[Effect of Tetrastigma hemsleyanum on sepsis and mechanism based on network pharmacology and experimental verification].

Based on network pharmacology and in vivo experiment, this study explored the therapeutic effect of Tetrastigma hemsle-yanum(SYQ) on sepsis and the underlying mechanism. The common targets of SYQ and sepsis were screened out by network pharmacology, and the "SYQ-component-target-sepsis" network was constructed. The protein-protein interaction(PPI) network was established by STRING. Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment were performed based on DAVID to predict the anti-sepsis mechanism of SYQ. The prediction results of network pharmacology were verified by animal experiment. The network pharmacology results showed that the key anti-sepsis targets of SYQ were tumor necrosis factor(TNF), interleukin(IL)-6, IL-1ß, IL-10, and cysteinyl asparate specific proteinase 3(caspase-3), which were mainly involved in Toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88)/nuclear factor kappaB(NF-κB) signaling pathway. The results of animal experiment showed that SYQ can decrease the content of C-reactive protein(CRP), procalcitonin(PCT), lactate dehydrogenase(LDH), IL-6, TNF-α, and IL-1ß, increase the content of IL-10, and down-regulate the protein levels of Bcl-2-associa-ted X(Bax)/B-cell lymphoma 2(Bcl2), cleaved caspase-3, TLR4, MyD88, and p-NF-κB p65/NF-κB p65. In summary, SYQ plays an anti-inflammatory role in the treatment of sepsis by acting on the key genes related to inflammation and apoptosis, such as TNF-α, IL-6, IL-lß, IL-10, Bax, Bcl2, and cleaved caspase-3. The mechanism is the likelihood that it suppresses the TLR4/MyD88/NF-κB signaling pathway, which verifies relative prediction results of network pharmacology.

Erythrocyte and plasma selenium in children with acute inflammatory response.

OBJECTIVES: Plasma selenium may not reflect selenium status in critically ill patients because it transiently decreases inversely with the magnitude of the systemic inflammatory response. The decision to supplement selenium should ideally be based on laboratory measurements that reliably reflect selenium status. We hypothesized that erythrocyte selenium, unlike plasma selenium, is not affected by the systemic inflammatory response in critically ill children. METHODS: In a prospective study of 109 critically ill children, plasma and erythrocyte selenium concentrations were evaluated on admission, and plasma selenoprotein P was evaluated on days 1, 2, and 3 of the ICU stay. The main outcome was the effect of systemic inflammation on the erythrocyte and plasma selenium concentrations. The magnitude of the systemic inflammatory response was measured using serum C-reactive protein (CRP) and procalcitonin levels. The covariates were age, sex, anthropometric nutritional status, diagnosis of severe sepsis/septic shock, and clinical severity on admission. Multiple linear regression and generalized estimating equations were used for statistical analysis. RESULTS: Erythrocyte selenium levels were not influenced by the magnitude of the inflammatory response or by the patient's clinical severity. Procalcitonin (ß coefficient=-0.99; 95%CI: -1.64; -0.34, p = 0.003) and clinical severity (ß coefficient= -11.13; 95%CI: -21.6; -0.63), p = 0.038) on admission were associated with decreased plasma selenium concentrations. Erythrocyte selenium was associated with selenoprotein P in the first three days of ICU stay (ß coefficient=0.32; 95%CI: 0.20; 0.44, p < 0.001). CONCLUSION: Unlike plasma selenium, erythrocyte selenium does not change in children with an acute systemic inflammatory response and is associated with selenoprotein P concentrations. Erythrocyte selenium is probably a more reliable marker than plasma selenium for evaluating the selenium status in critically ill children.

Procalcitonin metabolomics in the critically ill reveal relationships between inflammation intensity and energy utilization pathways.

Procalcitonin is a biomarker of systemic inflammation and may have importance in the immune response. The metabolic response to elevated procalcitonin in critical illness is not known. The response to inflammation is vitally important to understanding metabolism alterations during extreme stress. Our aim was to determine if patients with elevated procalcitonin have differences in the metabolomic response to early critical illness. We performed a metabolomics study of the VITdAL-ICU trial where subjects received high dose vitamin D3 or placebo. Mixed-effects modeling was used to study changes in metabolites over time relative to procalcitonin levels adjusted for age, Simplified Acute Physiology Score II, admission diagnosis, day 0 25-hydroxyvitamin D level, and the 25-hydroxyvitamin D response to intervention. With elevated procalcitonin, multiple members of the short and medium chain acylcarnitine, dicarboxylate fatty acid, branched-chain amino acid, and pentose phosphate pathway metabolite classes had significantly positive false discovery rate corrected associations. Further, multiple long chain acylcarnitines and lysophosphatidylcholines had significantly negative false discovery rate corrected associations with elevated procalcitonin. Gaussian graphical model analysis revealed functional modules specific to elevated procalcitonin. Our findings show that metabolite differences exist with increased procalcitonin indicating activation of branched chain amino acid dehydrogenase and a metabolic shift.

Individualising Therapy to Minimize Bacterial Multidrug Resistance.

The scourge of antibiotic resistance threatens modern healthcare delivery. A contributing factor to this significant issue may be antibiotic dosing, whereby standard antibiotic regimens are unable to suppress the emergence of antibiotic resistance. This article aims to review the role of pharmacokinetic and pharmacodynamic (PK/PD) measures for optimising antibiotic therapy to minimise resistance emergence. It also seeks to describe the utility of combination antibiotic therapy for suppression of resistance and summarise the role of biomarkers in individualising antibiotic therapy. Scientific journals indexed in PubMed and Web of Science were searched to identify relevant articles and summarise existing evidence. Studies suggest that optimising antibiotic dosing to attain defined PK/PD ratios may limit the emergence of resistance. A maximum aminoglycoside concentration to minimum inhibitory concentration (MIC) ratio of > 20, a fluoroquinolone area under the concentration-time curve to MIC ratio of > 285 and a ß-lactam trough concentration of > 6 × MIC are likely required for resistance suppression. In vitro studies demonstrate a clear advantage for some antibiotic combinations. However, clinical evidence is limited, suggesting that the use of combination regimens should be assessed on an individual patient basis. Biomarkers, such as procalcitonin, may help to individualise and reduce the duration of antibiotic treatment, which may minimise antibiotic resistance emergence during therapy. Future studies should translate laboratory-based studies into clinical trials and validate the appropriate clinical PK/PD predictors required for resistance suppression in vivo. Other adjunct strategies, such as biomarker-guided therapy or the use of antibiotic combinations require further investigation.