Oxytocin Attenuates Sympathetic Innervation with Inhibition of Cardiac Mast Cell Degranulation in Rats after Myocardial Infarction.

Sympathetic hyperinnervation is the leading cause of fatal ventricular arrhythmia (VA) after myocardial infarction (MI). Cardiac mast cells cause arrhythmias directly through degranulation. However, the role and mechanism of mast cell degranulation in sympathetic remodeling remain unknown. We investigated the role of oxytocin (OT) in stabilizing cardiac mast cells and improving sympathetic innervation in rats. MI was induced by coronary artery ligation. Western blotting, immunofluorescence, and toluidine staining of mast cells were performed to determine the expression and location of target protein. Mast cells accumulated significantly in peri-infarcted tissues and were present in a degranulated state. They expressed OT receptor (OTR), and OT infusion reduced the number of degranulated cardiac mast cells post-MI. Sympathetic hyperinnervation was attenuated as assessed by immunofluorescence for tyrosine hydroxylase (TH). Seven days post-MI, the arrhythmia score of programmed electrical stimulation was higher in vehicle-treated rats with MI than in rats treated with OT. An in vitro study showed that OT stabilized mast cells via the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Further in vivo studies on OTR-deficient mice showed worsening mast cell degranulation and worsening sympathetic innervation. OT pretreatment inhibited cardiac mast cell degranulation post-MI and prevented sympathetic hyperinnervation, along with mast cell stabilization via the PI3K/Akt pathway. SIGNIFICANCE STATEMENT: This is the first study to elucidate the role and mechanism of oxytocin (OT) in inflammatory-sympathetic communication mediated sympathetic hyperinnervation after myocardial infarction (MI), providing new approaches to prevent fatal arrhythmias.

Protective effect of human epicardial adipose-derived stem cells on myocardial injury driven by poly-lactic acid nanopillar array.

We investigated if poly-lactic acid (PLA) nanopillar array can trigger the differentiation of human epicardial (ADSCs) (heADSCs) into cardiomyocyte-like cells and explored the effects of these cardiomyocyte-like cells on myocardial infarction (MI) in vivo. PLA nanopillar array (200 nm diameter) and plain PLA film (PLA planar) induced heADSCs were marked with carboxyfluorescein. After 7 days, the expressions of myocardiocyte-specific genes were significantly enhanced in cells seeded on PLA nanopillar array compared with that on PLA planar, especially CACNA1C, KCNH2, and MYL2 genes (p < 0.05). However, the expressions of cardiac troponin T (cTNT), KCNQ1, and KCNA5 were lower than those in PLA planar-induced heADSCs (p < 0.05), whereas GATA4 tended to increase with time. The cells with positively stained α-actinin and cTNT were elevated in heADSCs induced by PLA nanopillar array compared with those induced by PLA planar only (p < 0.05). In vivo experiments showed that cardiac function was improved after injecting PLA-nanopillar array-induced heADSCs into the ischemic heart (p < 0.05, compared with PLA planar + MI group). Furthermore, tyrosine hydroxylase density was significantly lower (p < 0.05). PLA nanopillar array directly drives the differentiation of heADSCs into cardiomyocyte-like cells, and the induced heADSCs exhibit a protective effect on ischemic myocardium by improving cardiac function in MI rats.

Colorimetric and fluorescence dual-mode pH sensor based on nitrogen-doped carbon dots and its diverse applications.

A dual-mode pH sensor based on nitrogen-doped carbon dots (N-CDs) with the source of o-phenylenediamine and tryptophan has been constructed. Under the stimulation of pH, the N-CDs exhibited prominent both color and fluorescence changes, leading to the rarely discovered colorimetric and fluorescent dual-readouts for the evaluation of pH. The mathematic relationship was established between pH and fluorescence intensity of N-CDs, and between pH and the UV-Vis absorbance ratio at 630 nm and 488 nm of N-CDs, respectively, over a quite broad pH range of 2.2 to 12.0. Multiple techniques are used to explore the dual-mode pH-responsive mechanism, and the preliminary explanation is put forward. The experimental results show that the N-CDs have visualized pH sensing applicability for actual samples, including various water samples and HeLa cell. Furthermore, the N-CD ink is developed for successful information encryption and anti-counterfeiting. This work might provide valuable insights into the sensing mechanism of CDs, and the application potential of CDs in broader fields.

Synergistic effects of atorvastatin and rosiglitazone on endothelium protection in rats with dyslipidemia.

BACKGROUND: Endothelial dysfunction is implicated in the initiation and progression of atherosclerosis. Whether atorvastatin combined with rosiglitazone has synergistic effects on endothelial function improvement in the setting of dyslipidemia is unknown. METHODS: Dyslipidemia rat model was produced with high-fat and high-cholesterol diet administration. Thereafter, atorvastatin, rosiglitazone or atorvastatin combined with rosiglitazone were prescribed for 2 weeks. At baseline, 6 weeks of dyslipidemia model production, and 2 weeks of medical intervention, fasting blood was drawn for parameters of interest evaluation. At the end, myocardium was used for 15-deoxy-delta-12,14-PGJ2 (15-d-PGJ2) assessment. RESULTS: Initially, there was no significant difference of parameters between sham and dyslipidemia groups. With 6 weeks' high-fat and high-cholesterol diet administration, as compared to sham group, serum levels of triglyceride (TG), total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) were significantly increased. Additionally, nitric oxide (NO) production was reduced and serum levels of malondialdehyde (MDA), C-reactive protein (CRP) and asymmetric dimethylarginine (ADMA) were profoundly elevated in dyslipidemia group. After 2 weeks' medical intervention, lipid profile was slightly improved in atorvastatin and combined groups as compared to control group. Nevertheless, in comparison to control group, NO production was profoundly increased and serum levels of MDA, CRP and ADMA were significantly decreased with atorvastatin or rosiglitazone therapy. 15-d-PGJ2 expression of myocardium was also significantly elevated with atorvastatin or rosiglitazone treatment. Notably, these effects were further enhanced with combined therapy, suggesting that atorvastatin and rosiglitazone had synergistic effects on endothelial protection, and inflammation and oxidation amelioration. CONCLUSION: Atorvastatin and rosiglitazone therapy had synergistic effects on endothelium protection as well as amelioration of oxidative stress and inflammatory reaction in rats with dyslipidemia.

The protective effect of gamma aminobutyric acid B receptor activation on sympathetic nerve remodeling via the regulation of M2 macrophage polarization after myocardial infarction.

INTRODUCTION & OBJECTIVES: Acute myocardial infarction (AMI) in coronary heart disease is a leading cause of sudden death primarily due to malignant ventricular arrhythmias (VAs). Inflammatory cell infiltration and inflammation-induced overactivation of sympathetic nerves are the major cause of VAs in AMI pathophysiological processes. Type 2 macrophages play an anti-inflammatory role in AMI. Targeting macrophages may be a therapeutic strategy to prevent VAs post AMI. We found that gamma aminobutyric acid (GABA) promotes macrophages polarized to M2 and hypothesized that GABA might exert anti-inflammatory effects by promoting type 2 macrophage polarization in AMI. We aim to characterized GABAB receptor distribution, function, and mechanisms in M2 macrophage polarization and explored the functional aspect of GABAB receptor activation in sympathetic remodeling. RESULTS: Gamma aminobutyric acid B receptors were expressed on macrophage surface both in vitro and in vivo. GABAB receptor agonist baclofen, GABA promoted macrophage switch to M2. While GABAB receptor antagonist CGP52432 blocked a baclofen induced switch to M2 polarization. GABA and baclofen increased M2 macrophage percentage and CGP52432 blocked this process in vivo. Also, IL-10 and TGF-ß1 released by M2 were increased in both AMI and baclofen/AMI group; Serum NE levels were decreased by baclofen. All the above effects were reversed by CGP52432 treatment. Baclofen decreased TH and GAP-43 staining while CGP52432 enhanced their expression post AMI indicating GABAB receptor activation inhibited sympathetic nerve sprouting and activity by reducing NE release. CONCLUSIONS: Gamma aminobutyric acid B receptor activation promoted M2 polarization and protested AMI heart by regulating sympathetic nerve remodeling.

Protein intake from different sources and cognitive decline over 9 years in community-dwelling older adults.

Objectives: To examine the association of protein intake from different sources with cognitive decline. Methods: Our analysis included 3,083 participants aged 55-93 years from the China Health and Nutrition Survey. Cognition was assessed in 1997, 2000, 2004, 2006, and 2015. Diet intake was assessed using weighing methods in combination with 24-h dietary recalls for three consecutive days at each survey. Results: Participants consumed 13.94% of energy intake from total protein, with 11.47 and 2.47% from plant and animal sources, respectively. During a follow-up of 9 years, participants in quintile 5 of plant protein intake (% energy) had a higher risk [odds ratio (95% CI): 3.03 (1.22-7.53)] of cognitive decline compared with those in quintile 1. Higher animal protein intake (% total protein) was associated with a lower risk of cognitive decline [odds ratio (95% CI) for quintile 5 vs. quintile 1: 0.22 (0.07-0.71)]. Grains (plant source) protein intake was inversely but fish/shrimp and poultry (animal source) protein intake were positively associated with change in cognitive Z-score. Conclusion: Increasing animal protein consumption in a population with plant dominant diets may help to prevent cognitive decline.

MiR-873-5p inhibits cell migration, invasion and epithelial-mesenchymal transition in colorectal cancer via targeting ZEB1.

Recent studies have demonstrated that dysregulation of mircoRNAs (miRNAs) greatly affected biological processes of human cancers, including colorectal cancer. As a member of miRNAs family, miR-873-5p has been proved to be a tumor suppressor in some human cancers. Here, we aim to investigate the effects of miR-873-5p on the migration, invasion and epithelial-mesenchymal transition (EMT) of colorectal cancer cells. The low expression of miR-873-5p in colorectal cancer cells was identified by conducting qRT-PCR analysis. Gain of function assays were designed and conducted to demonstrate the specific function of miR-873-5p overexpression in colorectal cancer progression. Transwell assay and western blot assay were conducted and revealed that miR-873-5p inhibited cell migration, invasion and EMT formation. To find the downstream molecular mechanism of miR-873-5p, mechanism assays were designed and performed to find the downstream target of miR-873-5p. ZEB1 (Zinc finger E-box-binding homeobox 1) was certified to be the target of miR-873-5p through bioinformatics analysis, luciferase activity assay and pull-down assay. Finally, rescue assays were carried out to demonstrate the effects of miR-873-5p-ZEB1 axis on the migration, invasion and EMT process of colorectal cancer cells. In conclusion, we confirmed that miR-873-5p suppressed cell migration, invasion and EMT in colorectal cancer via targeting ZEB1.