Guideline development should be based on the quality of evidence, balance of benefits and harms, economic evaluation and patients' views and preferences. Therefore, these factors were considered in ...the development of a new guideline for therapeutic drug monitoring (TDM) of vancomycin.
To develop an evidence-based guideline for vancomycin TDM and to promote standardized vancomycin TDM in clinical practice in China.
We referred to the WHO Handbook for Guideline Development and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence and grade the strength of recommendations, according to economic evaluation and patients' views and preferences. We used the GRADE Grid method to formulate the recommendations.
The guideline presents recommendations about who should receive vancomycin TDM, how to monitor vancomycin efficacy and renal safety, therapeutic trough concentrations, time to start initial vancomycin TDM, loading dose and how to administer and adjust the vancomycin dose.
We developed an evidence-based guideline for vancomycin TDM, which provides recommendations for clinicians and pharmacists to conduct vancomycin TDM in China.
Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, but there is no effective drug available for GBM. Avasimibe is a potent inhibitor of acyl-coenzyme A: cholesterol ...acyltransferase-1 (ACAT-1), which was used to treat atherosclerosis. Experimental evidence and bioinformatics have shown that avasimibe has anticancer activity. In this study we investigated the anticancer effects of avasimibe on human glioblastoma cells and the underlying mechanisms. Our results showed that avasimibe dose-dependently inhibited the proliferation of U251 and U87 human glioblastoma cells with IC
values of 20.29 and 28.27 μM, respectively, at 48 h. Avasimibe (7.5, 15, 30 μM) decreased the DNA synthesis, and inhibited the colony formation of the tumor cells. Treatment of avasimibe also dose-dependently increased the apoptotic rate of tumor cells, decreased the mitochondrial membrane potential, induced the activity of caspase-3/7, and increased the protein expression of cleaved caspase-9, cleaved PARP and Bax in U251 and U87 cells. RNA-sequencing analyses revealed that avasimibe suppressed the expression of CDK2, cyclin E1, CDK4, cyclin D, CDK1, cyclin B1, Aurora A, and PLK1, while induced the expression of p53, p21, p27, and GADD45A, which was validated by Western blot analysis. These results demonstrated that avasimibe induced mitochondria-dependent apoptosis in glioblastoma cells, which was associated with arresting the cell cycle at G0/G1 phase and G2/M phase by regulating the p53/p21 pathway, p53/GADD45A and Aurora A/PLK1 signaling pathways. In U87 xenograft nude mice model, administration of avasimibe (15, 30 mg·kg
·d
, ip, for 18 days) dose-dependently inhibit the tumor growth. Taken together, our results demonstrated that avasimibe might be a promising chemotherapy drug in the treatment of GBM.
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Berberine (BBR) is a non-prescription drug to treat various bacteria-associated diarrheas. However, BBR has also been reported to cause diarrhea in clinic, with underlying mechanisms ...poorly understood. Because altered gut microbial ecology is a potential basis for diarrhea, this study was conducted to investigate the impact of BBR on gut microbiota of treatment-emergent diarrhea. BBR treatment (200 mg/kg, i.g.) in normal rats exhibited no significant changes in serum biochemical parameters but mild diarrhea occurred, accompanied with the decreased gastrointestinal transit time and increased fecal moisture, suggestive of the local effects of BBR in the intestine. Colon histology revealed the decreased abundance of mucus-filled goblet cells in BBR group. Although BBR-treated rats had the enlarged cecum with watery caecal digesta, short-chain fatty acids concentration was significantly lower than control group. Additionally, BBR caused gut microbiota dysbiosis by evaluating the decreased observed species number and Shannon index. BBR increased the relative abundances of families Porphyromonadaceae and Prevotellaceae as well as genera Parabacteroides, Prevotellaceae_UCG-001 and Prevotellaceae_NK3B31_group. Spearman’s correlation analysis revealed family Prevotellaceae and genus Prevotellaceae_UCG-001 as the most prominent drivers of the BBR treatment-emergent diarrhea, correlating positively with fecal moisture but negatively with gastrointestinal transit time. This study therefore demonstrated that the treatment-emergent mild diarrhea of BBR was most likely due to the dysbiosis of the gut microbiota.
The purpose of the present study was to examine the protective action and mechanisms of quercetin on the blood-brain barrier (BBB) in rats subjected to transient middle cerebral artery occlusion ...(tMCAO) and reperfusion. Quercetin (10, 30, 50 mg/kg) was intraperitoneally administered at the onset of reperfusion. The results showed that quercetin significantly reduced cerebral infarct volume, neurological deficit, BBB permeability and ROS generation via Sirt1/Nrf2/HO-1 signaling pathway. Moreover, EX527, a selective inhibitor of Sirt1, reversed these neuroprotective effects. Our findings indicate that quercetin has neuroprotective effects against cerebral ischemia-reperfusion injury by protecting BBB through Sirt1 signaling pathway in MCAO rats.
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TLR4 signal activated by lipopolysaccharide (LPS) is involved in the pathological process of the central nervous system (CNS) diseases and the suppression of TLR4 signal may become an effective ...treatment. TLR4-IN-C34, a TLR4 inhibitor, is expected to become a candidate compound with anti-neuroinflammatory response. In the present study, the anti-neuroinflammatory effects and possible mechanism of TLR4-IN-C34 were investigated in BV2 microglia cells stimulated by LPS. The results showed that TLR4-IN-C34 decreased the levels of pro-inflammatory factors and chemokines including NO, TNF-α, IL-1β, IL-6, and MCP-1 in the supernatant of LPS-stimulated BV2 cells. Further research indicated that TLR4-IN-C34 suppressed the expression or phosphorylation levels of inflammatory proteins regarding TLR4/MyD88/NF-κB/NLRP3 signaling pathway. In addition, TLR4-IN-C34 reduced ROS production in BV2 cells after LPS treatment. In conclusion, our findings suggest that anti-neuroinflammatory activity of TLR4-IN-C34 may be interrelated to the inhibition of TLR4/MyD88/NF-κB/NLRP3 signaling pathway and reduction of ROS generation.
•Cerebral I/R aggravates neurological function injury and neuroinflammation.•TLR4/MyD88 inflammatory signaling pathway plays an important role after cerebral I/R.•HRAS/RAF1 neurotrophic signaling ...pathway plays an important roles after cerebral I/R.
Numerous studies have shown that local excessive inflammatory response in brain tissue was an important pathogenesis of secondary injury following cerebral ischemia-reperfusion (I/R). However, the inflammatory-related targets and pathways after cerebral I/R injury are still unclear. This study was to investigate possible targets and mechanisms after cerebral I/R injury. Rats were subjected to transient or permanent middle cerebral artery occlusion (MCAO). Neurological deficit scores test was used to evaluate neurological function. Cerebral infarction was evaluated by MRI, TTC staining and Nissl staining. Microglia activation was detected by immunofluorescence using Iba-1 antibody. Inflammatory factors were detected by ELISA assay. RNA-sequencing transcriptome analysis was processed and the differential genes were verified by real-time quantitative PCR (qPCR) and western blotting. The results showed that neurological function of rats in I/R group was more severe than that in I group on the 7th after cerebral I/R. Therefore, the differences between cerebral ischemia and cerebral I/R for 7 days were studied in further study. The results showed that the levels of pro-inflammatory factors in I/R group were higher and the levels of anti-inflammatory factors were lower than those in I group. KEGG pathway and gene network enrichment analysis revealed that some common differential up- and down-regulated genes were involved in most of significant pathways. These common differential up-regulated genes belonged to TLR4/MYD88 inflammatory signaling pathway and common differential down-regulated genes belonged to HRAS/RAF1 neurotrophic signaling pathway. Interestingly, according to the genetic interaction analysis of string database, these up-regulated differential genes might promote the development of inflammation, while the down-regulated differential genes might inhibit the development of inflammation. Furthermore, qPCR and WB results verified that these pro-inflammatory genes in the I/R group were higher than those in the I group, while possible anti-inflammatory genes in the I/R group were lower than those in the I group. It is concluded that TLR4/MYD88 inflammatory signaling pathway and HRAS/RAF1 neurotrophic signaling pathway may play different roles after cerebral I or I/R and may be therapeutic targets for stroke recovery.
•Long-term PM1 and PM2.5 exposure can lead to decreased lung function in children.•Association of PM1 with children's lung function are larger than PM2.5.•PM1 and PM2.5 are associated with children’s ...large/small airways in early/late life.
Experimental data suggests that PM1 is more toxic than PM2.5 although the epidemiologic evidence suggests that the health associations are similar. However, few objective exposure data are available to compare the associations of PM1 and PM2.5 with children lung function. Our objectives are a) to evaluate associations between long-term exposure to PM1, PM2.5 and children’s lung function, and b) to compare the associations between PM1 and PM2.5. From 2012 to 2013, we enrolled 6,740 children (7–14 years), randomly recruited from primary and middle schools located in seven cities in northeast China. We measured lung function including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF), and maximal mid-expiratory flow (MMEF) utilizing two portable electronic spirometers. We dichotomized continuous lung function measures according the expected values for gender and age. The spatial resolution at which PM1 and PM2.5 estimated were estimated using a machine learning method and the temporal average concentrations were averaged from 2009 to 2012. A multilevel regression model was used to estimate the associations of PM1, PM2.5 exposure and lung function measures, adjusted for confounding factors. Associations with lower lung function were consistently larger for PM1 than for PM2.5. Adjusted odds ratios (OR) per interquartile range greater PM1 ranged from 1.53 for MMEF (95% confidence interval CI: 1.20–1.96) to 2.14 for FEV1 (95% CI: 1.66–2.76) and ORs for PM2.5 ranged from 1.36 for MMEF (95%CI: 1.12–1.66) to 1.82 for FEV1 (95%CI: 1.49–2.22), respectively. PM1 and PM2.5 had significant associations with FVC and FEV1 in primary school children, and on PEF and MMEF in middle school children. Long-term PM1 and PM2.5 exposure can lead to decreased lung function in children, and the associations of PM1 are stronger than PM2.5. Therefore, PM1 may be more hazardous to children’s respiratory health than PM2.5 exposure.
To determine chemical–protein interactions (CPI) is costly, time-consuming, and labor-intensive. In silico prediction of CPI can facilitate the target identification and drug discovery. Although many ...in silico target prediction tools have been developed, few of them could predict active molecules against multitarget for a single disease. In this investigation, naive Bayesian (NB) and recursive partitioning (RP) algorithms were applied to construct classifiers for predicting the active molecules against 25 key targets toward Alzheimer’s disease (AD) using the multitarget-quantitative structure–activity relationships (mt-QSAR) method. Each molecule was initially represented with two kinds of fingerprint descriptors (ECFP6 and MACCS). One hundred classifiers were constructed, and their performance was evaluated and verified with internally 5-fold cross-validation and external test set validation. The range of the area under the receiver operating characteristic curve (ROC) for the test sets was from 0.741 to 1.0, with an average of 0.965. In addition, the important fragments for multitarget against AD given by NB classifiers were also analyzed. Finally, the validated models were employed to systematically predict the potential targets for six approved anti-AD drugs and 19 known active compounds related to AD. The prediction results were confirmed by reported bioactivity data and our in vitro experimental validation, resulting in several multitarget-directed ligands (MTDLs) against AD, including seven acetylcholinesterase (AChE) inhibitors ranging from 0.442 to 72.26 μM and four histamine receptor 3 (H3R) antagonists ranging from 0.308 to 58.6 μM. To be exciting, the best MTDL DL0410 was identified as an dual cholinesterase inhibitor with IC50 values of 0.442 μM (AChE) and 3.57 μM (BuChE) as well as a H3R antagonist with an IC50 of 0.308 μM. This investigation is the first report using mt-QASR approach to predict chemical–protein interaction for a single disease and discovering highly potent MTDLs. This protocol may be useful for in silico multitarget prediction of other diseases.
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