Postoperative cognitive dysfunction (POCD) is a severe neurological complication after anesthesia and surgery. However, there is still a lack of effective clinical pharmacotherapy due to its unclear pathogenesis. Caffeic acid phenethyl ester (CAPE), which is obtained from honeybee propolis and medicinal plants, shows powerful antioxidant, anti-inflammatory, and immunomodulating properties. In this study, we aimed to evaluate whether CAPE mitigated cognitive impairment following anesthesia and surgery and its potential underlying mechanisms in aged mice. Here, isoflurane anesthesia and tibial fracture surgery were used as the POCD model, and H2O2-induced BV2 cells were established as the microglial oxidative stress model. We revealed that CAPE pretreatment suppressed oxidative stress and promoted the switch of microglia from the M1 to the M2 type in the hippocampus, thereby ameliorating cognitive impairment caused by anesthesia and surgery. Further investigation indicated that CAPE pretreatment upregulated hippocampal Sirt6/Nrf2 expression after anesthesia and surgery. Moreover, mechanistic studies in BV2 cells demonstrated that the potent effects of CAPE pretreatment on reducing ROS generation and promoting protective polarization were attenuated by a specific Sirt6 inhibitor, OSS_128167. In summary, our findings opened a promising avenue for POCD prevention through CAPE pretreatment that enhanced the Sirt6/Nrf2 pathway to suppress oxidative stress as well as favor microglia protective polarization.

BACKGROUND: A main obstacle in current valvular heart disease research is the lack of high-quality homogeneous functional heart valve cells. Human induced pluripotent stem cells (hiPSCs)-derived heart valve cells may help with this dilemma. However, there are no well-established protocols to induce hiPSCs to differentiate into functional heart valve cells, and the networks that mediate the differentiation have not been fully elucidated. METHODS: To generate heart valve cells from hiPSCs, we sequentially activated the Wnt, BMP4, VEGF (vascular endothelial growth factor), and NFATc1 signaling pathways using CHIR-99021, BMP4, VEGF-165, and forskolin, respectively. The transcriptional and functional similarity of hiPSC-derived heart valve cells compared with primary heart valve cells were characterized. Longitudinal single-cell RNA sequencing was used to uncover the trajectory, switch genes, pathways, and transcription factors of the differentiation. RESULTS: An efficient protocol was developed to induce hiPSCs to differentiate into functional hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells. After 6-day differentiation and CD144 magnetic bead sorting, ≈70% CD144 ⁺ cells and 30% CD144 ^– cells were obtained. On the basis of single-cell RNA sequencing data, the CD144 ⁺ cells and CD144 ^– cells were found to be highly similar to primary heart valve endothelial cells and primary heart valve interstitial cells in gene expression profile. Furthermore, CD144 ⁺ cells had the typical function of primary heart valve endothelial cells, including tube formation, uptake of low-density lipoprotein, generation of endothelial nitric oxide synthase, and response to shear stress. Meanwhile, CD144 ^– cells could secret collagen and matrix metalloproteinases, and differentiate into osteogenic or adipogenic lineages like primary heart valve interstitial cells. Therefore, we identified CD144 ⁺ cells and CD144 ^– cells as hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells, respectively. Using single-cell RNA sequencing analysis, we demonstrated that the trajectory of heart valve cell differentiation was consistent with embryonic valve development. We identified the main switch genes (NOTCH1, HEY1, and MEF2C), signaling pathways (TGF-β, Wnt, and NOTCH), and transcription factors (MSX1, SP5, and MECOM) that mediated the differentiation. Finally, we found that hiPSC-derived valve interstitial-like cells might derive from hiPSC-derived valve endothelial-like cells undergoing endocardial-mesenchymal transition. CONCLUSIONS: In summary, this is the first study to report an efficient strategy to generate functional hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells from hiPSCs, as well as to elucidate the differentiation trajectory and transcriptional dynamics of hiPSCs differentiated into heart valve cells.

Background: The effects of different sedative drugs on all-cause mortality rate, duration of ICU stay, and risk of delirium in mechanically ventilated ICU patients are unclear. This meta-analysis aimed to compare the effectiveness and safety of individual sedative drugs and drug combinations in mechanically ventilated ICU patients. Materials and methods: Medline, Embase, Cochrane, EBSCOhost, and ISI Web of Science databases were searched for studies that assessed sedation in ICU mechanically ventilated patients. A Bayesian random-effects model was used to combine the direct comparisons and indirect evidence. Results: Thirty-one randomized, controlled trials were included, which consisted of 4491 patients who received one of seven sedative drugs or a combination of drugs. There were no significant differences regarding the all-cause mortality rate. Compared to propofol, inhalation anesthetics (hazard ratio [HR] 0.121; 95% credible interval [CrI] -7.58 to 7.62), alpha agonists (HR 2.2; 95% CrI 0.776 to 5.22), propofol with benzodiazepines (HR 0.306; 95% CrI -6.97 to 7.65), ketamine with benzodiazepines (HR 6.57; 95% CrI -6.05 to 19.1) and placebo (HR 2.4; 95% CrI -5.37 to 10.3), benzodiazepines (HR 3.62; 95% CrI 0.834 to 6.2) may increase the duration of ICU stay. Compared to alpha agonists, propofol (HR 2.4; 95% CrI 0.304 to 21.1) and placebo (HR 6.12; 95% CrI 0.745 to 54.6), benzodiazepines (HR 2.59; 95% CrI 1.08 to 7.4) were associated with incremental risks of delirium. Conclusion: Compared to propofol, benzodiazepines may increase the duration of ICU stay. Compared to alpha agonists, benzodiazepines were associated with an increased risk of delirium.

Objective: To train medical corpsmen for skills of hemostasis and anti-shock on living goats, in an attempt to search for new methods in medics training. Methods: A total of 90 medical corpsmen from one certain group army received trainings about hemostasis and anti-shock skills on goats, whose forelimb radial veins and hind limb fibular arteries were incised to make a bleeding model. Both before and after such training, theoretical tests about basic knowledge and new concepts of hemostasis and anti-shock were performed in all 90 medical corpsmen. A further practical test including hemostasis and anti-shock was applied on 28 randomly selected medics after such training program. Results: After training, the average score in the theoretical test increased from 42.3 marks to 78.8 marks (full mark 100). In the further practical test, the successful rate of hemostasis after artery rupture increased from 53.6% to 78.6% after training, and the rate of correctly using tourniquet elevated to 61.5% from 25.0%, all with statistical significance (p < 0.01). Conclusion: Hemostasis and anti-shock training on living goats can significantly improve medics’ skills and help them to gain new knowledge and concepts in this field, thereby improving emergency treatment in future high-tech warfare.