Disruption of Estrogen Receptor Alpha in Rats Results in Faster Initiation of Compensatory Regeneration Despite Higher Liver Injury After Carbon Tetrachloride Treatment

McGreal, Steven R.; Rumi, K.; Soares, Michael J.; Woolbright, Benjamin L.; Jaeschke, Hartmut; Apte, Udayan

doi:10.1177/1091581817706067

Cited by 7 publications

(4 citation statements)

References 41 publications

(60 reference statements)

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“…In vivo experiments demonstrated that high expression of ESR1 leads to apoptosis and inflammation in hepatocytes, and that ERBB2 expression can be enhanced by suppressing ESR1 expression to attenuate hepatocyte apoptosis and inflammatory responses[38]. Besides, ESR1-mediated signalling inhibited liver regeneration by down-regulating Wnt signalling, which led to reduced activation of cell cycle protein D1 after chemical-induced liver injury[39]. Consequently, ESR1 has an important role in Aflatoxin B1-induced liver injury.…”

Section: Discussionmentioning

confidence: 99%

Efficient analysis of toxicity and mechanism of food contaminants using network toxicology and molecular docking strategy: A Case Study of Aflatoxin B1

Chu,

2024

Preprint

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The present study aims to promote network toxicology and molecular docking strategies for the efficient evaluation of the toxicity of food contaminants. With the example of liver injury induced by the food contaminant Aflatoxin B1, this study effectively investigated the putative toxicity of food contaminants and the potentially molecular mechanisms. Initially, we obtained a preliminary overview of the toxicity of Aflatoxin B1 by using the ProTox-II and ADMETlab 2.0 databases. Subsequently, it was possible to identify 156 potential targets associated with Aflatoxin B1 and liver injury by using the ChEMBL, SwissTargetPrediction, GeneCards and DisGeNET databases. These were further refined by the STRING 5.0 database and Cytoscape 3.9.0 software for 23 core targets, including AKT1, SRC and EGFR. Then, GO and KEGG pathway analyses performed by Metascape database indicated that the core targets of Aflatoxin B1-induced hepatotoxicity were mainly enriched in cancer-related signalling pathways. Speedy molecular docking using Quick Vina confirmed the strong binding energy between Aflatoxin B1 and the core targets. In summary, Aflatoxin B1 may induce liver injury by regulating cell proliferation, cell survival, cell growth, cellular immune responses, and cellular signalling cascade responses in hepatocytes. We have provided a theoretical basis for understanding the molecular mechanism of Aflatoxin B1 hepatotoxicity and for the prevention and treatment of Aflatoxin B1-induced cancers in food contaminants. Furthermore, our network toxicology and molecular docking methods also provide an effective method for the rapid evaluation of the toxicity of food contaminants, which effectively solves the cost and ethical problems associated with the use of experimental animals.

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Section: Discussionmentioning

confidence: 99%

Efficient analysis of toxicity and mechanism of food contaminants using network toxicology and molecular docking strategy: A Case Study of Aflatoxin B1

Chu,

2024

Preprint

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“…Altering the ERK signaling pathway through ERK2 deficiency can reduce liver fibrosis and inflammation [40]. ESR1-mediated signaling inhibits liver regeneration after chemical-induced liver injury by suppressing the Wnt signaling pathway, resulting in lower cyclin D1 activation [41]. During the development of acute liver failure, TNFmediated over-immune cascade response may contribute to massive hepatocyte apoptosis and impaired hepatocyte proliferation [42,43].…”

Section: Discussionmentioning

confidence: 99%

Identifying the Mechanism of Polygoni Cuspidati Rhizoma et Radix in Treating Acute Liver Failure Based on Network Pharmacology and Molecular Docking

Hong

Ding

Hong³

et al. 2022

Gastroenterology Research and Practice

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Background and Objective. Acute liver failure (ALF) is a rare clinical syndrome with a poor prognosis and leads to multiple organ failure. Polygoni Cuspidati Rhizoma et Radix (PCRR) is a commonly used Chinese medicine, which is recognized as a potential therapeutic herb against ALF. This study aimed to explore the pharmacological mechanisms of the therapeutic effect of PCRR in ALF via network pharmacology and molecular docking. Materials and Methods. The potential bioactive compounds of PCRR and their targets were collected from TCMSP, TCMID, and BATMAN-TCM databases with absorption, distribution, metabolism, and excretion protocols (oral bioavailability ≥30% and drug-likeness ≥0.18). The ALF-related target genes were identified using the GeneCards and OMIM databases. A protein-protein interaction (PPI) network among these targets was constructed using the Cytoscape software to obtain the core targets. The genes associated with ALF were analyzed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to identify the signaling pathways related to the therapeutic effect of PCRR in ALF. Results. In total, 10 bioactive compounds of PCRR and 200 targets related to them were obtained, and 2913 ALF-related target genes were identified. PPI network analysis pinpointed 15 core targets, namely, TP53, AKT1, JUN, HSP90AA1, MAPK1, RELA, TNF, ESR1, IL6, MYC, MAPK14, FOS, RB1, CDKN1A, and EGFR. GO enrichment and KEGG pathway analyses revealed that the therapeutic mechanisms of PCRR in ALF are related to cell metabolism, oxidative stress, inflammation, and hepatocyte apoptosis. Conclusion. This is the first study to explore the therapeutic mechanisms of PCRR in ALF via network pharmacology and molecular docking. This study provides a research platform with candidate ALF-related targets of PRCC for the development of therapeutics against ALF.

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“…For example, it was reported ATM signaling pathway plays an important protective function of causing liver failure in mice (Bandi et al, 2011). Furthermore, it was reported that Estrogen receptor alpha (ESR1)-mediated signaling inhibits liver regeneration by downregulation of Wnt signaling resulting in lower cyclin D1 activation in ESR1 knockout rats (McGreal et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Deep Learning on High-Throughput Transcriptomics to Predict Drug-Induced Liver Injury

Tong

Roberts

et al. 2020

Front. Bioeng. Biotechnol.

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Drug-induced liver injury (DILI) is one of the most cited reasons for the high drug attrition rate and drug withdrawal from the market. The accumulated large amount of high throughput transcriptomic profiles and advances in deep learning provide an unprecedented opportunity to improve the suboptimal performance of DILI prediction. In this study, we developed an eight-layer Deep Neural Network (DNN) model for DILI prediction using transcriptomic profiles of human cell lines (LINCS L1000 dataset) with the current largest binary DILI annotation data [i.e., DILI severity and toxicity (DILIst)]. The developed models were evaluated by Monte Carlo cross-validation (MCCV), permutation test, and an independent validation (IV) set. The developed DNN model achieved the area under the receiver operating characteristic curve (AUC) of 0.802 and 0.798, and balanced accuracy of 0.741 and 0.721 for training and an IV set, respectively, outperforming the conventional machine learning algorithms, including K-nearest neighbors (KNN), Support Vector Machine (SVM), and Random Forest (RF). Moreover, the developed DNN model provided a more balanced sensitivity of 0.839 and specificity of 0.603. Besides, we found the developed DNN model had a superior predictive performance for oncology drugs. Also, the functional and network analysis of genes driving the predictions revealed their relevance to the underlying mechanisms of DILI. The proposed DNN model could be a promising tool for early detection of DILI potential in the pre-clinical setting.

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Disruption of Estrogen Receptor Alpha in Rats Results in Faster Initiation of Compensatory Regeneration Despite Higher Liver Injury After Carbon Tetrachloride Treatment

Cited by 7 publications

References 41 publications

Efficient analysis of toxicity and mechanism of food contaminants using network toxicology and molecular docking strategy: A Case Study of Aflatoxin B1

Efficient analysis of toxicity and mechanism of food contaminants using network toxicology and molecular docking strategy: A Case Study of Aflatoxin B1

Identifying the Mechanism of Polygoni Cuspidati Rhizoma et Radix in Treating Acute Liver Failure Based on Network Pharmacology and Molecular Docking

Deep Learning on High-Throughput Transcriptomics to Predict Drug-Induced Liver Injury

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