Pain relief is a major concern for patients who have undergone surgery, and it is an eternal pursuit for anesthesiologists. However, postoperative pain management is far from satisfactory, though the past decades have witnessed great progress in the development of novel analgesics and analgesic techniques. A Cochrane systematic review showed that patient-controlled analgesia (PCA) achieved better pain relief and greater patient satisfaction than traditional "on-demand" parenteral analgesia, suggesting that it might be the manner of analgesia implementation that matters for effective postoperative pain management. A wireless intelligent PCA (Wi-PCA) system that incorporated remote monitoring, an intelligent alarm, intelligent analysis and assessment of the PCA equipment, as well as automatically recording and reserving key information functions under a wireless environment was introduced in our department in 2018. The practice showed that the Wi-PCA system significantly reduced the incidence of moderate to severe postoperative pain and relevant adverse effects, shortened hospital stays, and improved patient satisfaction with postoperative pain relief. Nevertheless, for both traditional and Wi-PCA, analgesics are only administered when pain occurs, leaving behind a realm of possibilities for better postoperative pain management. With the rapid development of machinery and deep learning algorithms, artificial intelligence (AI) is changing the mode of clinical decision making. Integrating the big data collected by state-of-the-art monitoring sensors, the Internet of Things and AI algorithms, an AI-assisted PCA (Ai-PCA) may be a promising future direction for postoperative pain management.

The blood-brain barrier (BBB) is an important barrier that separates brain tissue from peripheral blood. The permeability of the BBB can be destroyed by external harmful factors, such as lipopolysaccharide (LPS), which contributes to neuroinflammation and central nervous system diseases. The present study aims to investigate the protective effects of Omarigliptin against LPS-induced neuroinflammation and the underlying mechanism using a series of both in vivo and in vitro experiments. A neuroinflammation model was established by intraperitoneal injection of LPS into mice. We found that administration of Omarigliptin reduced LPS-induced inflammatory responses by inhibiting the expressions of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Importantly, we found that Omarigliptin protected the integrity of the BBB against LPS by increasing the expression of the tight junction proteins claudin-1 and claudin-5. Our results also demonstrate that Omarigliptin reduced LPS-induced increase in expressions of matrix matalloproteinases-2 (MMP-2) and matrix matalloproteinases-9 (MMP-9) at both the mRNA and protein levels. Notably, Omarigliptin showed a powerful beneficial effect against LPS-induced cell damage in bEnd.3 brain endothelial cells by reducing the release of high mobility group box chromosomal protein 1 (HMGB-1). Consistently, Omarigliptin ameliorated LPS-induced exacerbation of endothelial permeability by increasing the expressions of claudin-1 and claudin-5 and reducing the expression of MMP-2 and MMP-9. Mechanistically, Omarigliptin inhibited the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88/nuclear factor κB (TLR4/Myd88/NF-κB) signaling pathway. On the basis of these findings, we concluded that Omarigliptin might mitigate LPS-induced neuroinflammation and dysfunction of the integrity of the blood-brain barrier.

Following systemic inflammatory response syndrome (SIRS), the brain is one of the most sensitive organs vulnerable to an external stressor. According to our previous study, ketamine had a protective effect on alleviating SIRS-associated neuronal necroptosis and cecal epithelial cell necroptosis by inhibiting the RIP1-RIP3-MLKL pathway. In this study, we further provided valid evidence that ketamine could safeguard the integrity of the blood-brain barrier (BBB), modulate microglia over-activation, and prevent neural network damage, resulting in relieving cerebral edema and improving system symptoms significantly. Simultaneously, cecum damage was partly reversed by ketamine intervention, which was attributed to a decrease in circulating high mobility group protein 1 (HMGB1). Interestingly, the result showed less cecum injury and relieved BBB disturbance in Rip3-/- mice. Furthermore, circulating HMGB1 content between Rip3-/- mice and mice with ketamine intervention significantly decreased. Moreover, anti-HMGB1 neutralizing antibody identically reversed BBB damage, indicating that cecum-promoted HMGB1 releases extravagated SIRS and BBB leakage. In addition, we clarified that cecectomy reduced serum HMGB1 release level and alleviated BBB damage and microglial activation. Altogether, our work shed light on the new view about the pathogenesis of SIRS, establishing the connection between cecum damage and BBB damage. Besides, we identified ketamine as a candidate to protect the brain from damage like BBB leakage and microglia over-activation, which attributed to the effect on alleviating cecum damage and decreasing circulation HMGB1 release. Our results provided a new theoretical view and therapeutic target for the application of ketamine in SIRS.

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