An entropy weight method to integrate big omics and mechanistically evaluate DILI.

BACKGROUND AND AIMS: DILI accounts for more than half of acute liver failure cases in the United States and is a major health care issue for the public worldwide. As investigative toxicology is playing an evolving role in the pharmaceutical industry, mechanistic insights into drug hepatotoxicity can facilitate drug development and clinical medication. METHODS: By integrating multisource datasets including gene expression profiles of rat livers from open TG-GATE database and DrugMatrix, drug labels from FDA Liver Toxicity Knowledge Base, and clinical reports from LiverTox, and with the employment of bioinformatic and computational tools, this study developed an approach to characterize and predict DILI based on the molecular understanding of the processes (toxicity pathways). RESULTS: A panel of 11 pathways widely covering biological processes and stress responses was established using a training set of six positive and one negative DILI drugs from open TG-GATEs. An entropy weight method-based model was developed to weight responsive genes within a pathway, and an interpretable machine-learning (ML) model XGBoot-SHAP was trained to rank the importance of pathways to the panel activity. The panel activity was proven to differentiate between injured and noninjured sample points and characterize DILI manifestation using six training drugs. Next, the model was tested using an additional 89 drugs (61 positives + 28 negatives), and a precision of 86% and higher can be achieved. CONCLUSIONS: This study provides a novel approach to mechanisms-driven prediction modeling, as well as big data integration for insights into pharmacology and other human biology areas.

Identifying piRNAs that regulate BaP-induced lung injuries: A bottom-up approach from toxicity pathway investigation to animal validation.

PIWI-interacting RNAs (piRNAs) is an emerging class of small non-coding RNAs that has been recently reported to have functions in infertility, tumorigenesis, and multiple diseases in humans. Previously, 5 toxicity pathways were proposed from hundreds of toxicological studies that underlie BaP-induced lung injuries, and a "Bottom-up" approach was established to identify small non-coding RNAs that drive BaP-induced pulmonary effects by investigating the activation of these pathways in vitro, and the expression of the candidate microRNAs were validated in tissues of patients with lung diseases from publications. Here in this study, we employed the "Bottom-up" approach to identifying the roles of piRNAs and further validated the mechanisms in vivo using mouse acute lung injury model. Specifically, by non-coding RNA profiling in in vitro BaP exposure, a total of 3 suppressed piRNAs that regulate 5 toxicity pathways were proposed, including piR-004153 targeting CYP1A1, FGFR1, ITGA5, IL6R, NGRF, and SDHA, piR-020326 targeting CDK6, and piR-020388 targeting RASD1. Animal experiments demonstrated that tail vein injection of respective formulated agomir-piRNAs prior to BaP exposure could all alleviate acute lung injury that was shown by histopathological and biochemical evidences. Immunohistochemical evaluation focusing on NF-kB and Bcl-2 levels showed that exogenous piRNAs protect against BaP-induced inflammation and apoptosis, which further support that the inhibition of the 3 piRNAs had an important impact on BaP-induced lung injuries. This mechanism-driven, endpoint-supported result once again confirmed the plausibility and efficiency of the approach integrating in silico, in vitro, and in vivo evidences for the purpose of identifying key molecules.

Humic acid controls cadmium stabilization during Fe(II)-induced lepidocrocite transformation.

Abiotic reduction of iron (oxyhydr)oxides by aqueous Fe(II) is one of the key processes affecting the Fe cycle in soil. Lepidocrocite (Lep) occurs naturally in anaerobic, clayey, non-calcareous soils in cooler and temperate regions; however, little is known about the impacts of co-precipitated humic acid (HA) on Fe(II)-induced Lep transformation and its consequences for heavy metal immobilization. In this study, the Fe(II)-induced phase transformation of Lep-HA co-precipitates was analyzed as a function of the C/Fe ratio, and its implications for subsequent Cd(II) concentration dynamic in dissolved and solid form was further investigated. The results revealed that secondary Fe(II)-bearing magnetite commonly formed during the Fe(II)-induced transformation of Lep, which further changed the mobility and distribution of Cd(II). The co-precipitated HA resulted in a decrease in the Fe solid phase transformation as the C/Fe ratios increased. Magnetite was found to be a secondary mineral in the 0.3C/Fe ratio Lep-HA co-precipitate, while only Lep was observed at a C/Fe ratio of 1.2 using X-ray diffraction (XRD) and Mössbauer spectroscopy. Based on XRD, scanning electron microscopy (SEM), Mössbauer, X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared spectroscopy (FTIR) results, newly formed magnetite may immobilize Cd(II) through surface complexes, incorporation, or structural substitution. The presence of HA was beneficial for binding Cd(II) and affected the mineralogical transformation of Lep into magnetite, which further induced the distribution of Cd(II) into the newly formed secondary minerals. These results provide insights into the behavior of Cd(II) in response to reaction between humic matter and iron (oxyhydr)oxides in anaerobic environments.