Discovery of novel positive allosteric modulators targeting GluN1/2A NMDARs as anti-stroke therapeutic agents.

Excitotoxicity due to excessive activation of NMDARs is one of the main mechanisms of neuronal death during ischemic stroke. Previous studies have suggested that activation of either synaptic or extrasynaptic GluN2B-containing NMDARs results in neuronal damage, whereas activation of GluN2A-containing NMDARs promotes neuronal survival against ischemic insults. This study applied a systematic in silico, in vitro, and in vivo approach to the discovery of novel and potential GluN1/2A NMDAR positive allosteric modulators (PAMs). Ten compounds were obtained and identified as potential GluN1/2A PAMs by structure-based virtual screening and calcium imaging. The neuroprotective activity of the candidate compounds was demonstrated in vitro. Subsequently, compound 15 (aegeline) was tested further in the model of transient middle cerebral artery occlusion (tMCAO) in vivo, which significantly decreased cerebral infarction. The mechanism by which aegeline exerts its effect on allosteric modulation was revealed using molecular dynamics simulations. Finally, we found that the neuroprotective effect of aegeline was significantly correlated with the enhanced phosphorylation of cAMP response element-binding protein (CREB). Our study discovered the neuroprotective effect of aegeline as a novel PAM targeting GluN1/2A NMDAR, which provides a potential opportunity for the development of therapeutic agents for ischemic stroke.

Effect of Serum Bilirubin Levels on Contrast-induced Acute Kidney Injury: A Systematic Evaluation and Meta-analysis.

Contrast-induced acute kidney injury (CI-AKI) is an important complication following the use of iodinated contrast media. Bilirubin has a protective effect but may also aggravate CI-AKI. The purpose of this systematic review was to assess whether bilirubin is a risk factor for CI-AKI. We searched the databases PubMed, Embase, Web of Science, Cochrane Library, Scopus, Ovid Medline, CNKI (China National Knowledge Infrastructure), VPCS (Vip Paper Check System), Wanfang, and CBM (Chinese BioMedical Literature Database) from the initial date to May 6, 2023. We summarized the results by directly combining the effect-size odds ratio (OR) and 95% confidence interval (CI) and identified sources of heterogeneity through subgroup analysis, sensitivity analysis, and meta-regression analysis. A total of 10 studies (14 data sets) were included: 7 retrospective studies (10 data sets) and 3 prospective studies (4 data sets), involving 12776 participants. The incidence of CI-AKI of 16% (95% CI: 14-19%). Total bilirubin was positively associated with the occurrence of CI-AKI (OR = 1.80; 95% CI: 1.36-2.38). Both low and high bilirubin concentrations were risk factors for CI-AKI. The incidence of CI-AKI was higher in the low bilirubin group than in the high bilirubin group.

Perioperative management and drug selection for sedated/anesthetized patients undergoing MRI examination: A review.

In recent years, magnetic resonance imaging (MRI) technology has become an indispensable imaging tool owing to significant improvements in MRI that have opened up new diagnostic perspectives. Due to the closed environment, long imaging time, and need to remain still during the examination process, the examiner may cannot cooperate with the completion of the examination of the procedure, which increases the need for deep sedation or anesthesia. Achieving this can sometimes be challenging, especially in the special nontraditional environment of MRI equipment (unfamiliar and narrow spaces, away from patients, strong magnetic fields) and in special populations requiring sedation/anesthesia during examinations, which pose certain challenges for the perioperative anesthesia management of MRI. A simple "checklist" is necessary because it allows the anesthesiologist to become familiar with the particular environment and human and material resources as quickly as possible. For the choice of sedative/anesthetic, the traditional drugs, such as midazolam and ketamine, are still used due to the ease of administration despite their low sedation success rate, prolonged recovery, and significant adverse events. Currently, dexmedetomidine, with respiratory drive preservation, propofol, with high effectiveness and rapid recovery, and sevoflurane, which is mild and nonirritating, are preferred for sedation/anesthesia in children and adults undergoing MRI. Therefore, familiarity with the perioperative management of patient sedation and general anesthesia and drug selection in the MRI environment is critical for successful surgical completion and for the safe and rapid discharge of MRI patients receiving sedation/anesthesia.

Design and synthesis of novel GluN2A NMDAR positive allosteric modulators via scaffold hopping strategy as anti-stroke therapeutic agents.

NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo . Activation of NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action, whereas over activating GluN2B-containing receptor results in excitotoxicity, increasing neuronal apoptosis. Our previous study has identified Npam 43 as a NMDAR positive allosteric modulators. However, the cis-trans isomerization impedes the development of Npam 43 as potential neuroprotective agents. To discover more potent and selective GluN2A NMDAR positive allosteric modulators, 38 derivatives were synthesized and evaluated their neuroprotective effect on glutamate-exposed PC-12 cells. The allosteric activities of compounds were evaluated using calcium imaging approaches. Among them, compound 5c exhibit GluN1/2A selectivity over GluN1/2B and show neuroprotective activity in vitro and in vivo. This study reported a series of GluN1/2A positive allosteric modulators as neuroprotective agents, and provided a potential opportunity to discover new drugs for stroke treatment.

Recent Progress in antibacterial hydrogel coatings for targeting biofilm to prevent orthopedic implant-associated infections.

The application of orthopedic implants for bone tissue reconstruction and functional restoration is crucial for patients with severe bone fractures and defects. However, the abiotic nature of orthopedic implants allows bacterial adhesion and colonization, leading to the formation of bacterial biofilms on the implant surface. This can result in implant failure and severe complications such as osteomyelitis and septic arthritis. The emergence of antibiotic-resistant bacteria and the limited efficacy of drugs against biofilms have increased the risk of orthopedic implant-associated infections (OIAI), necessitating the development of alternative therapeutics. In this regard, antibacterial hydrogels based on bacteria repelling, contact killing, drug delivery, or external assistance strategies have been extensively investigated for coating orthopedic implants through surface modification, offering a promising approach to target biofilm formation and prevent OIAI. This review provides an overview of recent advancements in the application of antibacterial hydrogel coatings for preventing OIAI by targeting biofilm formation. The topics covered include: (1) the mechanisms underlying OIAI occurrence and the role of biofilms in exacerbating OIAI development; (2) current strategies to impart anti-biofilm properties to hydrogel coatings and the mechanisms involved in treating OIAI. This article aims to summarize the progress in antibacterial hydrogel coatings for OIAI prevention, providing valuable insights and facilitating the development of prognostic markers for the design of effective antibacterial orthopedic implants.

[Relationship between urban green-land landscape patterns and air pollution in the central district of Yichang city].

In this paper, four types of landscape structures and their green-land landscape patterns, including the landscapes of dominant green-land patch pattern, even green-land patch pattern, dominant wooded corridor pattern and building or concrete covering pattern (control) in the central district of Yichang city in Hubei Province, were analyzed respectively on the basis of landscape ecological theory. The atmospheric noise and the contents of SO2, NOx and total suspension particle (TSP) of the landscapes were monitored respectively by comparative method. The results showed that the landscape of building or concrete covering pattern (control) was mostly composed of woodless corridors and building or concrete covering patches with the tiptop green-land fragmentation index (18.125 3 ind x hm(-2)) and only had 1.00% green-land coverage, which had a relatively higher atmospheric noise and the highest TSP content in the landscape. The landscape of dominant green-land patch pattern had the highest green-land coverage (up to 43.59%) dominated by great green-land patches and the least fragmentation index (0.453 9 ind x hm(-2)), in which, the atmospheric noise weakened by 28.12% and the TSP content reduced significantly by 86.42%, comparing to the control. The landscape of even green-land patch pattern had the relatively lower green-land coverage (11.34%) and fragmentation index (2.751 1 ind x hm(-2)), which was mainly composed of the middle or small green-land patches and wooded corridors with a regular distribution. In the landscape, the TSP content reduced obviously by 46.62% of the control, while the effect of dust retention was only 53.95% of that in the landscape of dominant green-land patch pattern. In the landscape of dominant wooded corridor pattern, which was a traffic center and turned into a main pollution resource in the city, there were a relatively higher green-land fragmentation index (6.870 0 ind x hm(-2)) and the highest wooded corridor density (0.844 3 hm x hm(-2)) with only 6.13% green-land coverage, and the atmospheric noise and the TSP and NOx content increased by 21.47%, 5.08% and 9.06%, respectively, comparing to control. It was obvious that the greater the average area of the green-land patch and the lower the fragmentation index of green-land patches, the more effective the green-land on purifying air pollution.

[Synthetic evaluation on stand quality of protection forests in the Three Gorges Reservoir Region in western Hubei Province].

Stand qualities of 19 kinds of protection forests in the Three Gorges Reservoir Region in Western Hubei Province were evaluated synthetically by using 12 indexes, and could be classified into four different grades. The relationships between stand quality and some major factors such as crown density, elevation, and origin were also discussed in this paper. The results showed that elevation was a very important factor that influenced the stand quality, and the stand quality of natural forest was higher than other forests. Moreover, some strategies on protection forest construction and stand quality optimization were put forward.