Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in most parts of the world. Although there is no first-line drug approved for the treatment of NAFLD, polyene phosphatidylcholine (PPC) is used by clinicians to treat NAFLD patients. This study aimed to evaluate the efficacy of PPC on a mice model of NAFLD, and to study the PPC’s mechanism of action. The mice were fed a choline-deficient, L-amino acid-defined (CDAA) diet to induce NAFLD and were subsequently treated with PPC. The treatment effects were evaluated by the liver index, histopathological examination, and routine blood chemistry analyses. Lipidomics and metabolomics analyses of 54 samples were carried out using ultraperformance liquid chromatography (UPLC) coupled to a mass spectrometer to select for changes in metabolites associated with CDAA diet-induced NAFLD and the effects of PPC treatment. The intestinal flora of mice were extracted for gene sequencing to find differences before and after the induction of NAFLD and PPC treatment. PPC significantly improved the CDAA diet-induced NAFLD condition in mice. A total of 19 metabolites including 5 polar metabolites and 14 lipids showed marked changes. In addition, significant differences in the abundance of Lactobacillus were associated with NAFLD. We inferred that the protective therapeutic effect of PPC on the liver was related to the supplement of phosphatidylcholine, lysophosphatidylcholine, and sphingomyelin (PC, LPC, and SM, resectively) and acylcarnitine metabolism. This study developed a methodology for exploring the pathogenesis of NAFLD and can be extended to other therapeutic agents for treating NAFLD.

This study aimed to examine specific niches and usage for the aztreonam/amoxicillin/clavulanate combination and to use population pharmacokinetic simulations of clinical dosing regimens to predict the impact of this combination on restricting mutant selection. The in vitro susceptibility of 19 New-Delhi metallo-β-lactamase (NDM)-producing clinical isolates to amoxicillin/clavulanate and aztreonam alone and in co-administration was determined based on the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC). The fractions of a 24-h duration that the free drug concentration was within the mutant selection window (fT_MSW) and above the MPC (fT_>MPC) in both plasma and epithelial lining fluid were determined from simulations of 10,000 subject profiles based on regimens by renal function categories. This combination reduced the MIC of aztreonam and amoxicillin/clavulanate to values below their clinical breakpoint in 7/9 K. pneumoniae and 8/9 E. coli, depending on the β-lactamase genes detected in the isolate. In the majority of the tested isolates, the combination resulted in fT_>MPC > 90% and fT_MSW < 10% for both aztreonam and amoxicillin/clavulanate. Clinical dosing regimens of aztreonam and amoxicillin/clavulanate were sufficient to provide mutant restriction coverage for MPC and MIC ≤ 4 mg/L. This combination has limited coverage against NDM- and extended-spectrum β-lactamase co-producing E. coli and K. pneumoniae and is not effective against isolates carrying plasmid-mediated AmpC and KPC-2. This study offers a potential scope and limitations as to where the aztreonam/amoxicillin/clavulanate combination may succeed or fail.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in most parts of the world. Currently, there is no drug approved for the treatment of NAFLD, and polyene phosphatidylcholine (PPC) is an important drug for clinical doctors to treat patients with NAFLD. Through the analysis of liver index, histopathological inspection and blood routine, it was obvious that PPC could significantly improve Choline-Deficient L-amino acid-defined (CDAA) diet induced NAFLD mice in the present work. We performed lipidomics and metabolomics analysis of 54 samples using ultraperformance liquid chromatography (UPLC) coupled to Thermo LTQ Orbitrap mass spectrometer to select differential metabolites associated with CDAA modeling and PPC treatment. A total of 19 differential metabolites including 5 polar metabolites and 14 lipids were obtained. We inferred that the protective therapeutic effect of PPC on liver was related to the supplement of phosphatidylcholine，lysophosphatidylcholine and sphingomyelin(PC, LPC, SM) and acylcarnitine metabolism. In addition, we analyzed the gut microbiota of mice before and after modeling and treatment, significant differences in the abundance of lactobacillus associated with NAFLD were found. This study provides more reference and data for exploring the pathogenesis of NAFLD and the therapeutic mechanism of PPC, and a methodological reference for the study of the mechanism.