The combination of tetracyclines effectively ameliorates liver fibrosis via inhibition of EphB1/2.

Eph receptor tyrosine kinase EphB1/2 contributes to the development of liver fibrosis, suggesting the rationale that EphB1/2 inhibitors may be effective in liver fibrosis therapy. Since tetracycline antibiotics were recently demonstrated as EphB kinase inhibitors, in present study we investigated their therapeutic potential against liver fibrosis. Our results showed that the tetracycline combination of demeclocycline (D), chlortetracycline (C), and minocycline (M) inhibited the activation of hepatic stellate cells (HSCs) in vitro and alleviated CCl4-induced animal model of liver fibrosis in vivo. Mechanistically, DCM combination inhibited EphB1/2 phosphorylation and subsequent activation of the MAPK signaling. Moreover, we found that short-term and low-dose DCM combination treatment decreased tissue inflammation and improved liver fibrosis in mice. Thus, our study indicates that tetracyclines may be repurposed for the treatment of liver fibrosis.

Astrocyte KDM4A mediates chemokines and drives neutrophil infiltration to aggravate cerebral ischemia and reperfusion injury.

Neutrophils plays a crucial role in acute ischemic brain injury and have emerged as potential treatment targets to mitigate such injuries. Lysine-specific demethylase 4 A (KDM4A), a member of the histone lysine demethylase family of enzymes involved in transcriptional regulation of gene expression, is upregulated during hypoxic events. However, the exact role of KDM4A in the pathological process of ischemic stroke remains largely unexplored. Our findings reveal that there was an upregulation of KDM4A levels in reactive astrocytes within both stroke mouse models and in vitro oxygen-glucose deprivation/regeneration (OGD/R) models. Using a conditional knockout mouse, we observed that astrocytic Kdm4a knockout regulates neutrophil infiltration and alleviates brain injury following middle cerebral artery occlusion reperfusion. Furthermore, Kdm4a deficiency astrocytes displayed lower chemokine C-X-C motif ligand 1 (CXCL1) level upon OGD/R and decreased neutrophil infiltration in a transwell system. Mechanistically, KDM4A, in cooperation with nuclear factor-kappa B (NF-κB), activates Cxcl1 gene expression by demethylating histone H3 lysine 9 trimethylation at Cxcl1 gene promoters in astrocytes upon OGD/R injury. Our findings suggest that astrocyte KDM4A-mediated Cxcl1 activation contributes to neutrophil infiltration via cooperation with NF-κB, and KDM4A in astrocytes may serve as a potential therapeutic target to modulate neutrophil infiltration after stroke.

Atomic-Level Insights into Hollow Silica-Based Materials for Drug Delivery: Effects of Wettability and Porosity.

Experimental evidence has demonstrated that the drug carrier capacity can be significantly enhanced through the use of hollow silica particles. Nevertheless, the effects of varying functional drug carrier surfaces and porous structures remain ambiguous. This study employs molecular dynamics simulations to examine the effects of varying the surface wettability, pore size, and flow velocity on the transfer process. The different levels of wettability of the silica surface with the coarse-grained water model is illustrated by adjusted interaction parameters. The effect of wettability is investigated. With weak interactions, the flow molecules form a nanodroplet to transfer through the porous structure. A strong interaction will lead to molecules flowing as a liquid film to transfer through the structure. Interestingly, the "contradiction effect" is observed when the flow molecules fail to penetrate the porous structure with weak interactions, during which surface tension dominates their flow behavior. Moreover, different porous structures are considered. The flow behaviors are divided into three processes: (1) fast flowing, (2) transient point, and (3) penetration flowing. Furthermore, the concept of surface molecules is defined to quantitatively measure the effect of porosity. A recommended contact angle is proposed. The results will pave the way for more carrier structures in medical engineering.

Machine learning in predicting antimicrobial resistance: a systematic review and meta-analysis.

INTRODUCTION: Antimicrobial resistance (AMR) is a global health threat; rapid and timely identification of AMR improves patient prognosis and reduces inappropriate antibiotic use. METHODS: Relevant literature in PubMed, Web of Science, Embase and Institute of Electrical and Electronics Engineers prior to 28 September 2021 was searched. Any study that deployed machine learning (ML) or a risk score as a tool to predict AMR was included in the final review; there were 25 studies that employed the ML algorithm to predict AMR. RESULTS: Extended spectrum ß-lactamases, methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem resistance were the most common outcomes in studies with a specific resistance pattern. The most common algorithms in ML prediction were logistic regression (n = 14 studies), decision tree (n = 14) and random forest (n = 7). The area under the curve (AUC) range for ML prediction was 0.48-0.93. The pooled AUC for ML prediction was 0.82 (0.78-0.85). Compared with risk score, higher specificity [87% (82-91) vs. 37% (25-51)] was indicated for ML prediction, but not sensitivity [67% (62-72) vs. 73% (67-79)]. CONCLUSIONS: Machine learning might be a potential technology for AMR prediction; however, retrospective methodology for model development, nonstandard data processing and scarcity of validation in a randomised controlled trial or real-world study limit the application of these models in clinical practice.

Effectiveness and safety of adjunctive inhaled antibiotics for ventilator-associated pneumonia: A systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: The efficacy and safety of adjunctive inhaled antibiotic therapy for ventilator-associated pneumonia (VAP) was systematically reviewed based on updated studies. METHODS: We searched four databases and four clinical trial registration platforms to identify relevant studies published prior to May 19, 2020. Randomized controlled trials (RCTs) assessing adjunctive antibiotic inhalation treatment for VAP patients were eligible for this review. Two reviewers independently screened the articles and extracted the data. Information on inhaled therapy and clinical outcomes was collected. Study quality was assessed with the Cochrane risk of bias tool. The meta-analysis was conducted with Review Manager and R software. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines were used to evaluate the quality of evidence for each pooled outcome. RESULTS: Eleven RCTs and 1210 patients were included in this analysis after the application of the inclusion and exclusion criteria. Compared with the use of intravenous injection alone, the use of adjunctive inhaled antibiotic therapy improved the rates of clinical cure (relative risk (RR) 1.13, 95% CI [1.02,1.26]) and microbiological eradication (RR 1.45, 95% CI [1.19,1.76]) in VAP patients. However, despite these improvements, mortality was not reduced (RR 1.00, 95% CI [0.82,1.21]). Adjunctive antibiotics delivered through the respiratory tract were not associated with a higher risk of renal impairment but were associated with an increased risk of bronchospasm (RR 2.74, 95% CI [1.31,5.73] during treatment. CONCLUSIONS: Adjunctive inhaled antibiotics improved the clinical outcomes in VAP patients, but the increased rates clinical cure and microbiological eradication were not associated with reduced mortality. The use of nebulized antibiotics is not supported by the currently available evidence as a routine therapeutic strategy for VAP. PROSPERO REGISTRATION NUMBER: CRD42020186970.

Quality of therapeutic drug monitoring guidelines is suboptimal: an evaluation using the Appraisal of Guidelines for Research and Evaluation II instrument.

OBJECTIVES: Although therapeutic drug monitoring (TDM) guidelines are available, systematic evaluations of their methodological quality are scarce. This study aimed to assess the quality of current TDM guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. STUDY DESIGN AND SETTING: We performed a systematic search to identify the relevant TDM guidelines in PubMed, EMBASE, CNKI, Wan Fang Database, CBM, VIP, four main guideline databases (NICE, NGC, GIN, and WHO guideline databases), and official websites of the governments and societies associated with TDM from the inception date to May 2018. Four independent appraisers rated the quality of each TDM guideline using the AGREE II instrument, and the mean score of each AGREE II item was calculated. The overall agreement among the appraisers was evaluated using the intraclass correlation coefficient (ICC). RESULTS: Twenty-eight TDM guidelines satisfied the eligibility criteria from among 12,235 references. The overall agreement among the appraisers was substantial (0.700-0.880). The mean scores for the six AGREE II domains were scope and purpose, 67.7% (95% CI, 64.0-71.4%); stakeholder involvement, 39.8% (95% CI, 33.3-46.3%); rigor of development, 36.0% (95% CI, 28.1-43.9%); clarity and presentation, 61.6% (95% CI, 55.7-67.4%); applicability, 30.6% (95% CI, 26.4-34.8%); and editorial independence, 49.2% (95% CI, 40.0-58.6%). The reviewers recommended only four guidelines, and most of the TDM guidelines were rated as "recommended with modifications." CONCLUSION: Overall, the quality of TDM guidelines is suboptimal according to the evaluation using the AGREE II instrument. The domains of applicability, rigor of development, stakeholder involvement, and editorial independence of the guidelines need to be reported. In addition, guideline developers closely adhering to the AGREE II instrument and the Grading of Recommendations Assessment Development and Evaluation system are required to draft high-quality and reliable TDM guidelines.

Volatile anesthetics versus total intravenous anesthesia in patients undergoing coronary artery bypass grafting: An updated meta-analysis and trial sequential analysis of randomized controlled trials.

BACKGROUND: The benefits of volatile anesthetics in coronary artery bypass grafting (CABG) patients remain controversial. We aimed to conduct an updated meta-analysis to assess whether the use of volatile anesthetics during CABG could reduce mortality and other outcomes. METHODS: We searched eight databases from inception to June 2019 and included randomized controlled trials (RCTs) comparing the effects of volatile anesthetics versus total intravenous anesthesia (TIVA) in CABG patients. The primary outcomes were operative mortality and one-year mortality. The secondary outcomes included the length of stay in the intensive care unit (ICU) and hospital and postoperative safety outcomes (myocardial infarction, heart failure, arrhythmia, stroke, delirium, postoperative cognitive impairment, acute kidney injury, and the use of intra-aortic balloon pump (IABP) or other mechanical circulatory support). Trial sequential analysis (TSA) was performed to control for random errors. RESULTS: A total of 89 RCTs comprising 14,387 patients were included. There were no significant differences between the volatile anesthetics and TIVA groups in operative mortality (relative risk (RR) = 0.92, 95% confidence interval (CI): 0.68-1.24, p = 0.59, I2 = 0%), one-year mortality (RR = 0.64, 95% CI: 0.32-1.26, p = 0.19, I2 = 51%), or any of the postoperative safety outcomes. The lengths of stay in the ICU and hospital were shorter in the volatile anesthetics group than in the TIVA group. TSA revealed that the results for operative mortality, one-year mortality, length of stay in the ICU, heart failure, stroke, and the use of IABP were inconclusive. CONCLUSIONS: Conventional meta-analysis suggests that the use of volatile anesthetics during CABG is not associated with reduced risk of mortality or other postoperative safety outcomes when compared with TIVA. TSA shows that the current evidence is insufficient and inconclusive. Thus, future large RCTs are required to clarify this issue.

Physiologically Based Pharmacokinetic Modeling of Oxycodone in Children to Support Pediatric Dosing Optimization.

PURPOSE: Physiologically-based pharmacokinetic (PBPK) modeling offers a unique modality to predict age-specific pharmacokinetics. The objective of this study was to assess the ability of PBPK model to predict plasma exposure of oxycodone, a widely used opioid for pain management, in adults and children. METHODS: A full PBPK model of oxycodone following intravenous and oral administration was developed using a 'bottom-up' and 'top-down' combined strategy. The model was then extrapolated to pediatrics through a reasonable scaling method. The adult and pediatric model was evaluated using data from 17 clinical PK studies by testing predicted/observed goodness of fit. The mean fold error for PK parameters was calculated. Finally, we used the validated PBPK model to visualize adult-children dose conversion for oxycodone. RESULTS: The developed PBPK model successfully predicted the oxycodone disposition in adults, wherein the predicted versus observed AUC, Cmax, and tmax were within 0.90 to 1.20-fold difference. After scaling anatomy/physiology, protein binding, and clearance, the model showed satisfactory prediction performance for pediatric populations as predicted AUC were within the 1.50-fold range of the observed values. According to the application of PBPK model, we found that different intravenous doses should be given in children of different ages compared to a standard 0.1 mg/kg in adults, while a progressive increasing dose with age growth following oral administration is recommended for children. CONCLUSIONS: The current example provides the opportunity for using the PBPK model to guide dose adjustment of oxycodone in the design of future pediatric clinical studies.

The drug use to treat community-acquired pneumonia in children: A cross-sectional study in China.

To evaluate the rationality of drug use to treat community-acquired pneumonia (CAP) in children of a Chinese hospital using a set of developed indicators.We performed a retrospective cross-sectional study in West China Second University Hospital. Hospitalized children (0-18 years old) diagnosed with CAP from October 2015 to January 2016 were included. A set of developed indicators for assessing rational drug use (RDU) to treat CAP in children were used to evaluate the rationality of drug use. The data of the indicators were compared with the recommendations of the available guidelines, analyzing the situation of drug use in the children diagnosed with CAP.Eight hundred ninety-four children were included, 99.4% of them received antibiotics and 87.4% received more than 1 antibiotic. Antibiotics were administered intravenously in 880 (99.0%) children. About 20 (2.2%) children received antiviral agents and 19 (2.1%) children received antiviral drugs combined with antibiotics. About 208 (23.3%) children received traditional Chinese medicines and the injection of traditional Chinese medicines was given in 20 (2.2%) children.This study illustrated that drug use was partly not consistent with the recommendations of current guidelines, especially antibiotics. The drug use of CAP in children needs to pay more attention to.

Upregulation of M3 muscarinic receptor inhibits cardiac hypertrophy induced by angiotensin II.

BACKGROUND: M3 muscarinic acetylcholine receptor (M3-mAChR) is stably expressed in the myocardium, but its pathophysiological role remains largely undefined. This study aimed to investigate the role of M3-mAChR in cardiac hypertrophy induced by angiotensin II (Ang II) and elucidate the underlying mechanisms. METHODS: Cardiac-specific M3-mAChR overexpression transgenic (TG) mice and rat H9c2 cardiomyoblasts with ectopic expression of M3-mAChR were established. Models of cardiac hypertrophy were induced by transverse aortic constriction (TAC) or Ang II infusion in the mice in vivo, and by isoproterenol (ISO) or Ang II treatment of H9c2 cells in vitro. Cardiac hypertrophy was evaluated by electrocardiography (ECG) measurement, hemodynamic measurement and histological analysis. mRNA and protein expression were detected by real-time RT-PCR and Western blot analysis. RESULTS: M3-mAChR was upregulated in hypertrophic heart, while M2-mAChR expression did not change significantly. M3-mAChR overexpression significantly attenuated the increased expression of atrial natriuretic peptide and ß-myosin heavy chain induced by Ang II both in vivo and in vitro. In addition, M3-mAChR overexpression downregulated AT1 receptor expression and inhibited the activation of MAPK signaling in the heart. CONCLUSION: The upregulation of M3-mAChR during myocardial hypertrophy could relieve the hypertrophic response provoked by Ang II, and the mechanism may involve the inhibition of MAPK signaling through the downregulation of AT1 receptor.

Choline inhibits angiotensin II-induced cardiac hypertrophy by intracellular calcium signal and p38 MAPK pathway.

Choline, an agonist of M(3) muscarinic acetylcholine receptors, is a precursor and metabolite of acetylcholine and is also a functional modulator of cellular membrane. However, the effect of choline on cardiac hypertrophy is not fully understood. The present study was therefore designed to explore whether choline could prevent cardiac hypertrophy induced by angiotensin II (Ang II) and clarify its potential mechanisms. Cardiac hypertrophy was induced by 0.6 mg kg(-1) day(-1) Ang II for 2 weeks in the presence or absence of choline pretreatment, while cardiomyocyte hypertrophy was induced by Ang II 0.1 µM for 48 h. We found that choline pretreatment attenuated the increment cell size of cardiomyocytes induced by Ang II both in vivo and in vitro. The high ANP and ß-MHC levels induced by Ang II were also reversed by choline in cardiomyocytes. Meanwhile, choline pretreatment prevented the augment of reactive oxygen species (ROS) and intracellular calcium concentration in Ang II-treated cardiomyocytes. Furthermore, the upregulated phospho-p38 mitogen-activated protein kinase (MAPK) and calcineurin levels by Ang II in ventricular myocytes were attenuated by choline. In conclusion, choline prevents Ang II-induced cardiac hypertrophy through inhibition of ROS-mediated p38 MAPK activation as well as regulation of Ca(2+)-mediated calcineurin signal transduction pathway. Our results provide new insights into the pharmacological role of choline in cardiovascular diseases.

Activation of cardiac M3 muscarinic acetylcholine receptors has cardioprotective effects against ischaemia-induced arrhythmias.

Increasing evidence indicates the important roles of M(3) muscarinic acetylcholine receptors (M(3) mAChR) in the regulation and maintenance of cardiac function and heart disease. In the present study, we investigated whether the M(3) mAChR mediates the cardioprotection against ischaemia-induced arrhythmias and the mechanisms involved. Myocardial ischaemia was established in Wistar rats by occlusion of the left anterior descending coronary artery. Rats were treated with choline chloride (an M(3) mAChR agonist; 10 mg/kg, i.v.) 10 min before occlusion. In addition, 4-diphenylacetoxy-N-methylpiperidine-methiodide (4-DAMP; 0.12 µg/kg, i.v.) was administered 5 min before choline in the 4-DAMP-treated group. Ischaemia-induced arrhythmias were evaluated in each group for a period of 1 h after occlusion. After 24 h occlusion, protein and mRNA levels of L-type Ca(2+) channels and the Na(+) /Ca(2+) exchanger (NCX) were determined. Ischaemia-induced arrhythmias following coronary artery occlusion were diminished by choline and this effect was reversed in the 4-DAMP-treated group. In vitro, the effects of myocardial ischaemia were simulated by incubating isolated ventricular cardiomyocytes with Tyrode's solution (pH 6.8). Intracellular Ca(2+) overload was confirmed and this was decreased by choline. Furthermore, choline reduced the L-type Ca(2+) current (I(C) (a,) (L) ) compared with cardiomyocytes incubated in Tyrode's solution (pH 6.8) alone. Choline reduced the 'ischaemia'-induced upregulated expression of L-type Ca(2+) channels and NCX at both the protein and mRNA level. Based on these results, choline has an obvious protective effect against ischaemia-induced arrhythmias that is mediated via activation of cardiac M(3) mAChR, which reduces Ca(2+) overload mediated by L-type Ca(2+) channels and the NCX.