Uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and ␥-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis-(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [ 3 H]MK-801 with a K i value of 0.27 M, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced longterm potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation.Neurodegenerative disorders are among the leading cause of death in the elderly, and this medical problem is expected to become more serious as the population continues to age. N-Methyl-D-aspartate (NMDA)3 receptor overactivation-induced excitotoxicity is clearly implicated in a variety of acute and chronic neurodegenerative disorders (1-4). Thus, the NMDA receptor has been considered an attractive therapeutic target for the development of neuroprotectants. However, the NMDA receptor, as the major excitatory neurotransmitter receptor in the central nervous system, mediates many important physiological processes, such as excitatory neurotransmission, synaptic plasticity, learning and memory, and cell survival (5-8). The therapeutic potential of many NMDA receptor antagonists, therefore, was limited, and they failed in clinical trials because of their psychotropic side effects and memoryimpairing effects resulting from the blockade of NMDA receptor-mediated physiological activities (9, 10). Clinically well tolerated and effective NMDA receptor antagonists for the therapy of neurodegenerative disorders have been pursued over the past several decades.The strategies applie...

For the first time, we identified 15 cases of Candida auris in Shenyang, China, and then performed a risk factor assessment for these patients compared with 30 control subjects who were hospitalized in the same ward during the same period of time as the infected patients. We found that diarrhea, gastrointestinal decompression, infection, or colonization with other Candida isolates (especially Candida albicans) and tetracycline antibiotics were all risk factors for C. auris infection or colonization. Diarrhea and tetracycline antibiotics were independent risk factors. We suggest clinicians pay special attention to the emergence of multidrug-resistant C. auris infections or colonization.

Background Carbapenem-resistant Enterobacter cloacae complex (CREC) is a new emerging threat to global public health. The objective of the study was to investigate the clinical characteristics and molecular epidemiology of CREC infections in the medical center of northeast China. Methods Twenty-nine patients were infected/colonized with CREC during a ten-year period (2010–2019) by WHONET analysis. Antibiotic susceptibilities were tested with VITEK 2 and micro broth dilution method (for polymyxin B and tigecycline). Carbapenemase encoding genes, β-lactamase genes, and seven housekeeping genes for MLST were amplified and sequenced for 18 cryopreserved CREC isolates. Maximum likelihood phylogenetic tree was built with the concentrated sequences to show the relatedness between the 18 isolates. Results There was a rapid increase in CREC detection rate during the ten-year period, reaching 8.11% in 2018 and 6.48% in 2019. The resistance rate of CREC isolates to imipenem and meropenem were 100.0 and 77.8%, however, they showed high sensitivity to tigecycline, polymyxin B and amikacin. The 30-day crude mortality of CREC infection was 17.4%, indicating that it may be a low-virulence bacterium. Furthermore, molecular epidemiology revealed that ST93 was the predominant sequence type followed by ST171 and ST145, with NDM-1 and NDM-5 as the main carbapenemase-encoding genes. Moreover, E. hormaechei subsp. steigerwaltii and E. hormaechei subsp. oharae were the main species, which showed different resistance patterns. Conclusion Rising detection rate of CREC was observed in a tertiary hospital, which showed heterogeneity in drug resistance patterns, resistance genes, and MLST types. Effective infection prevention and control measures should be taken to reduce the spread of CREC.

Purpose. Hepatocellular carcinoma (HCC) accounts for approximately ninety percent of primary liver cancer. This study attempted to investigate the effects of the long noncoding RNA MIR100HG (MIR100HG) in HCC and the underlying molecular mechanism. Materials and Methods. qRT-PCR was implemented to analyze the expression of MIR100HG, microRNA-146b-5p (miR-146b-5p), and Chromobox 6 (CBX6). The correlation between MIR100HG and clinicopathological features of HCC patients was assessed. Additionally, the effects of MIR100HG knockdown on HCC cell viability, migration, and invasion were explored. The interactions among MIR100HG, miR-146b-5p, and CBX6 were confirmed. Furthermore, rescue experiments were conducted to investigate whether MIR100HG knockdown modulates HCC cell behaviors through modulating the miR-146b-5p/CBX6 axis. Results. The expression of MIR100HG and CBX6 was enhanced, while miR-146b-5p was inhibited in HCC cells. High MIR100HG expression was positively associated with the TNM tumor stage and Edmondson-Steiner grading in HCC patients. MIR100HG knockdown considerably reduced the HCC cell viability, migration, and invasion. In addition, MIR100HG directly targeted miR-146b-5p, and miR-146b-5p directly targeted CBX6 in HCC cells. Moreover, miR-146b-5p suppression or CBX6 elevation evidently rescued the suppressed viability, migration, and invasion of HCC cells caused by MIR100HG knockdown. Conclusions. Knockdown of MIR100HG inhibited the viability, migration, and invasion of HCC cells by targeting the miR-146b-5p/CBX6 axis, offering a potential therapeutic target for HCC therapy.