system was used to produce intraoperative deep-limited bone tunnel. During follow-up, the location of the bone block and the healing situation were checked by knee X-ray and spiral CT scan. Blood loss, operation time and nerve vascular injuries were evaluated. RESULTS: Mean intraoperative blood loss was 123.53 ± 74.05 ml in the improved tibial inlay group compared with 332 ± 114.26 ml in the traditional tibial inlay group (t = 6.12, P < 0.05). Mean operation time was 235.27 ± 58.88 min in the improved tibial inlay group compared with 346.37 ± 59.67 min in the traditional tibial inlay group (t = 5.19, P < 0.05). Posterior drawer test were negative in 15 cases, slight positive in 2 with improved tibial inlay technique compared with 14 negative cases and 2 positive cases of traditional tibial Inlay technique. The X-ray and spiral CT scan showed the location of the bone block were perfect and healed well with the patent who received improved tibial inlay technology after 12 weeks postoperatively. CONCLUSION: Accurate depth-limited bone tunnel can be produced by the tibia tunnel drill system with minor trauma, less bleeding and reducing of nerves or vessels and the recent clinical effects of PCL reconstruction were pretty good.