ObjectiveTo investigate the effects of jujuboside A （JuA） on the learning and memory abilities and histopathological changes in the rat model of vascular cognitive impairment （VCI） and explore the potential mechanisms by which JuA treats VCI. MethodsA total of 50 male SPF-grade SD rats were randomized into a sham operation group （n=10）， a blank control group （n=10）， and a modeling group （n=30）. The rats in the modeling group underwent bilateral carotid artery ligation （2-VO） for the modeling of VCI. After stabilization， the VCI rats were randomized into model， JuA （20 mg·kg^-¹）， and donepezil （0.45 mg·kg^-¹） groups. After 4 weeks of gavage， the novel object recognition and Morris water maze tests were conducted to evaluate the learning and memory abilities of rats. Nissl staining was employed to evaluate the morphology and number of hippocampal neurons. Real-time PCR was employed to measure the mRNA levels of glycogen synthase kinase-3β （GSK-3β）， cAMP response element-binding protein （CREB）， B cell lymphoma-2 （Bcl-2）， phosphatidylinositol 3-kinase （PI3K）， and protein kinase B （Akt） in the hippocampal tissue. Western blot was employed to quantify the protein levels of GSK-3β， p-GSK-3β， p-CREB， Bcl-2， PI3K， p-PI3K， Akt， and p-Akt in the hippocampal tissue. ResultCompared with the sham operation group， the model group exhibited declines in the learning and memory abilities （P<0.01）， neuronal damage and decreased neurons in the hippocampal CA1 region （P<0.01）， up-regulation in the mRNA level of GSK-3β （P<0.01）， and down-regulation in the mRNA levels of PI3K， Akt， CREB， and Bcl-2， as well as the protein levels of p-PI3K， p-Akt， p-GSK-3β， p-CREB， and Bcl-2 （P<0.01）. In comparison to the model group， both the JuA and donepezil groups demonstrated improvements in the learning and memory abilities （P<0.05， P<0.01）， with reduced neuronal damage and increased neurons （P<0.05， P<0.01）. In addition， the two groups showed down-regulation in the mRNA level of GSK-3β （P<0.01） and up-regulation in the mRNA levels of PI3K， Akt， CREB， and Bcl-2 and the protein levels of p-PI3K， p-Akt， p-GSK-3β， p-CREB， and Bcl-2 （P<0.05， P<0.01）. There were no statistically significant differences between the blank control and sham operation groups in terms of the learning and memory abilities， neuron count， and mRNA and protein levels of PI3K/Akt/GSK-3β pathway-related factors. ConclusionJuA can ameliorate the cognitive impairment in the rat model of VCI by activating the PI3K/Akt signaling pathway， reducing the apoptosis of hippocampal neurons， and alleviating the hippocampal neuronal damage.

[This corrects the article DOI: 10.1016/j.apsb.2022.05.019.].

ObjectiveTo systematically sort out the knowledge framework and conceptual logic relationship of "disease-syndrome-treatment-prescription-medicine" in the existing literature on traditional Chinese medicine（TCM） treatment of diabetic peripheral neuropathy（DPN）， to construct of the knowledge map of TCM treatment of DPN， and to promote the explicitation of the implicit knowledge in the literature on the treatment of DPN with TCM. MethodTaking the literature of China National Knowledge Infrastructure about TCM treatment of DPN as the main data source， TCM-related concepts and entities were constructed by manual citation， and the corresponding relationships between the entities were established. Structured data were formed by processing with Python 3.7， and the knowledge graph was constructed based on Neo4j 3.5.34 graph database. ResultThe resulting knowledge graph with TCM diagnosis and treatment logic， defined 12 node labels such as prescriptions， Chinese medicines and syndrome types at the schema layer， as well as 4 types of relationships， such as inclusion， correspondence， selection and composition. It could support the query and discovery of nodes（syndrome elements， syndrome types and treatment methods）， as well as the relationship between each node. ConclusionBased on the literature data， this study constructed a knowledge map for TCM treatment of DPN， which brought together various methods of TCM treatment of DPN， including internal and external treatment. The whole chain knowledge structure of syndrome differentiation and classification for DPN treatment is formed from syndrome element analysis， syndrome type composition to treatment method selection， which can provide new ideas and methods for literature data to serve clinical and scientific research work， as well as reference for visualization of TCM literature knowledge， intellectualization of TCM knowledge services and the standardization of TCM diagnosis and treatment.

To investigate the differences in methylation levels of cuproptosis related genes in cervical cancer and their effects on clinical prognosis.Methods:The methylation data of 310 cervical tissue specimens were acquired from public databases. The UALCAN database was used to analyze the methylation level differences of 12 cuproptosis-related genes and study their level in different stages or grades of cervical cancer. Genes with statistically significant differences were selected for prognosis analysis using the EWAS datahub. Finally, gene-enrichment analysis, pathway analysis, immune infiltration analysis, the mutation rate and tumor mutation burden (TMB) of the genes in cervical cancer were analyzed using the cBioportal database. Two independent samples rank-sum test was used for differences in methylation levels and immune cell infiltration; comparative analyses of overall survival were performed using KM survival curves and Log-rank two-sided tests. TMB analyses were performed using the Wilcoxon Test for statistical analyses; Pearson correlation analysis was used for assessment in GSEA and pathway analyses.Results:The methylationβvalue of Cyclin Dependent Kinase Inhibitor 2A (CDKN2A gene) in the cervical cancer tissues of patients was 0.075 which was significantly higher than the methylationβvalue of 0.049 in normal human tissues ( P=0.008). Dihydrolipoamide S-Acetyltransferase (DLAT gene) methylation with a β value of 0.102 was significantly higher than normal human tissue methylation with a β value of 0.08 ( P=0.002), and the methylation level β value of Lipoyltransferase 1 (LIPT1 gene) in cervical cancer tissues was 0.06,which was significantly lower than normal human tissue methylation value of 0.092 ( P=0.009). Patients with CDKN2A gene methylation levels≥0.199 had an overall survival of 14.75 years, which was lower than that of patients with methylation levels<0.199 (17.56 years) ( P=0.034).The results of gene enrichment analysis indicated that it mainly involves biological processes such as the response to type I interferon and DNA replication. The expression of CDKN2A gene is positively correlated with the number of neutrophils and dendritic cells in the tumor microenvironment( P<0.05), and negatively correlated with the number ofmacrophages( P<0.05). TMB was higher in the group of variants of the CDKN2A gene than in the group of non-variants ( P=0.019). Conclusion:CDKN2A methylation is a potential biomarker for predicting the prognosis of cervical cancer.

Objective:To investigate the correlation between hearing loss and microvascular complications in diabetes.Methods:This cross-sectional study conducted the data from 572 patients with diabetes hospitalized in the Endocrinology Department of the General Hospital of Southern Theater Command from September 2022 to July 2023. All participants underwent electrical audiometry and acoustic immittance in the ENY department. Based on the audiometric results, participants were categorized into normal hearing group and hearing loss group. Additionally, 572 non-diabetic patients from the outpatient department were enrolled as the non-diabetic group. The general information and laboratory results were collected and compared using t test, rank sum test or χ2 test. Binary logistic regression analysis was used to evaluate the association of diabetic hearing loss with diabetic kidney disease(DKD), diabetic retinopathy (DR), and diabetic peripheral neuropathy (DPN). Results:Among 572 patients with diabetes, 429 suffered from hearing loss and 143 were normal. χ2 test showed significant differences in combined DKD and DPN between two groups, but not in DR. Multivariate binary logistic regression analysis identified DKD and DPN as risk factors for hearing loss, but no correlation was found with DR. Conclusion:Diabetic patients with DKD or DPN should be monitored for potential hearing loss. Early screening and treatment are crucial to prevent severe hearing impairment.

Objective To analyze the pharmacodynamic interaction of esketamine and propofol in hysteroscopic surgery by response surface method.Methods Forty-five patients underwent elective hystero-scopic surgery,aged 18.5-64.0 years,BMI 18.5-28.0 kg/m2,ASA physical status Ⅰ or Ⅱ.Compound propofol target control infusion of esketamine(0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,and 0.8 μg/ml)with different plasma drug concentrations were selected to keep the plasma drug concentration of esketamine unchanged,and the plasma drug concentration of propofol was increased step by step.To evaluate body re-sponse caused by dilation of the cervix.A response surface model was used to analyze the pharmacodynamic interaction of esketamine and propofol.Results The three-dimensional response surface of esketamine(0.0-0.8 μg/ml)and propofol(1.0-7.0 μg/ml)showed that the two have an additive effect in sedation and inhibition of body activity reaction caused by dilated cervix.The median effective concentration(EC50)of esketamine was 0.61 μg/ml(95％CI 0.41-0.81 μg/ml),and the EC50 of propofol was 4.69 μg/ml(95％CI 3.17-6.21 μg/ml)when inhibits the body activity reaction caused by dilated cervix.Conclusion Response surface method can qualitatively and quantitatively analyze the pharmacodynamic interaction of es-ketamine and propofol.Esketamine and propofol have additive effects in inhibiting the body activity reaction caused by dilated cervix.

The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system has been widely used for genome engineering and transcriptional regulation in many different organisms. Current CRISPR-activation (CRISPRa) platforms often require multiple components because of inefficient transcriptional activation. Here, we fused different phase-separation proteins to dCas9-VPR (dCas9-VP64-P65-RTA) and observed robust increases in transcriptional activation efficiency. Notably, human NUP98 (nucleoporin 98) and FUS (fused in sarcoma) IDR domains were best at enhancing dCas9-VPR activity, with dCas9-VPR-FUS IDR (VPRF) outperforming the other CRISPRa systems tested in this study in both activation efficiency and system simplicity. dCas9-VPRF overcomes the target strand bias and widens gRNA designing windows without affecting the off-target effect of dCas9-VPR. These findings demonstrate the feasibility of using phase-separation proteins to assist in the regulation of gene expression and support the broad appeal of the dCas9-VPRF system in basic and clinical applications.
Humans ; Transcriptional Activation ; RNA, Guide, CRISPR-Cas Systems ; Gene Expression Regulation ; CRISPR-Cas Systems/genetics*

Metabolic reprogramming is a hallmark of cancer, including lung cancer. However, the exact underlying mechanism and therapeutic potential are largely unknown. Here we report that protein arginine methyltransferase 6 (PRMT6) is highly expressed in lung cancer and is required for cell metabolism, tumorigenicity, and cisplatin response of lung cancer. PRMT6 regulated the oxidative pentose phosphate pathway (PPP) flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phospho-gluconate dehydrogenase (6PGD) and α-enolase (ENO1). Furthermore, PRMT6 methylated R324 of 6PGD to enhancing its activity; while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate (2-PG) binding to ENO1, respectively. Lastly, targeting PRMT6 blocked the oxidative PPP flux, glycolysis pathway, and tumor growth, as well as enhanced the anti-tumor effects of cisplatin in lung cancer. Together, this study demonstrates that PRMT6 acts as a post-translational modification (PTM) regulator of glucose metabolism, which leads to the pathogenesis of lung cancer. It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

Objective:To investigate the impact of sarcopenia on mortality in maintenance hemodialysis (MHD) patients.Methods:It was a retrospective cohort study. MHD patients admitted to the blood purification center of Guangzhou Red Cross Hospital in March 2021 were recruited. Demographic data and laboratory indicators, grip strength, and bioelectrical impedance analysis indexes were collected. The patients were divided into sarcopenia group and non-sarcopenia group based on whether they had sarcopenia or not. By following up for 18 months, the survival status of the patients was documented. Kaplan-Meier method, multivariate Cox regression model, and Fine-Gray competing risk model were used to assess the relationship between sarcopenia and all-cause mortality, cardio-cerebrovascular disease mortality, and infection-related disease mortality.Results:A total of 143 MHD patients were enrolled in this study, with age of 65 (58,74) years old and 89 males (62.24%). The prevalence of sarcopenia was 25.17% (36/143). The sarcopenia group had older age ( Z=3.486, P<0.001), higher single-pool Kt/V ( Z=3.634, P<0.001), interleukin-6 ( Z=3.434, P<0.001) and extracellular water/intracellular water ratio ( Z=2.477, P=0.013), and lower body mass index ( Z=-3.210, P=0.001), serum phosphorus ( t=2.475, P=0.015), serum creatinine ( t=3.319, P=0.001), serum albumin ( t=2.851, P=0.005), serum prealbumin ( t=3.384, P<0.001), extracellular water ( Z=-5.124, P<0.001), intracellular water ( Z=-5.417, P<0.001), grip strength ( Z=-3.796, P<0.001) and appendicular skeletal muscle mass index ( t=3.862, P<0.001) than those in the non-sarcopenia group. Kaplan-Meier survival curves showed that the overall survival rate in the sarcopenia group was lower than that in the non-sarcopenia group (Log-rank test χ2=15.99, P<0.001). Multivariable Cox regression analysis demonstrated that sarcopenia was independently correlated with all-cause mortality in MHD patients after adjusting for confounding factors ( HR=2.75, 95% CI 1.07-7.10, P=0.036). Fine-Gray competing risk model result showed that there was no statistically significant difference in cardio-cerebrovascular disease mortality between sarcopenia group and non-sarcopenia group ( SHR=4.99, 95% CI 0.94-26.85, P=0.069); the risk of infection-related disease mortality in sarcopenia group was 5.76 folds than that in non-sarcopenia group ( SHR=5.76, 95% CI 1.15-28.96, P=0.034). Conclusions:There is prevalent sarcopenia in MHD patients. Moreover, sarcopenia is an independent risk factor of all-cause mortality and infection-related disease mortality in MHD patients.