Microbial trimethylamine (TMA)-lyase activity promotes the development of atherosclerosis by generating of TMA, the precursor of TMA N-oxide (TMAO). TMAO is well documented, but same can not be said of TMA-producing bacteria. This work aimed to identify TMA-producing genera in human intestinal microbiota. We retrieved the genomes of human-associated microorganisms from the Human Microbiome Project database comprising 1751 genomes, Unified Human Gastrointestinal Genome collection consisting 4644 gut prokaryotes, recapitulated 4930 species-level genome bins and public gut metagenomic data of 2134 individuals from 11 populations. By sequence searching, 216 TMA-lyase-containing species from 102 genera were found to contain the homologous sequences of cntA/B, yeaW/X, and/or cutC/D. We identified 13 strains from 5 genera with cntA sequences, and 30 strains from 14 genera with cutC showing detectable relative abundance in healthy individuals. Lachnoclostridium (p = 2.9e−05) and Clostridium (p = 5.8e−04), the two most abundant cutC-containing genera, were found to be much higher in atherosclerotic patients compared with healthy persons. Upon incubation with choline (substrate), L. saccharolyticum effectively transformed it to TMA at a rate higher than 98.7% while that for C. sporogenes was 63.8–67.5% as detected by liquid chromatography-triple quadrupole mass spectrometry. In vivo studies further showed that treatment of L. saccharolyticum and choline promoted a significant increase in TMAO level in the serum of ApoE^−/− mice with obvious accumulation of aortic plaque in same. This study discloses the significance and efficiency of the gut bacterium L. saccharolyticum in transforming choline to TMA and consequently promoting the development of atherosclerosis.

Rationale: Reactive oxygen species (ROS) burst from mitochondrial complex I is considered the critical cause of ischemia/reperfusion (I/R) injury. Ginsenoside Rb1 has been reported to protect the heart against I/R injury; however, the underlying mechanism remains unclear. This work aimed to investigate if ginsenoside Rb1 attenuates cardiac I/R injury by inhibiting ROS production from mitochondrial complex I.

An accurate and efficient ab initio molecular dynamics (AIMD) simulation of liquid water was made possible using the fragment-based approach (J. F. Liu, X. He and J. Z. H. Zhang, Phys. Chem. Chem. Phys., 2017, 19, 11931–11936). In this study, we advance the AIMD simulations using the fragment-based coupled cluster (CC) theory, more accurately revealing the structural and dynamical properties of liquid water under ambient conditions. The results show that the double-donor hydrogen-bond configurations in liquid water are nearly in balance with the single-donor configurations, with a slight bias towards the former. Our observation is in contrast to the traditional tetrahedral water structure. The hydrogen-bond switching dynamics in liquid water are very fast, with a hydrogen-bond life time of around 0.78 picoseconds, determined using AIMD simulation at the CCD/aug-cc-pVDZ level. This time scale is remarkably shorter than the ∼3.0 picoseconds that is commonly obtained from traditional nonpolarized force fields and density functional theory (DFT) based first-principles simulations. Additionally, the obtained radial distribution functions, triplet oxygen angular distribution, diffusion coefficient, and the dipole moment of the water molecule are uniformly in good agreement with the experimental observations. The current high-level AIMD simulation sheds light on the understanding of the structural and dynamical properties of liquid water.

Background: As new biomarkers of coronary artery diseases (CAD) emerge via metabolomics, the underlying functional mechanisms remain to be elucidated. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms. Methods: A cohort of 2324 patients who underwent coronary angiography from 4 independent centers was studied. A combination of ultra–performance liquid chromatography and quadrupole time-of-flight mass spectrometry in the negative ion mode was used for untargeted analysis of metabolites in plasma. Significant differential metabolites were identified by cross-comparisons with and within CAD types, including normal coronary artery, nonobstructvie coronary atherosclerosis, stable angina, unstable angina, and acute myocardial infarction. A tandem liquid chromatography-mass spectrometry–based approach using isotope-labeled standard addition was subsequently performed for targeted analysis of the metabolic marker N -acetylneuraminic acid (Neu5Ac). A functional metabolomics strategy was proposed to investigate the role of Neu5Ac in the progression of CAD by using in vitro and in vivo models. Results: We identified a total of 36 differential metabolites, 35 of which were confirmed with reference compounds. Elevation of Neu5Ac was observed in plasma during CAD progression in center 1 ( P =4.0e-64, n=2019) and replicated in 3 independent centers (n=305). The increased level of Neu5Ac in plasma was confirmed by accurate targeted quantification. Mechanistically, Neu5Ac was able to trigger myocardial injury in vitro and in vivo by activation of the Rho/Rho-associated coiled-coil containing protein kinase signaling pathway through binding to RhoA and Cdc42, but not Rac1. Silencing neuraminidase-1, the enzyme that regulates Neu5Ac generation, ameliorated oxygen-glucose deprivation–induced injury in cardiomyocytes and ligation/isoprenaline-induced myocardial ischemia injury in rats. Pharmacological inhibition of neuraminidase by anti-influenza drugs, oseltamivir and zanamivir, also protected cardiomyocytes and the heart from myocardial injury. Conclusions: Functional metabolomics identified a key role for Neu5Ac in acute myocardial infarction, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for CAD.

Rationale: Glucagon is involved in hepatic gluconeogenesis, playing a key role in type 2 diabetes. Ginsenosides are reported to have antidiabetic activities. Ginsenoside Rg1 is a major propanaxatriol-type saponin in ginseng. This study aims to investigate the regulatory effects of Rg1 on glucagon-induced hepatic glucose production.