Celastrol Combats Methicillin-Resistant Staphylococcus aureus by Targeting Δ1 -Pyrroline-5-Carboxylate Dehydrogenase.

The emergence and rapid spread of methicillin-resistant Staphylococcus aureus (MRSA) raise a critical need for alternative therapeutic options. New antibacterial drugs and targets are required to combat MRSA-associated infections. Based on this study, celastrol, a natural product from the roots of Tripterygium wilfordii Hook. f., effectively combats MRSA in vitro and in vivo. Multi-omics analysis suggests that the molecular mechanism of action of celastrol may be related to Δ1 -pyrroline-5-carboxylate dehydrogenase (P5CDH). By comparing the properties of wild-type and rocA-deficient MRSA strains, it is demonstrated that P5CDH, the second enzyme of the proline catabolism pathway, is a tentative new target for antibacterial agents. Using molecular docking, bio-layer interferometry, and enzyme activity assays, it is confirmed that celastrol can affect the function of P5CDH. Furthermore, it is found through site-directed protein mutagenesis that the Lys205 and Glu208 residues are key for celastrol binding to P5CDH. Finally, mechanistic studies show that celastrol induces oxidative stress and inhibits DNA synthesis by binding to P5CDH. The findings of this study indicate that celastrol is a promising lead compound and validate P5CDH as a potential target for the development of novel drugs against MRSA.

Serum Metabolomic Profiles for Distinguishing Lung Cancer From Pulmonary Tuberculosis: Identification of Rapid and Noninvasive Biomarker.

BACKGROUND: Pulmonary tuberculosis (PTB) and lung cancer (LC) have similar clinical symptoms and atypical imaging findings, which are easily misdiagnosed. There is an urgent need for a noninvasive and accurate biomarker to distinguish LC from PTB. METHODS: A total of 694 subjects were enrolled and divided into discovery set (n = 122), identification set (n = 214), and validation set (n = 358). Metabolites were identified by multivariate and univariate analyses. Receiver operating characteristic curve were used to evaluate the diagnostic efficacy of biomarkers. RESULTS: Seven metabolites were identified and validated. Phenylalanylphenylalanine for distinguishing LC from PTB yielded an area under the curve of 0.89, sensitivity of 71%, and specificity of 92%. It also showed good diagnostic abilities in discovery set and identification set. Compared with that in healthy volunteers (median [interquartile range], 1.57 [1.01, 2.34] µg/mL), it was elevated in LC (4.76 [2.74, 7.08] µg/mL; ratio of median, [ROM] = 3.03, P < .01) and reduced in PTB (1.06 [0.51, 2.09] µg/mL; ROM = 0.68, P < .05). CONCLUSIONS: The metabolomic profile of LC and PTB was described and a key biomarker identified. We produced a rapid and noninvasive method to supplement existing clinical diagnostic examinations for distinguishing LC from PTB.

Comparative efficacy of Chinese herbal injections for treating severe pneumonia: A protocol for systematic review and Bayesian network meta-analysis of randomized controlled trials.

BACKGROUND: Severe pneumonia (SP) has a high mortality and is responsible for significant healthcare cost. Chinese herbal injections (CHIs) have been widely used in China as a novel and promising treatment option for SP. Therefore, this study will assess and rank the effectiveness of CHIs to provide more sights for the selection of SP treatment. METHOD: Seven databases will be searched, including PubMed, the Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Database, and the Chinese Scientific Journal Database (VIP) from their inception up to October, 2021. The literatures screening, data extraction and the quality assessment of included studies will be conducted independently by two reviewers. Then Bayesian network meta-analysis (NMA) will be performed by WinBUGS 14.0 and STATA 14.0 software. Surface under the cumulative ranking curve (SUCRA) probability values will be applied to rank the examined treatments. The risk of bias of each included study will be evaluated using the Revised Cochrane risk-of-bias tool for randomized trials (ROB 2). Publication bias will be reflected by a funnel plot. RESULTS: The results of this NMA will be disseminated through a peer-reviewed journal publication. CONCLUSION: Our study findings maybe reveal which CHI or CHIs will be better in the treatment of SP and provide more therapy strategies for clinical practitioners and patients. PROSPERO REGISTRATION NUMBER: CRD42021244587. STRENGTHS AND LIMITATIONS OF THIS STUDY: Bayesian network meta-analysis (NMA) can integrate direct evidence with indirect evidence of severe pneumonia treated by Chinese herbal injections to generate a clinically useful ranking of these regimens. This NMA will address Chinese herbal injections for SP and its findings may help to provide more sights for selection of SP treatment. Evidence drawn from an NMA is limited and should be interpreted with caution. We only included studies in Chinese and English languages, which may increase the publication bias.

[A comparison of the infection related critical illness scores for predicting mortality in patients with infection or suspected infection: a network Meta-analysis].

OBJECTIVE: To evaluate the prognostic accuracy of the sequential organ failure assessment (SOFA), quick sequential organ failure assessment (qSOFA) and systemic inflammatory response syndrome (SIRS) criteria in predicting the mortality in patients with infection or suspected infection by using network Meta-analysis. METHODS: Five databases including Wanfang Data, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), PubMed, Web of Science were searched from February 23, 2016 to September 5, 2020 to identify the relevant literatures comparing the prognostic accuracy of two or more scores for mortality in patients with infection or suspected infection. The literatures screening, data extraction and the quality assessment of the included studies were all conducted independently by two reviewers. Stata 14.0 software was used to test the heterogeneity between the original studies of pairwise comparison of each of the three scoring systems. Ring inconsistency test was used to judge the consistency between direct comparison and indirect comparison. Then network Meta-analysis was performed and the results were ranked. The predictive ability of the three scoring systems was evaluated by surface under cumulative ranking curve (SUCRA). A "comparison-correction" funnel plot was drawn to assess whether there was publication bias in the included studies. RESULTS: A total of 38 studies were enrolled, the overall quality was high. Network meta-analysis showed that SOFA had a great prognostic performance in predicting mortality for patients with infection or suspected infection, which was followed by qSOFA [mean difference (MD) = 0.07, 95% confidence interval (95%CI) was 0.05-0.09] and SIRS scores (MD = 0.16, 95%CI was 0.14-0.18), and the qSOFA score was better than SIRS score (MD = 0.09, 95%CI was 0.07-0.11). In the order of predicting the death risk of patients with infection or suspected infection, SOFA score had higher predictive value, followed by qSOFA score, and SIRS score was the lowest, with SUCRA values of 1.0, 0.5 and 0, respectively. Funnel plot showed that all the studies were distributed on both sides of the midline, but the distribution was not symmetrical, suggesting that there was a high possibility of publication bias and small sample effect. CONCLUSIONS: SOFA score had the best prognostic performance in predicting mortality of patients with infection or suspected infection as compared with qSOFA score and SIRS score. However, the funnel plot showed that included literatures may exist small sample effects or publication bias. So the final results should be validated by more prospective studies with multicenters and large samples.

[Network Meta-analysis of Chinese medical injections for heart failure].

To assess the clinical efficacy of Chinese medical injection (CMI) for heart failure by using network Meta-analysis method. The relative randomized controlled trials (RCTs) of CMI for heart failure were retrieved from China National Knowledge Infrastructure (CNKI), WanFang Database, Chinese Biomedical Literature Database (SinoMed), PubMed, Cochrane Library and EMbase in July 2017. RCTs on the comparison of two kinds of CMIs for heart failure were included. Two researchers independently completed the literature screening, data extraction and quality evaluation according to the pre-determined inclusion and exclusion criteria, and the results were crossed checked. The data were analyzed by Win Bugs, and STATA software was used for plotting. Finally, 13 RCTs were included, involving 5 kinds of CMIs and 1 538 patients. According to the quality evaluation, the appropriate random dividing methods were reported in only two RCTs, double-blindness was used in only one RCT, and even none of the RCTs mentioned allocation concealment. Network Meta-analysis showed that Shenmai injection had the greatest effect in the clinical efficacy for patients with heart failure, which was followed by Shenfu Injection. However, Shenfu Injection was most effective in improving the patients' left ventricular ejection fraction (LVEF), which was followed by Shenmai Injection. Therefore, Shenfu Injection and Shenmai Injection had certain advantages in treating heart failure. However, due to the limited sample size and the poor literature quality, more studies were required to verify the strength of evidence. We suggest that further studies shall pay more attention to the improvement of the methodological quality, increase the follow-up period, and strengthen the observation of cardiovascular end points.