Glycyrrhetinic Acid Triggers a Protective Autophagy by Inhibiting the JAK2/STAT3 Pathway in Cerebral Ischemia/Reperfusion Injury.

Cerebral ischemia/reperfusion injury (CIRI) is a common feature of ischemic stroke leading to a poor prognosis. Effective treatments targeting I/R injury are still insufficient. The study aimed to investigate the mechanisms, by which glycyrrhizic acid (18ß-GA) in ameliorates CIRI. Our results showed that 18ß-GA significantly decreased the infarct volume, neurological deficit scores, and pathological changes in the brain tissue of rats after middle cerebral artery occlusion. Western blotting showed that 18ß-GA inhibited the expression levels of phosphorylated JAK2 and phosphorylated STAT3. Meanwhile, 18ß-GA increased LC3-II protein levels in a reperfusion duration-dependent manner, which was accompanied by an increase in the Bcl-2/Bax ratio. Inhibition of 18ß-GA-induced autophagy by 3-methyladenine (3-MA) enhanced apoptotic cell death. In addition, 18ß-GA inhibited the JAK2/STAT3 pathway, which was largely activated in response to oxygen-glucose deprivation/reoxygenation. However, the JAK2/STAT3 activator colivelin TFA abolished the inhibitory effect of 18ß-GA, suppressed autophagy, and significantly decreased the Bcl-2/Bax ratio. Taken together, these findings suggested that 18ß-GA pretreatment ameliorated CIRI partly by triggering a protective autophagy via the JAK2/STAT3 pathway. Therefore might be a potential drug candidate for treating ischemic stroke.

Application of quantitative EEG in acute ischemic stroke patients who underwent thrombectomy: A comparison with CT perfusion.

OBJECTIVE: This study aimed to evaluate the predictive value of quantitative electroencephalography (QEEG) in the outcome of patients with acute ischemic stroke (AIS) who underwent mechanical thrombectomy (MT) and to assess the correlation between clinical outcome and QEEG and CT perfusion (CTP) data. METHODS: Twenty-nine MT patients were included in this prospective study. Continuous electroencephalography (EEG) monitoring was performed, in which delta power, the δ/α ratio (DAR), and the (θ + Î´)/(α + ß) ratio (DTABR) were calculated. The clinical scores at different points were recorded. Based on the modified Ranking scale, the patients were divided into good and poor outcome groups. Several CTP parameters were recorded before MT. The correlation between QEEG, CTP parameters, and clinical scores was analyzed using the Spearman correlation analysis. The predictive value of QEEG indices and CTP parameters for the 3-month outcome was compared using the receiver operating characteristic (ROC) curve. RESULTS: Delta power except for 7 days after MT, DAR, DATBR, and several CTP parameters were all significantly associated with the clinical scores. Although some CTP parameters were associated with the clinical scores, they were less powerful than QEEG in predicting a good or poor outcome at 3 months. Among the different explored EEG indicators, the predictive value of delta 24 h after MT was the highest. CONCLUSIONS: QEEG indices may have a certain predictive value for the outcome of AIS patients who underwent MT. SIGNIFICANCE: QEEG may become a new prognostic tool in AIS patients who underwent MT, facilitating the planning and management of related rehabilitation plans.

Reduction of gut microbial diversity and short chain fatty acids in BALB/c mice exposure to microcystin-LR.

Gut microbiota has been shown to play critical roles in host health. The present study was to determine the toxicological effects of microcystin-LR (MCLR) on gut microbial community and metabolites using 16S rDNA sequencing and gas chromatography-mass spectrometry (GC-MS). MCLR was administered to BALB/c mice by gavage for eight weeks. Results of the microbial alpha-diversity (Sobs, Chao1, ACE and Shannon indexes) decreased in MCLR-treated group versus controls. Phylum Candidatus Saccharibacteria decreased significantly in MCLR-treated group versus controls. Correspondingly, more than thirties genera in relative abundance decreased, especially short chain fatty acid (SCFA)-producing bacteria (e.g., Alistipes and Ruminococcus). These results indicated that the gut microbial community structure was remarkably changed by MCLR. Furthermore, concentrations of SCFAs were significantly decreased after MCLR exposure (P < 0.01), where butyrate decreased as high as 4.9-fold. Consequently, sub-chronic exposure to MCLR could not only alter the microbial composition but metabolites. This study offered novel insights into the toxic mechanism of MCs from gut microbiota, and facilitated further clarification of risks to human health from MCs exposure.

Preparation and Characterization of PVA-Co-PE Drug-Loaded Nanofiber Membrane by Electrospinning Technology.

A new transdermal drug delivery system of nanofiber membrane with good biocompatibility and high drug loading was developed by electrospinning technology in this study. Using vinyl alcohol-co-ethylene (PVA-co-PE) polymer as a spinning matrix and non-steroidal anti-inflammatory drug (NSAID) sulindac (SUL) as a model drug, the SUL@PVA-co-PE nanofiber membrane was prepared and characterized systematically. The morphology, molecular vibrational transitions, thermogravimetric attributes, and in vitro drug release and transdermal characteristics of drug-loaded nanofiber membranes were analyzed. The results indicated that the surface of PVA-co-PE nanofibers was uniform and smooth with the diameter ranged from 461 to 696 nm. Notably in vitro simulation experiments demonstrated that SUL@PVA-co-PE nanofiber membrane could provide a continuous drug release to reach the effective concentration of the drug, and exhibited significantly higher cumulative drug permeability compared to commercially available patches, Taken together, PVA-co-PE nanofiber membranes exhibited the characteristics of high drug loading and stability, and represented the potential to be utilized as a new transdermal drug delivery carrier with pronounced development prospect.

Pharmacokinetics, Tissue Distribution, and Druggability Prediction of the Natural Anticancer Active Compound Cytisine N-Isoflavones Combined with Computer Simulation.

Cytisine N-methylene-(5,7-dihydroxy-4'-methoxy)-isoflavone (CNF2) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides. Preliminary pharmacodynamic studies demonstrated its activity in inhibiting breast cancer cell metastasis. This study examined the pharmacokinetics, absolute bioavailability, and tissue distribution of CNF2 in rats, and combined computer-aided technology to predict the druggability of CNF2. The binding site of CNF2 and the breast cancer target human epidermal growth factor receptor-2 (HER2) were examined with molecular docking technology. Next, ACD/Percepta software was used to predict the druggability of CNF2 based on the quantitative structure-activity relationship (QSAR). Finally, a simple and effective HPLC method was used to determine plasma pharmacokinetics and tissue distribution of CNF2 in rats. Prediction and experimental results show that compared with the positive control HER2 inhibitor SYR127063, CNF2 has a stronger binding affinity with HER2, suggesting that its efficacy is stronger; and the structure of CNF2 complies with the Lipinski's Rule of Five and has good drug-likeness. The residence time of CNF2 in rats is less than 4 h, and the metabolic rate is relatively fast; But the absolute bioavailability of CNF2 in rats was 6.6%, mainly distributed in the stomach, intestine, and lung tissues, where the CNF2 contents were 401.20, 144.01, and 245.82 µg/g, respectively. This study constructed rapid screening and preliminary evaluation of active compounds, which provided important references for the development and further research of such compounds.