Die Bedeutung von Cytochrom P4502E1 bei der alkoholischen Lebererkrankung und bei der alkoholmediierten Karzinogenese

Seitz, Helmut K.; Mueller, Sebastian

doi:10.1055/a-0784-8815

Cited by 7 publications

(4 citation statements)

References 64 publications

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Section: Introductionmentioning

confidence: 99%

“…Cytochrome P450 2E1 (CYP2E1) is a member of the CYP superfamily in the mammalian liver that undergoes dramatic changes during both alcohol-induced and immune-mediated liver injury and is involved in injury mechanisms [1–2]. Insights into the complex mechanisms of immune-mediated CYP suppression have been obtained using bacterial sepsis as an acute model of inflammation [2]. Reduced hepatic CYP expression and activity were shown to be primarily due to transcriptional suppression but might also involve posttranslational protein modifications induced by mediators produced as a consequence of inflammation and infection [3].…”

Section: Introductionmentioning

confidence: 99%

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NF-κB-mediated regulation of rat CYP2E1 by two independent signaling pathways

Kang

et al. 2019

PLoS ONE

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Cytochrome P450 2E1 (CYP2E1) plays an important role in both alcohol-induced and immune-mediated liver injury. However, the mechanism underlying CYP2E1 transcriptional regulation has not been clarified. This study focused on the NF-κB-mediated transcriptional regulation of rat CYP2E1 by two independent signaling pathways in alcohol-induced and immune-mediated liver injury rat models. Male Sprague-Dawley rats were used in pharmacokinetic, molecular pharmacology, and morphology experiments. A rat model of alcohol-induced liver injury (AL) was established by feeding an ethanol-containing diet (42 g/kg/day) for 5 weeks as indicated. A rat immune-mediated liver injury (IM) model was established by the sequential injection of bacillus Calmette-Guérin (BCG, 125 mg/kg, once) via the tail vein after test day 21 and 10 μg/kg LPS 13 days later. HPLC, real-time PCR, western blot and ELISA analyses were performed. CYP2E1 expression was enhanced during the process of alcohol-induced liver injury (increased by 56%, P < 0.05) and significantly reduced during that of immune-mediated liver injury (reducedby52%, P < 0.05). NF-κB was activated in both the AL and IM groups (increased by 56% and76%, respectively, P < 0.05). Compared to those in the livers of AL model rats, the interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and iNOS levels in IM model rat livers were increased (increased by 26%, 21% and 101%, respectively, P < 0.05). The differential changes in CYP2E1 in the processes of alcohol-induced and immune-mediated liver injury may result from the differential expression of inflammatory cytokines and iNOS after NF-κB activation, leading to the NF-κB-mediated transcriptional regulation of rat CYP2E1 by two independent signaling pathways.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NF-κB-mediated regulation of rat CYP2E1 by two independent signaling pathways

Kang

et al. 2019

PLoS ONE

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“…Therefore, it is reasonable to use proteomic methods to study the pharmacological mechanism of TCM compounds. A total of 14 main related pathways were obtained by KEGG pathway enrichment analysis of significantly differentially expressed proteins, of which 3 were significantly related, namely Arachidonic acid metabolism, Retinol metabolism and HIF-1 signaling pathway (24)(25)(26). Acetaldehyde will damage mitochondria in liver cells, and the generation of free radicals will increase the transcription of COX-2 and activate PLA2, resulting in the production of a large amount of arachidonic acid in the cells and arachidonic acid under the action of COX-2.…”

Section: Discussionmentioning

confidence: 99%

Proteomics and network pharmacology of Ganshu Nuodan capsules in the prevention of alcoholic liver disease

Yang,

Wang,

Cui

et al. 2023

Front. Endocrinol.

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IntroductionGanshu Nuodan is a liver-protecting dietary supplement composed of Ganoderma lucidum (G. lucidum) spore powder, Pueraria montana (Lour.) Merr. (P. montana), Salvia miltiorrhiza Bunge (S. miltiorrhiza) and Astragalus membranaceus (Fisch.) Bunge. (A. membranaceus). However, its pharmacodynamic material basis and mechanism of action remain unknown.MethodsA mouse model of acute alcohol liver disease (ALD) induced by intragastric administration of 50% alcohol was used to evaluate the hepatoprotective effect of Ganshu Nuodan. The chemical constituents of Ganshu Nuodan were comprehensively identified by UPLC-QTOF/MS, and then its pharmacodynamic material basis and potential mechanism of action were explored by proteomics and network pharmacology.ResultsGanshu Nuodan could ameliorate acute ALD, which is mainly manifested in the significant reduction of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and malondialdehyde (MDA) content in liver and the remarkably increase of glutathione (GSH) content and superoxide dismutase (SOD) activity in liver. Totally 76 chemical constituents were identified from Ganshu Nuodan by UPLC-QTOF/MS, including 21 quinones, 18 flavonoids, 11 organic acids, 7 terpenoids, 5 ketones, 4 sterols, 3 coumarins and 7 others. Three key signaling pathways were identified via proteomics studies, namely Arachidonic acid metabolism, Retinol metabolism, and HIF-1 signaling pathway respectively. Combined with network pharmacology and molecular docking, six key targets were subsequently obtained, including Ephx2, Lta4h, Map2k1, Stat3, Mtor and Dgat1. Finally, these six key targets and their related components were verified by molecular docking, which could explain the material basis of the hepatoprotective effect of Ganshu Nuodan.ConclusionGanshu Nuodan can protect acute alcohol-induced liver injury in mice by inhibiting oxidative stress, lipid accumulation and apoptosis. Our study provides a scientific basis for the hepatoprotective effect of Ganshu Nuodan in acute ALD mice and supports its traditional application.

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“…Normally, the liver would exert anti-oxidative and anti-inflammatory processes by converting arachidonic acid into biologically active cyclic trienoic acid through arachidonic acid epoxygenase ( Wells et al, 2016 ). However, CYP450 activation induces arachidonic acid hydroxylation and epoxidation, which partially lead to oxidative stress and liver peroxidation after alcohol intake ( Seitz and Mueller, 2019 ). Additionally, alcohol can cause the decrease of retinol content in liver, and activation CYP2E1 is the main reason for this effect ( Clugston et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of the Expression Profiles of Hepatic lncRNAs in the Mouse Model of Alcoholic Liver Disease

et al. 2021

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Background and Aim: The worldwide prevalence of alcoholic liver disease (ALD) due to escalating alcohol consumption has presented an unprecedented pressure on human health. A few studies have determined long non-coding RNAs (lncRNAs) involved in the pathogenesis of liver diseases. However, the roles of lncRNAs in ALD development is still poorly understood.Methods: An ALD mouse model was established and confirmed. Expression profiles of lncRNAs were obtained by whole transcriptome sequencing. The altered lncRNAs in ALD mice were further verified by qRT-PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to enrich the functions of these lncRNAs. In combination with miRNA and mRNA profiles, we constructed concise endogenous RNA (ceRNA) networks. The function of the most up/downregulated lnRNA was further verified and investigated in both ALD model and AML-12 cells.Results: Totally, five downregulated lncRNAs were obtained and verified in ALD mice. The GO term and KEGG pathway analyses revealed that the identified lncRNAs were associated with alcohol-induced hepatic oxidative damage, cellular inflammation, and lipid metabolism. Combination the differentially modulated miRNAs and mRNAs with ceRNA network analysis, we constructed five ceRNA networks and obtained 30 miRNAs and 25 mRNAs that may participate in ALD. Further, we verified and investigate the function of the most downregulated lnc_1700023H06Rik. Depletion lnc_1700023H06Rik reduced genes encoding for lipid metabolism, especially mRNA Acat2 (ENSMUST00000159697) and Pgrmc2 (ENSMUST00000058578) both in vivo and in vitro. Knocking down lnc_1700023H06Rik induced triglyceride accumulation and lactate dehydrogenase leakage in AML12 cells, consisting with that in alcohol-treated cells.Conclusion: The five remarkably downregulated lncRNAs in ALD mouse model were identified as novel biomarkers, highlighting the key role of lncRNAs in the development of ALD. The effect of lnc_1700023H06Rik plays a pivotal role in lipid deposition and its pathological pathway in ALD needs further investigation.

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Die Bedeutung von Cytochrom P4502E1 bei der alkoholischen Lebererkrankung und bei der alkoholmediierten Karzinogenese

Cited by 7 publications

References 64 publications

NF-κB-mediated regulation of rat CYP2E1 by two independent signaling pathways

NF-κB-mediated regulation of rat CYP2E1 by two independent signaling pathways

Proteomics and network pharmacology of Ganshu Nuodan capsules in the prevention of alcoholic liver disease

Comprehensive Analysis of the Expression Profiles of Hepatic lncRNAs in the Mouse Model of Alcoholic Liver Disease

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