Correlation of PPM1A Downregulation with CYP3A4 Repression in the Tumor Liver Tissue of Hepatocellular Carcinoma Patients

Flannery, Patrick; Abbott, Kodye L.; Pondugula, Satyanarayana R.

doi:10.1007/s13318-019-00595-3

Cited by 10 publications

(10 citation statements)

References 44 publications

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“…5c. TGF-β1 is known to decrease the CYP3A4 activity by several pathways, such as the hPXR pathway [52]. The addition of fibrosis-inducing stimulus also downregulated the albumin release by four-folds, as shown in Fig.…”

Section: Albumin Urea and Cyp450 Measurementsmentioning

confidence: 76%

“…In the liver fibrosis-on-chip model, albumin and urea release compromised significantly after treatment with TGF-β1 for modeling fibrosis. TGF-β1 suppresses the activity of CYP3A4 activity and results in a lack of drug response for anti-fibrosis therapy [52]. ROS are also an essential player in reducing the efficiency of CYP3A4 by altering the protein secretion involved in autocrine and paracrine signaling [53].…”

Section: Albumin Urea and Cyp450 Measurementsmentioning

confidence: 99%

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Real-time monitoring of liver fibrosis through embedded sensors in a microphysiological system

et al. 2021

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Hepatic fibrosis is a foreshadowing of future adverse events like liver cirrhosis, liver failure, and cancer. Hepatic stellate cell activation is the main event of liver fibrosis, which results in excessive extracellular matrix deposition and hepatic parenchyma's disintegration. Several biochemical and molecular assays have been introduced for in vitro study of the hepatic fibrosis progression. However, they do not forecast real-time events happening to the in vitro models. Trans-epithelial electrical resistance (TEER) is used in cell culture science to measure cell monolayer barrier integrity. Herein, we explored TEER measurement's utility for monitoring fibrosis development in a dynamic cell culture microphysiological system. Immortal HepG2 cells and fibroblasts were co-cultured, and transforming growth factor β1 (TGF-β1) was used as a fibrosis stimulus to create a liver fibrosis-on-chip model. A glass chip-based embedded TEER and reactive oxygen species (ROS) sensors were employed to gauge the effect of TGF-β1 within the microphysiological system, which promotes a positive feedback response in fibrosis development. Furthermore, albumin, Urea, CYP450 measurements, and immunofluorescent microscopy were performed to correlate the following data with embedded sensors responses. We found that chip embedded electrochemical sensors could be used as a potential substitute for conventional end-point assays for studying fibrosis in microphysiological systems.

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Section: Albumin Urea and Cyp450 Measurementsmentioning

confidence: 76%

Section: Albumin Urea and Cyp450 Measurementsmentioning

confidence: 99%

Real-time monitoring of liver fibrosis through embedded sensors in a microphysiological system

et al. 2021

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“…CYP2E1 is a unique gene expressed in the liver but not expressed in HCC [ 26 ]. CYP3A4 expression is significantly low in the liver tumor tissue of patients with HCC [ 27 ]. Low SLC22A7 expression indicates a high risk of poor prognosis [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Interpreting the Molecular Mechanisms of Yinchenhao Decoction on Hepatocellular Carcinoma through Absorbed Components Based on Network Pharmacology

Sun

Han

Yang

et al. 2021

BioMed Research International

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To investigate the mechanisms through which Yinchenhao decoction (YCHD) inhibits hepatocellular carcinoma (HCC), we analyzed YCHD ingredients absorbed into the bloodstream by using network pharmacology. We conducted a weighted gene coexpression network analysis on gene expression data collected from the Gene Expression Omnibus and The Cancer Genome Atlas databases to derive an HCC gene set; moreover, we used four online prediction system databases to predict the potential targets of YCHD ingredients absorbed into the bloodstream. We discovered that YCHD directly interfered with 17 HCC-related disease targets. Subsequent gene ontology enrichment analyses of these 17 disease targets revealed that YCHD exhibited effects through 17 biological processes, 7 molecular functions, and 9 cellular components. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated 14 pathways through which YCHD inhibits HCC. We observed similar trends in how the 17 small molecules interfered with the key target set. We surmised that YCHD inhibits HCC by regulating inflammatory and metabolic pathways. Network pharmacological analysis of YCHD ingredients absorbed into the bloodstream may provide new insights and serve as a new method for discovering the molecular mechanisms through which YCHD inhibits HCC.

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“…HepG2 human hepatocellular carcinoma cells were purchased from the American Type Culture Collection (ATCC) and grown in DMEM (HyClone) supplemented with 10% fetal bovine serum (FBS) and the other additives (HyClone), as described previously. − The assay media for HepG2 experiments were comprised of phenol red-free DMEM supplemented with 5% charcoal/dextran-treated FBS (HyClone). Cryopreserved human primary hepatocytes were purchased from Corning, Triangle Research Labs, or Invitrogen.…”

Section: Methodsmentioning

confidence: 99%

“…Luciferase reporter gene assays were performed in HepG2 cells as previously described. ,− HepG2 cells were transiently transfected with pcDNA3-hPXR and pGL3-CYP3A4-luc plasmids using jetPRIME (Polyplus Transfection). After 24 h transfection, the cells were plated in 96-well assay plates (PerkinElmer) and treated with DMSO or the compounds for 24 h. A Neolite Reporter Gene Assay System (PerkinElmer) was used to determine the luciferase activity using a FLUOstar Optima microplate reader (BMG Labtech).…”

Section: Methodsmentioning

confidence: 99%

Gefitinib Inhibits Rifampicin-Induced CYP3A4 Gene Expression in Human Hepatocytes

et al. 2022

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During multidrug combination chemotherapy, activation of the nuclear receptor and the transcription factor human pregnane xenobiotic receptor (hPXR) has been shown to play a role in the development of chemoresistance. Mechanistically, this could occur due to the cancer drug activation of hPXR and the subsequent upregulation of hPXR target genes such as the drug metabolism enzyme, cytochrome P450 3A4 (CYP3A4). In the context of hPXR-mediated drug resistance, hPXR antagonists would be useful adjuncts to PXR-activating chemotherapy. However, there are currently no clinically approved hPXR antagonists in the market. Gefitinib (GEF), a tyrosine kinase inhibitor used for the treatment of advanced non-small-cell lung cancer and effectively used in combinational chemotherapy treatments, is a promising candidate owing to its hPXR ligand-like features. We, therefore, investigated whether GEF would act as an hPXR antagonist when combined with a known hPXR agonist, rifampicin (RIF). At therapeutically relevant concentrations, GEF successfully inhibited the RIF-induced upregulation of endogenous CYP3A4 gene expression in human primary hepatocytes and human hepatocells. Additionally, GEF inhibited the RIF induction of hPXR-mediated CYP3A4 promoter activity in HepG2 human liver carcinoma cells. The computational modeling of molecular docking predicted that GEF could bind to multiple sites on hPXR including the ligand-binding pocket, allowing for potential as a direct antagonist as well as an allosteric inhibitor. Indeed, GEF bound to the ligand-binding domain of the hPXR in cell-free assays, suggesting that GEF directly interacts with the hPXR. Taken together, our results suggest that GEF, at its clinically relevant therapeutic concentration, can antagonize the hPXR agonist-induced CYP3A4 gene expression in human hepatocytes. Thus, GEF could be a potential candidate for use in combinational chemotherapies to combat hPXR agonist-induced chemoresistance. Further studies are warranted to determine whether GEF has sufficient hPXR inhibitor abilities to overcome the hPXR agonist-induced chemoresistance.

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Correlation of PPM1A Downregulation with CYP3A4 Repression in the Tumor Liver Tissue of Hepatocellular Carcinoma Patients

Cited by 10 publications

References 44 publications

Real-time monitoring of liver fibrosis through embedded sensors in a microphysiological system

Real-time monitoring of liver fibrosis through embedded sensors in a microphysiological system

Interpreting the Molecular Mechanisms of Yinchenhao Decoction on Hepatocellular Carcinoma through Absorbed Components Based on Network Pharmacology

Gefitinib Inhibits Rifampicin-Induced CYP3A4 Gene Expression in Human Hepatocytes

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