The interaction of Synapsin 2a and Synaptogyrin-3 regulates fear extinction in mice.

The mechanisms behind a lack of efficient fear extinction in some individuals are unclear. Here, by employing a principal components analysis-based approach, we differentiated the mice into extinction-resistant and susceptible groups. We determined that elevated synapsin 2a (Syn2a) in the infralimbic cortex (IL) to basolateral amygdala (BLA) circuit disrupted presynaptic orchestration, leading to an excitatory/inhibitory imbalance in the BLA region and causing extinction resistance. Overexpression or silencing of Syn2a levels in IL neurons replicated or alleviated behavioral, electrophysiological, and biochemical phenotypes in resistant mice. We further identified that the proline-rich domain H in the C-terminus of Syn2a was indispensable for the interaction with synaptogyrin-3 (Syngr3) and demonstrated that disrupting this interaction restored extinction impairments. Molecular docking revealed that ritonavir, an FDA-approved HIV drug, could disrupt Syn2a-Syngr3 binding and rescue fear extinction behavior in Syn2a-elevated mice. In summary, the aberrant elevation of Syn2a expression and its interaction with Syngr3 at the presynaptic site were crucial in fear extinction resistance, suggesting a potential therapeutic avenue for related disorders.

Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington's disease.

Huntington's disease (HD) is caused by Huntingtin (Htt) gene mutation resulting in the loss of striatal GABAergic neurons and motor functional deficits. We report here an in vivo cell conversion technology to reprogram striatal astrocytes into GABAergic neurons in both R6/2 and YAC128 HD mouse models through AAV-mediated ectopic expression of NeuroD1 and Dlx2 transcription factors. We found that the astrocyte-to-neuron (AtN) conversion rate reached 80% in the striatum and >50% of the converted neurons were DARPP32+ medium spiny neurons. The striatal astrocyte-converted neurons showed action potentials and synaptic events, and projected their axons to the targeted globus pallidus and substantia nigra in a time-dependent manner. Behavioral analyses found that NeuroD1 and Dlx2-treated R6/2 mice showed a significant extension of life span and improvement of motor functions. This study demonstrates that in vivo AtN conversion may be a disease-modifying gene therapy to treat HD and other neurodegenerative disorders.

Negative Association of Circulating MicroRNA-126 with High-sensitive C-reactive Protein and Vascular Cell Adhesion Molecule-1 in Patients with Coronary Artery Disease Following Percutaneous Coronary Intervention.

BACKGROUND: Percutaneous coronary intervention (PCI) causes endothelial damage, resulting in an inflammatory response with elevation of markers such as high-sensitive C-reactive protein (hs-CRP) and vascular cell adhesion molecule-1 (VCAM-1), which are associated with restenosis after PCI. Evidence suggests that microRNA-126 (miR-126) plays an important role in vascular inflammation, but its correlation with PCI-mediated inflammation has not been investigated. In this study, we investigated the effect of PCI on circulating miR-126 and inflammation markers such as hs-CRP and VCAM-1. METHODS: We enrolled 130 patients with coronary artery disease (CAD) in the Second Hospital of Jilin University from October 2015 to December 2015. Among them, 82 patients with CAD, defined as at least one major epicardial vessel with >70% stenosis who planned to undergo PCI, were divided into acute coronary syndrome (ACS) group (46 patients) and stable angina (SA) group (36 patients). Forty-eight patients confirmed by coronary angiography without PCI were used as controls. The plasmas of all patients were collected prior to PCI and at 30 min, 24 h, and 72 h after PCI. The plasma VCAM-1 and hs-CRP were detected by enzyme-linked immunosorbent assay, and the miR-126 was evaluated by quantitative reverse transcription-polymerase chain reaction. RESULTS: Plasma concentrations of hs-CRP and VCAM-1 in patients with either ACS (n = 46) or SA (n = 36) were significantly higher than in controls (n = 48) (P < 0.01) prior to PCI, and increased further at 24 h and 72 h after PCI, compared with prior PCI. Moreover, VCAM-1 was positively correlated with balloon time and pressure. In contrast, the plasma concentration of miR-126 was significantly lower in patients with CAD than in controls, and further decreased with time post-PCI. A negative correlation was observed between miR-126 and hs-CRP and VCAM-1 at 72 h after PCI. CONCLUSION: There was a negative correlation of miR-126 with the PCI-induced markers of inflammation such as hs-CRP and VCAM-1.

Diagnostic Value of Serum YKL-40 Level for Coronary Artery Disease: A Meta-Analysis.

OBJECTIVE: This meta-analysis aimed to identify the value of serum YKL-40 level for the diagnosis of coronary artery disease (CAD). METHODS: Through searching the following electronic databases: the Cochrane Library Database (Issue 12, 2013), Web of Science (1945 ∼ 2013), PubMed (1966 ∼ 2013), CINAHL (1982 ∼ 2013), EMBASE (1980 ∼ 2013), and the Chinese Biomedical Database (CBM; 1982 ∼ 2013), related articles were determined without any language restrictions. STATA statistical software (Version 12.0, Stata Corporation, College Station, TX) was chosen to deal with statistical data. Standard mean difference (SMD) and its corresponding 95% confidence interval (95% CI) were calculated. RESULTS: Eleven clinical case-control studies that recruited 1,175 CAD patients and 1,261 healthy controls were selected for statistical analysis. The main findings of our meta-analysis showed that serum YKL-40 level in CAD patients was significantly higher than that in control subjects (SMD = 2.79, 95% CI = 1.73 ∼ 3.85, P < 0.001). Ethnicity-stratified analysis indicated a higher serum YKL-40 level in CAD patients than control subjects among China, Korea, and Denmark populations (China: SMD = 2.97, 95% CI = 1.21 ∼ 4.74, P = 0.001; Korea: SMD = 0.66, 95% CI = 0.17 ∼ 1.15, P = 0.008; Denmark: SMD = 1.85, 95% CI = 1.42 ∼ 2.29, P < 0.001; respectively), but not in Turkey (SMD = 4.52, 95% CI = -2.87 ∼ 11.91, P = 0.231). CONCLUSION: The present meta-analysis suggests that an elevated serum YKL-40 level may be used as a promising diagnostic tool for early identification of CAD.

The protective effect of microRNA-320 on left ventricular remodeling after myocardial ischemia-reperfusion injury in the rat model.

The primary objective of this study investigated the role of microRNA-320 (miR-320) on left ventricular remodeling in the rat model of myocardial ischemia-reperfusion (I/R) injury, and we intended to explore the myocardial mechanism of miR-320-mediated myocardium protection. We collected 120 male Wistar rats (240-280 g) in this study and then randomly divided them into three groups: (1) sham surgery group (sham group: n=40); (2) ischemia-reperfusion model group (I/R group: n=40); and (3) I/R model with antagomir-320 group (I/R+antagomir-320 group: n=40). Value changes of heart function in transesophageal echocardiography were recorded at various time points (day 1, day 3, day 7, day 15 and day 30) after surgery in each group. Myocardial sections were stained with hematoxylin and eosin (H&E) and examined with optical microscope. The degree of myocardial fibrosis was assessed by Sirius Red staining. Terminal dUTP nick end-labeling (TUNEL) and qRT-PCR methods were used to measure the apoptosis rate and to determine the miR-320 expression levels in myocardial tissues. Transesophageal echocardiography showed that the values of left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP) and ±dp/dtmax in the I/R group were obviously lower than those in the sham group, while the left ventricular end-diastolic pressure (LVEDP) value was higher than that in the sham group. The values of LVEF, LVFS, LVSP and ±dp/dtmax showed a gradual decrease in the I/R group, while the LVEDP value showed an up tendency along with the extension of reperfusion time. The H&E staining revealed that rat myocardial tissue in the I/R group presented extensive myocardial damage; for the I/R+antagomir-320 group, however, the degree of damage in myocardial cells was obviously better than that of the I/R group. The Sirius Red staining results showed that the degree of myocardial fibrosis in the I/R group was more severe along with the extension of the time of reperfusion. For the I/R+antagomir-320 group, the degree of myocardial fibrosis was less severe than that in the I/R group. Tissues samples in both the sham and I/R+antagomir-320 groups showed a lower apoptosis rate compared to I/R group. The qRT-PCR results indicated that miR-320 expression in the I/R group was significantly higher than that in both the sham and I/R+antagomir-320 groups. The expression level of miR-320 is significantly up-regulated in the rat model of myocardial I/R injury, and it may be implicated in the prevention of myocardial I/R injury-triggered left ventricular remodeling.

Acetyl-L-carnitine attenuates homocysteine-induced Alzheimer-like histopathological and behavioral abnormalities.

Hyperhomocystinemia could induce tau protein hyperphosphorylation, ß-amyloid (Aß) accumulation, and memory deficits as seen in Alzheimer disease (AD), the most common cause of senile dementia with no effective cure currently. To search for possible treatment for AD, we produced a hyperhomocysteinemia model by vena caudalis injection of homocystine (Hcy) for 2 weeks and studied the effects of acetyl-L-carnitine (ALC) in rats. We found that simultaneous supplement of ALC could improve the Hcy-induced memory deficits remarkably, with attenuation of tau hyperphosphorylation and Aß accumulation. Supplement of ALC almost abolished the Hcy-induced tau hyperphosphorylation at multiple AD-related sites. Supplementation of ALC also suppressed the phosphorylation of ß-amyloid precursor proteins (APP), which may underlie the reduction of Aß. Our data suggest that ALC could be a promising candidate for arresting Hcy-induced AD-like pathological and behavioral impairments.

The impact of silica gel pore and particle sizes on HPLC column efficiency and resolution for an immobilized, cyclodextrin-based, chiral stationary phase.

In this study, the CD derivative, mono (6(A)-azido-6(A)-deoxy)-per(p-chlorophenylcarbamonylated) ß-CD was chemically immobilized onto the surface of an amino-functionalized silica gel with different pore (100, 300, and 500Å) and particle (3, 5, and 10 µm) sizes to obtain novel chiral stationary phases. The impact of pore and particle size on the amount of immobilized Ph-ß-CD, column performance, and enantioselectivity was investigated by evaluating the separation of a variety of racemates in both the normal- and the reversed-phase modes. Experimental results revealed that the retention factor and resolution of racemates generally decreased with increasing pore size; the column prepared with the smallest (3 µm) silica gel particle size gave the best column performance and enantioselectivity in both the normal- and the reversed-phase modes.