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Aims: The basolateral amygdala (BLA) plays an integral role in anxiety disorders (such as post traumatic stress disorder) stem from dysregulated fear memory. The excitability of glutamatergic neurons in the BLA correlates with fear memory, and the afterhyperpolarization current (IAHP) mediated by small‐conductance calcium‐activated potassium channel subtype 2 (SK2) dominates the excitability of glutamatergicneurons. This study aimed to explore the effect of MPP2 interacts with SK2 in the excitability of glutamatergic neurons in the BLA and the extinction of conditioned fear in mice. Methods: Fear memory was analyzed via freezing percentage. Western blotting and fluorescence quantitative PCR were used to determine the expression of protein and mRNA respectively. Electrophysiology was employed to measure the excitability of glutamatergic neurons and IAHP. Results: Fear conditioning decreased the levels of synaptic SK2 channels in the BLA, which were restored following fear extinction. Notably, reduced expression of synaptic SK2 channels in the BLA during fear conditioning was caused by the increased activity of protein kinase A (PKA), while increased levels of synaptic SK2 channels in the BLA during fear extinction were mediated by interactions with membrane‐palmitoylated protein 2 (MPP2). Conclusions: Our results revealed that MPP2 interacts with the SK2 channels and rescues the excitability of glutamatergic neurons by increasing the expression of synaptic SK2 channels in the BLA to promote the normalization of anxiety disorders and provide a new direction for the treatment. [ABSTRACT FROM AUTHOR]

Many nanoproteases contain tetravalent metal ions and catalyze peptide‐bond hydrolysis only at high temperature (60 °C). Here, we report a new and effective strategy to explore nanoproteases from nanoparticles containing low valent metal ions. We found that flower‐like CuCoO2 nanoparticles (CuCoO2 NPs) containing low valent Cu+ possessed excellent catalytic activity towards selective cleavage of peptide bonds with hydrophobic residues in bovine serum albumin (BSA) at room temperature. CuCoO2 NPs exhibited excellent stability and had great reusability. CuCoO2 NPs also hydrolyzed heat‐denatured and surfactant‐denatured BSA. Mechanism analysis revealed that the high Lewis acidity of Co3+ and the low valence of Cu+ were both essential for the high protease activity of CuCoO2 NPs. The flower‐like structure of CuCoO2 NPs and the strong nucleophilicity of Cu+‐bound hydroxyl endow them with excellent catalytic performance. The findings open a new way for the design and discovery of high‐efficiency nanoproteases. [ABSTRACT FROM AUTHOR]

Myocardial ischemia‐reperfusion injury (MI/R) leads to the inevitable clinical consequences of myocardial infarction and subsequent heart failure. Trimetazidine (TMZ), an anti‐ischemic agent, exerts protective potential in MI/R but had limited efficacy for some patients. Here we sought to investigate the single and combined application of gentiopicroside (GPS) and TMZ in MI/R. Notably, GPS had little cytotoxicity to cardiomyocytes. GPS attenuated hypoxia/reoxygenation (H/R)‐induced cell death, reactive oxygen species production, lactate dehydrogenase and malondialdehyde releases, and antioxidant stress enzyme superoxide dismutase activity, indicating the protective efficacy of GPS against H/R‐induced oxidative injury. Importantly, GPS enhanced the protective efficacy of TMZ against H/R‐mediated cardiomyocyte injury. Additionally, GPS mitigated the transcription and releases of pro‐inflammatory cytokine interleukin‐6 and tumor necrosis factor‐α in H/R‐treated cardiomyocytes, which were enhanced after co‐treatment with TMZ. Mechanistically, GPS activated the AMP‐activated protein kinase (AMPK) signaling to inhibit H/R‐induced NOD‐like receptor pyrin domain‐containing protein 3 (NLRP3) inflammasome, which was further enhanced after costimulation with TMZ. Importantly, blocking the AMPK signaling reversed the protective roles of GPS and its combination with TMZ in H/R‐induced oxidative insult and inflammation. In vivo, both GPS and TMZ alleviated the abnormal cardiac structure, cardiomyocyte apoptosis, and cardiac dysfunction in MI/R rats, which were further enhanced after administration with GPS and TMZ together. Furthermore, GPS intensified TMZ‐mediated inhibition of oxidative injury, inflammation, and the AMPK/NLRP3 signaling in MI/R rats. Collectively, GPS enhances the protective efficacy of TMZ against MI/R injury through AMPK activation‐mediated inhibition of NLRP3 inflammasome signaling, implying a promising therapeutic agent for the treatment of MI/R. [ABSTRACT FROM AUTHOR]

Objective: Coronary heart disease (CHD) is a disorder resulting from organic and functional coronary artery stenosis (CAS), thus causing reduced oxygenated blood in the heart. miRNAs are useful biomarkers in the diagnosis of atherosclerosis, CHD, and acute coronary syndrome. Vascular endothelial growth factor (VEGF) is closely related to CHD. This study explored the correlation of miR‐296 and VEGF‐B expression levels in peripheral blood with CAS degree in CHD patients. Methods: Totally 220 CHD patients were enrolled and classified into mild‐(71 cases)/moderate‐(81 cases)/severe‐CAS (68 cases) groups, with another 80 healthy cases as controls. The serum miR‐296 and VEGF‐B expression levels were detected using reverse transcription quantitative polymerase chain reaction. The correlation between miR‐296 and CAS‐related indexes was assessed via Pearson analysis. The binding relationship of miR‐296 and VEGF‐B was first predicted and their correlation was further analyzed via the Pearson method. The clinical diagnostic efficacy of miR‐296 or VEGF‐B on CAS degree was evaluated by the receiver operating characteristic curve. Results: Serum miR‐296 was downregulated in CHD patients and was the lowest in patients with severe‐CAS. miR‐296 was negatively‐correlated with high‐sensitivity C‐reactive protein, brain natriuretic peptide, and cardiac troponin I. miR‐296 targeted VEGF‐B. VEGF‐B was upregulated in CHD patients and inversely‐related to miR‐296. Low expression of miR‐296 and high expression of VEGF‐B both had high clinical diagnostic values on CAS degree in CHD patients. miR‐296 combined with VEGF‐B increased the diagnostic value on CAS. Conclusion: Low expression of miR‐296 combined with high expression of its target VEGF‐B predicts CAS degree in CHD patients. [ABSTRACT FROM AUTHOR]

The title compound, 3,5-Dimethyl-pyrazole-1-carbodithioic acid benzyl ester, has been synthesized and structurally characterized by X-ray single crystal diffraction, elemental analysis, IR spectra, and UV-Vis spectrum. The crystal belongs to orthorhombic, space group P212121, with a = 5.3829(15), b = 11.193(3), c = 21.824(6) Å, V = 1315.0(6) Å3, and Z = 4. The molecules are connected via intermolecular C-H···N hydrogen bonds into 1D infinite chains. The crystal structure is consolidated by the intramolecular C-H···S hydrogen bonds. Furthermore, Density functional theory (DFT) calculations of the structure, stabilities, orbital energies, composition characteristics of some frontier molecular orbitals and Mulliken charge distributions of the title compound were performed by means of Gaussian 03W package and taking B3LYP/6-31G(d) basis set. The time-dependent DFT (TD-DFT) calculations have been employed to calculate the electronic spectrum of the title compound, and the UV-Vis spectra has been discussed on this basis. The results show that DFT method at B3LYP/6-31G(d) level can well reproduce the structure of the title compound. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012 [ABSTRACT FROM AUTHOR]