Choline and trimethylamine N-oxide supplementation in normal chow diet and western diet promotes the development of atherosclerosis in Apoe -/- mice through different mechanisms.

Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite, has been shown to aggravate cardiovascular disease. However, the mechanisms of TMAO in the setting of cardiovascular disease progress remain unclear. Here, we aim to investigate the effects of TMAO on atherosclerosis (AS) development and the underlying mechanisms. Apoe -/- mice received choline or TMAO supplementation in a normal diet and a western diet for 12 weeks. Choline or TMAO supplementation in both normal diet and western diet significantly promoted plaque progression in Apoe-/- mice. Besides, serum lipids levels and inflammation response in the aortic root were enhanced by choline or TMAO supplementation. In particular, choline or TMAO supplementation in the western diet changed intestinal microbiota composition and bile acid metabolism. Therefore, choline or TMAO supplementation may promote AS by modulating gut microbiota in mice fed with a western diet and by other mechanisms in mice given a normal diet, even choline or TMAO supplementation in a normal diet can promote AS.

Synthesis of polyaspartic acid-capped 2-aminoethylamino acid as a green water treatment agent and study of its inhibition performance and mechanism for calcium scales.

Polyaspartic acid (PASP), a well-known green scale inhibitor for industrial water treatment, might be decomposed with prolonged duration, and its anti-scaling performance against CaCO3 and CaSO4 is diminished at a low concentration (<10 mg L-1) and a high temperature. With semi-ethylenediaminetetraacetic acid (EDTA) tetrasodium salt as the mimicking model, novel phosphorus-free PASP-capped 2-aminoethylamino acid (PASP-ED2A) containing side chains bearing multi-functional groups is rationally designed and successfully prepared via the ring-opening reaction of cheap poly(succinimide) under mild reaction conditions with the assistance of readily available 2-aminoethyl amino acid. The static scale inhibition method is used to evaluate the scale inhibition performance of the as-synthesized PASP derivative. Scanning electron microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy are utilized to monitor the crystallization process of calcium carbonate and calcium sulfate scales, and density functional theory calculations are conducted to shed light on the relationship between the molecular structure and scale inhibition mechanism of PASP-ED2A. Results show that the as-prepared PASP-ED2A shows better scale inhibition performance for CaCO3 and CaSO4 than PASP with a low concentration, a high temperature, and an extended duration. Particularly, PASP-ED2A with a concentration of 10 mg L-1 exhibits the best scale inhibition performance for CaCO3; its scale inhibition capacity is about two times as much as that of PASP. The reason lies in that the coordination atoms in the molecular structure of PASP-ED2A can chelate with Ca2+ to inhibit the combination of Ca2+ with anions and prevent the generation of CaCO3 and CaSO4 scales. The PASP-ED2A derivative can more efficiently retard the formation and growth of CaCO3 and CaSO4 crystal nuclei and exerts better inhibition performance against CaCO3 and CaSO4 scales than PASP.

Lepipyrrolins A-B, two new dimeric pyrrole 2-carbaldehyde alkaloids from the tubers of Lepidium meyenii.

Nine new pyrrole alkaloids, including two undescribed dimeric pyrrole 2­carbaldehyde alkaloids, lepipyrrolins A-B (1-2), seven pyrrole-alkaloid derivatives, macapyrrolins D-J (3-9), along with three known ones (10-12) were isolated from the rhizomes of Lepidium meyenii. Their structures and absolute configurations were demonstrated by extensive spectroscopic data (1D, 2D NMR, HRESIMS), and calculated electronic circular dichroism (ECD) experiment. Compounds 1, 3-12 were tested for their nitric oxide inhibitory effects. Furthermore, compound 1 was evaluated for its cytotoxic activity against five human tumor cell lines (HL-60, SMMC-7221, A549, MCF-7, and SW480) in vitro, and displayed selective cytotoxicity against SMMC-7721 with IC50 value of 16.78 ± 0.49 µM.

High-Fidelity Drug-Induced Liver Injury Screen Using Human Pluripotent Stem Cell-Derived Organoids.

BACKGROUND & AIMS: Preclinical identification of compounds at risk of causing drug induced liver injury (DILI) remains a significant challenge in drug development, highlighting a need for a predictive human system to study complicated DILI mechanism and susceptibility to individual drug. Here, we established a human liver organoid (HLO)-based screening model for analyzing DILI pathology at organoid resolution. METHODS: We first developed a reproducible method to generate HLO from storable foregut progenitors from pluripotent stem cell (PSC) lines with reproducible bile transport function. The qRT-PCR and single cell RNA-seq determined hepatocyte transcriptomic state in cells of HLO relative to primary hepatocytes. Histological and ultrastructural analyses were performed to evaluate micro-anatomical architecture. HLO based drug-induced liver injury assays were transformed into a 384 well based high-speed live imaging platform. RESULTS: HLO, generated from 10 different pluripotent stem cell lines, contain polarized immature hepatocytes with bile canaliculi-like architecture, establishing the unidirectional bile acid transport pathway. Single cell RNA-seq profiling identified diverse and zonal hepatocytic populations that in part emulate primary adult hepatocytes. The accumulation of fluorescent bile acid into organoid was impaired by CRISPR-Cas9-based gene editing and transporter inhibitor treatment with BSEP. Furthermore, we successfully developed an organoid based assay with multiplexed readouts measuring viability, cholestatic and/or mitochondrial toxicity with high predictive values for 238 marketed drugs at 4 different concentrations (Sensitivity: 88.7%, Specificity: 88.9%). LoT positively predicts genomic predisposition (CYP2C9∗2) for Bosentan-induced cholestasis. CONCLUSIONS: Liver organoid-based Toxicity screen (LoT) is a potential assay system for liver toxicology studies, facilitating compound optimization, mechanistic study, and precision medicine as well as drug screening applications.