D-allose Inhibits TLR4/PI3K/AKT Signaling to Attenuate Neuroinflammation and Neuronal Apoptosis by Inhibiting Gal-3 Following Ischemic Stroke.

BACKGROUND: Ischemic stroke (IS) occurs when a blood vessel supplying the brain becomes obstructed, resulting in cerebral ischemia. This type of stroke accounts for approximately 87% of all strokes. Globally, IS leads to high mortality and poor prognosis and is associated with neuroinflammation and neuronal apoptosis. D-allose is a bio-substrate of glucose that is widely expressed in many plants. Our previous study showed that D-allose exerted neuroprotective effects against acute cerebral ischemic/reperfusion (I/R) injury by reducing neuroinflammation. Here, we aimed to clarify the beneficial effects D-allose in suppressing IS-induced neuroinflammation damage, cytotoxicity, neuronal apoptosis and neurological deficits and the underlying mechanism in vitro and in vivo. METHODS: In vivo, an I/R model was induced by middle cerebral artery occlusion and reperfusion (MCAO/R) in C57BL/6 N mice, and D-allose was given by intraperitoneal injection within 5 min after reperfusion. In vitro, mouse hippocampal neuronal cells (HT-22) with oxygen-glucose deprivation and reperfusion (OGD/R) were established as a cell model of IS. Neurological scores, some cytokines, cytotoxicity and apoptosis in the brain and cell lines were measured. Moreover, Gal-3 short hairpin RNAs, lentiviruses and adeno-associated viruses were used to modulate Gal-3 expression in neurons in vitro and in vivo to reveal the molecular mechanism. RESULTS: D-allose alleviated cytotoxicity, including cell viability, LDH release and apoptosis, in HT-22 cells after OGD/R, which also alleviated brain injury, as indicated by lesion volume, brain edema, neuronal apoptosis, and neurological functional deficits, in a mouse model of I/R. Moreover, D-allose decreased the release of inflammatory factors, such as IL-1ß, IL-6 and TNF-α. Furthermore, the expression of Gal-3 was increased by I/R in wild-type mice and HT-22 cells, and this factor further bound to TLR4, as confirmed by three-dimensional structure prediction and Co-IP. Silencing the Gal-3 gene with shRNAs decreased the activation of TLR4 signaling and alleviated IS-induced neuroinflammation, apoptosis and brain injury. Importantly, the loss of Gal-3 enhanced the D-allose-mediated protection against I/R-induced HT-22 cell injury, inflammatory insults and apoptosis, whereas activation of TLR4 by the selective agonist LPS increased the degree of neuronal injury and abolished the protective effects of D-allose. CONCLUSIONS: In summary, D-allose plays a crucial role in inhibiting inflammation after IS by suppressing Gal-3/TLR4/PI3K/AKT signaling pathway in vitro and in vivo.

d-allose protects brain microvascular endothelial cells from hypoxic/reoxygenated injury by inhibiting endoplasmic reticulum stress.

Ischemic stroke is an acute brain disease with a high mortality rate. Currently, the only effective method is to restore the blood supply. But the inflammation and oxidative stress induced by this approach can damage the integrity of the endothelial system, which hampers the patient's outcome. d-allose has the biological activity to protect against ischemia-reperfusion injury, however, the underlying mechanism remains unclear. Here, brain microvascular endothelial cells (RBMECs) were used as the study material to establish an IR-injury model. Cell viability of RBMECs was suppressed after hypoxia/reoxygenation (H/R) treatment and significantly increased after d-allose supplementation. RNAseq results showed 180 differentially expressed genes (DEGs) between the therapy group (H/R + Dal) and the model group (H/R), of which 151 DEGs were restored to control levels by d-allose. Enrichment analysis revealed that DEGs were mainly involved in protein processing in endoplasmic reticulum. 6 DEGs in the unfolded protein response (UPR) pathway were verified by qRT-PCR. All of them were significantly down-regulated by d-allose, indicating that endoplasmic reticulum stress (ERS) was relieved. In addition, d-allose significantly inhibited the phosphorylation level of eIF2α, a marker of ERS. The downstream molecules of Phosphorylation of eIF2α, Gadd45a and Chac1, which trigger cycle arrest and apoptosis, respectively, were also significantly inhibited by d-allose. Thus, we conclude that d-allose inhibits the UPR pathway, attenuates eIF2α phosphorylation and ERS, restores the cell cycle, inhibits apoptosis, and thus enhances endothelial cell tolerance to H/R injury.

Socioeconomic and environmental factors of poverty in China using geographically weighted random forest regression model.

Correlations between socioeconomic factors and poverty in regression models do not reflect actual relationships, especially when data exhibit patterns of spatial heterogeneity. Spatial regression models can estimate the relationships between socioeconomic factors and poverty in defined geographical areas, explaining the imbalanced distribution of poverty, but the relationships between these factors and poverty are not always linear however, and conventional simple linear local regression models do not accurately capture these nonlinear relationships. To fill this gap, we used a local regression method, geographically weighted random forest regression (GW-RFR), that integrates a spatial weight matrix (SWM) and random forest (RF). The GW-RFR evaluates the spatial variations in the nonlinear relationships between variables. A county-level poverty data set of China was employed to estimate the performance of the GW-RFR against the random forest (RF). In this poverty application, the value of [Formula: see text] was 0.128 higher than that of the RF, the NRMSE value was 1.6% lower than the RF, and the MAE value was 0.295 lower than the RF. These results showed that the relationship between poverty factors and poverty varies with space at the county level in China, and the GW-RFR was suitable for dealing with nonlinear relationships in local regression analysis.

Effects of Apolipoprotein Ε Îµ4 allele on early postoperative cognitive dysfunction after anesthesia.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is one of the main causes of morbidity after noncardiac surgery; however, the pathogenic mechanisms of POCD have remained unclear until now. In this study, we performed a pilot study to investigate the association between apolipoprotein E (ApoE) ε4 and POCD in older patients undergoing intravenous anesthesia (IVA) and inhalation anesthesia (IAA). METHODS: In total, 180 patients from Shenzhen People's Hospital were recruited and randomly divided into an IVA group and an IAA group. The IVA group and IAA group received propofol and sevoflurane treatment, respectively. Within 7 days after surgery, the mini-mental state examination (MMSE) was used daily to assess the cognitive function of both groups of patients. The genotypes of the ApoE gene were detected using the restriction fragment length polymorphism technique. In addition, the serum levels of (soluble protein-100ß) S­100ß and (Interleukin- 6) L­6 were also analyzed. RESULTS: Compared to the preoperative and IVA groups, the MMSE score in the IAA group significantly decreased at 3 days after surgery. Furthermore, the IAA group had a higher percentage of patients who scored less than 25 points than the IVA group at 3 days after surgery. The decrease in the MMSE score was closely related to the ApoE ε4 allele in the IAA group, but this correlation was not observed in the IVA group. The levels of S­100ß and IL­6 were increased sharply in patients with the ε4/ε4 genotype who received IAA compared with IVA at 1 day after surgery. CONCLUSION: The results of the study indicated that the ApoΕ Îµ4/ε4 genotype was a risk factor for early POCD in older patients undergoing sevoflurane anesthesia.

Distribution of the environmental and socioeconomic risk factors on COVID-19 death rate across continental USA: a spatial nonlinear analysis.

The COVID-19 outbreak has become a global pandemic. The spatial variation in the environmental, health, socioeconomic, and demographic risk factors of COVID-19 death rate is not well understood. Global models and local linear models were used to estimate the impact of risk factors of the COVID-19, but these do not account for the nonlinear relationships between the risk factors and the COVID-19 death rate at various geographical locations. We proposed a local nonlinear nonparametric regression model named geographically weighted random forest (GW-RF) to estimate the nonlinear relationship between COVID-19 death rate and 47 risk factors derived from the US Environmental Protection Agency, National Center for Environmental Information, Centers for Disease Control and the US census. The COVID-19 data were employed to a global regression model random forest (RF) and a local model GW-RF. The adjusted R2 of the RF is 0.69. The adjusted R2 of the proposed GW-RF is 0.78. The result of GW-RF showed that the risk factors (i.e. going to work by walking, airborne benzene concentration, householder with a mortgage, unemployment, airborne PM2.5 concentration and per cent of the black or African American) have a high correlation with the spatial distribution of the COVID-19 death rate, and these key factors driven from the GW-RF were mapped, which could provide useful implications for controlling the spread of the COVID-19 pandemic.

Target-controlled infusion of propofol and remifentanil combined with dexmedetomidine reduces functional endoscopic sinus surgery bleeding.

The aim of the present study was to investigate the effects of target-controlled infusion (TCI) of propofol and remifentanil combined with dexmedetomidine on functional endoscopic sinus surgery (FESS) bleeding and surgical field. 62 patients scheduled to undergo FESS were randomly divided into experimental group (intravenous 0.5 µg kg-1 h-1 dexmedetomidine after 0.5 µg kg-1 bolus within 15 min until the end of surgery) or control group (intravenous saline administration at the same dose). All patients underwent endotracheal intubation under general anesthesia with TCI of propofol and remifentanil for anesthesia induction and maintenance. During anesthesia, arterial pressure (MAP), heart rate (HR), intraoperative propofol and remifentanil dosage and intraoperative blood loss were recorded. Surgeons rated their satisfaction with the surgical field using the Numeric Rating Scale (NRS). Following surgery, visual analog scale (VAS) was assessed. During tracheal intubation and extubation, HR and MAP in the experimental group were significantly lower compared with the control group (P<0.05); HR was also significantly lower compared with the control group throughout surgery (P<0.05). The mean infusion rate of propofol and remifentanil was significantly lower in the experimental group compared with the control group (P=0.001 and P=0.045, respectively). Blood loss in the experimental group was significantly lower compared with the control group (P=0.007). NRS and VAS scores in the experimental group were significantly improved compared with control group (P<0.01). In conclusion, TCI of propofol and remifentanil for FESS combined with dexmedetomidine reduced intraoperative bleeding and improved the quality of surgical field compared with the same procedure without dexmedetomidine. Dexmedetomidine also reduced the increase in MAP and HR during tracheal intubation and extubation, and improved postoperative analgesia quality.