Background: The α₂-adrenoreceptor agonist dexmedetomidine is known to provide renoprotection against ischemia and reperfusion (I/R) injury. However the underlying molecular mechanisms remain unclear. The purpose of this study was to investigate whether the Janus kinase and signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a role in dexmedetomidine’s renoprotection. Methods: I/R model was induced by bilateral renal pedicle clamping for 45 min followed by 48 h of reperfusion in male Wistar rat. Sham laparotomy served as controls. Animals received dexmedetomidine (50 μg/kg, i.p.) in the absence or presence of atipamezole (250 μg/kg, i.p.), or vehicle (DMSO) in the absence or presence of selective JAK2 inhibitor tyrphostin AG490 (10 mg/kg, i.p.) before ischemia. Renal function, histology, apoptosis, expression of cleaved caspase 3 protein, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and phosphorylations of JAK2, STAT1 and STAT3 were assessed. Results: The animals treated with either dexmedetomidine or AG490 exhibited an improved renal functional recovery, attenuated histological lesions and reduced number of apoptotic tubular epithelial cells. Either dexmedetomidine or AG490 inhibited the phosphorylations of JAK2 and its downstream molecule STAT1 and STAT3, accompanied by down-regulation the expression of cleaved caspase 3, ICAM-1 and MCP-1 proteins, and significantly ameliorated renal I/R injury. Conclusions: Dexmedetomidine protects kidney against I/R injury, at least in part, through its inhibitory effects on injury-induced activation of JAK/STAT signaling pathway. If our data can be extrapolated to clinical setting, then dexmedetomidine may therefore serve as a clinical strategy to treat/prevent perioperative renal I/R injury.

Background: Cognitive deficits are common in patients with sepsis. Previous studies in sepsis-associated encephalopathy (SAE) implicated the C-X-C chemokine receptor type (CXCR) 5. The present study used a mouse model of SAE to examine whether CXCR5 down-regulation could attenuate cognitive deficits. Methods: Sepsis was induced in adult male C57BL/6 J and CXCR5^−/− mice by cecal ligation and puncture (CLP). At 14–18 days after surgery, animals were tested in a Morris water maze, followed by a fear conditioning test. Transmission electron microscopy of hippocampal sections was used to assess levels of autophagy. Primary microglial cultures challenged with lipopolysaccharide (LPS) were used to examine the effects of short interfering RNA targeting CXCR5, and to investigate the possible involvement of the p38MAPK/NF-κB/STAT3 signaling pathway. Results: CLP impaired learning and memory and up-regulated CXCR5 in hippocampal microglia. CLP activated hippocampal autophagy, as reflected by increases in numbers of autophagic vacuoles, conversion of microtubule-associated protein 1 light chain 3 (LC3) from form I to form II, accumulation of beclin-1 and autophagy-related gene-5, and a decrease in p62 expression. CLP also shifted microglial polarization to the M1 phenotype, and increased levels of IL-1β, IL-6 and phosphorylated p38MAPK. CXCR5 knockout further enhanced autophagy but partially reversed all the other CLP-induced effects, including cognitive deficits. Similar effects on autophagy and cytokine expression were observed after knocking down CXCR5 in LPS-challenged primary microglial cultures; this knockdown also partially reversed LPS-induced up-regulation of phosphorylated NF-κB and STAT3. The p38MAPK agonist P79350 partially reversed the effects of CXCR5 knockdown in microglial cultures. Conclusions: CXCR5 may act via p38MAPK/NF-κB/STAT3 signaling to inhibit hippocampal autophagy during sepsis and thereby contribute to cognitive dysfunction. Down-regulating CXCR5 can restore autophagy and mitigate the proinflammatory microenvironment in the hippocampus.

Objective: This study aims to analyze the changes of fecal short chain fatty acids (SCFAs) content and gut microbiota composition in sepsis associated encephalopathy (SAE) mice, further evaluating the effect of SCFAs on cognitive function and the underlying mechanism in SAE mice.Methods: A total of 55 male adult C57BL/6 mice (2–3 months of age, 20–25 g) were divided into four groups randomly: sham group (n = 10), cecal ligation and puncture group (CLP group, n = 15), CLP+SCFAs group (n = 15), and CLP+SCFAs+GLPG0974 group (n = 15). Seven days after surgery, fecal samples were collected for microbiota composition and SCFA analysis from 6 mice in each group randomly. Behavioral test was applied to assess cognitive impairment at the same time. After that, mice were sacrificed and brain tissue was harvested for inflammatory cytokines analysis.Results: The levels of acetic acid (.57 ± 0.09 vs 2.00 ± 0.24, p < 0.001) and propionic acid (.32 ± 0.06 vs .66 ± 0.12, p = 0.002) were significantly decreased in the CLP group compared with the sham group. The administration of SCFAs significantly increased the levels of acetic acid (1.51 ± 0.12 vs. 0.57 ± 0.09, p < 0.001) and propionic acid (0.54 ± 0.03 vs. 0.32 ± 0.06, p = 0.033) in CLP+SCFAs group compared with CLP group. Relative abundance of SCFAs-producing bacteria, including Allobaculum (0.16 ± 0.14 vs. 15.21 ± 8.12, p = 0.037), Bacteroides (1.82 ± 0.38 vs. 15.21 ± 5.95, p = 0.002) and Bifidobacterium (0.16 ± 0.06 vs. 2.24 ± 0.48, p = 0.002), significantly decreased in the CLP group compared with the sham group. The behavioral tests suggested that cognitive function was impaired in SAE mice, which could be alleviated by SCFAs pretreatment. ELISA tests indicated that the levels of IL-1β, IL-6, and TNF-α were elevated in SAE mice and SCFAs could lower them. However, the GPR43 antagonist, GLPG0974, could reverse the cognitive protective effect and anti-neuroinflammation effect of SCFAs.Conclusion: Our study suggested that in SAE, the levels of acetate and propionate decreased significantly, accompanied by gut microbiota dysbiosis, particularly a decrease in SCFAs-producing bacteria. GPR43 was essential for the anti-neuroinflammation and cognitive protective effect of SCFAs in SAE.

It has been reported that postoperative cognitive dysfunction (POCD) is correlated with the degeneration of the central nervous system, oxidative stress, inflammation, and endocrine and immune dysfunction. Increased age, predisposed comorbidity, long surgery time, and prolonged stay in the intensive care unit have been reported to be risk factors for developing POCD for cardiac surgery. In the present study, the risk factors of early POCD after colorectal surgery were investigated. Eighty patients, who provided informed consents for their participation in this study, were enrolled and received colorectal surgery under general anesthesia. Neuropsychological tests were performed preoperatively and on postoperative day seven. The risk factors for POCD were analyzed using a multivariate logistic regression model. Nineteen patients were diagnosed with POCD (24.7%). Diabetes history (OR = 8.391 [2.208–31.882], P = 0.012), fasting over 3 days after surgery (OR = 5.236 [1.998–13.721], P = 0.001) and an SIRS score of > 3 on the second day after surgery (OR = 6.995 [1.948–25.111], P = 0.003) were risk factors for early POCD in colorectal cancer patients. The risk factors for early POCD after colorectal surgery included diabetes history, fasting over 3 days, and an SIRS score of > 3 on the second day.

Background: Aberrant hippocampal neurogenesis is an important pathological feature of sepsis-associated encephalopathy. In the current study, we examined the potential role of the long noncoding RNA (lncRNA) sex-determining region Y-box 2 (SOX2) overlapping transcript (SOX2OT), a known regulator of adult neurogenesis in sepsis-induced deficits in hippocampal neurogenesis and cognitive function. Methods: Sepsis was induced in adult C57BL/6 J male mice by cecal ligation and perforation (CLP) surgery. Randomly selected CLP mice were transfected with short interfering RNAs (siRNAs) against SOX2OT or SOX2, or with scrambled control siRNA. Cognitive behavior was tested 8–12 days post-surgery using a Morris water maze. Western blotting and RT-qPCR were used to determine expression of SOX2, Ki67, doublecortin (DCX), nestin, brain lipid-binding protein, and glial fibrillary acidic protein (GFAP) in the hippocampus. The number of bromodeoxyuridine (BrdU)⁺/DCX⁺ cells, BrdU⁺/neuronal nuclei (NeuN)⁺ neurons, and BrdU⁺/GFAP⁺ glial cells in the dentate gyrus were assessed by immunofluorescence. Results: CLP mice showed progressive increases in SOX2OT and SOX2 mRNA levels on days 3, 7, and 14 after CLP surgery, accompanied by impaired cognitive function. Sepsis led to decrease in all neuronal markers in the hippocampus, except GFAP. Immunofluorescence confirmed the decreased numbers of BrdU⁺/DCX⁺ cells and BrdU⁺/NeuN⁺ neurons, and increased numbers of BrdU⁺/GFAP⁺ cells. SOX2OT knockdown partially inhibited the effects of CLP on levels of SOX2 and neuronal markers, neuronal populations in the hippocampus, and cognitive function. SOX2 deficiency recapitulated the effects of SOX2OT knockdown. Conclusion: SOX2OT knockdown improves sepsis-induced deficits in hippocampal neurogenesis and cognitive function by downregulating SOX2 in mice. Inhibiting SOX2OT/SOX2 signaling may be effective for treating or preventing neurodegeneration in sepsis-associated encephalopathy.

Acute kidney injury (AKI) is a common and serious complication after the repair of Type A acute aortic dissection (TA-AAD). However, previous models have failed to account for the impact of blood pressure fluctuations on predictive performance. This study aims to develop machine learning (ML) models combined with intraoperative medicine and blood pressure time-series data to improve the accuracy of early prediction for postoperative AKI risk. Indicators reflecting the duration and depth of hypotension were obtained by analyzing continuous mean arterial pressure (MAP) monitored intraoperatively with multiple thresholds (<65, 60, 55, 50) set in the study. The predictive features were selected by logistic regression and the least absolute shrinkage and selection operator (LASSO), and 4 ML models were built based on the above features. The performance of the models was evaluated by area under receiver operating characteristic curve (AUROC), calibration curve and decision curve analysis (DCA). Shapley additive interpretation (SHAP) was used to explain the prediction models. Among the indicators reflecting intraoperative hypotension, 65 mmHg showed a statistically superior difference to other thresholds in patients with or without AKI (p < .001). Among 4 models, the extreme gradient boosting (XGBoost) model demonstrated the highest AUROC: 0.800 (95% 0.683–0.917) and sensitivity: 0.717 in the testing set and was verified the best-performing model. The SHAP summary plot indicated that intraoperative urine output, cumulative time of mean arterial pressure lower than 65 mmHg outside cardiopulmonary bypass (OUT_CPB_MAP_65 time), autologous blood transfusion, and smoking were the top 4 features that contributed to the prediction model. With the introduction of intraoperative blood pressure time-series variables, we have developed an interpretable XGBoost model that successfully achieve high accuracy in predicting the risk of AKI after TA-AAD repair, which might aid in the perioperative management of high-risk patients, particularly for intraoperative hemodynamic regulation.