Expression Levels of GABA-A Receptor Subunit Alpha 3, <i>Gabra3</i> and Lipoprotein Lipase, <i>Lpl</i> Are Associated with the Susceptibility to Acetaminophen-Induced Hepatotoxicity

Kim, Minjeong; Yun, Jun Won; Shin, Kilho; Cho, Yejin; Yang, Minsuk; Nam, Ki Taek; Lim, Kyung Min

doi:10.4062/biomolther.2016.076

Cited by 9 publications

(6 citation statements)

References 42 publications

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“…Meanwhile, Dio3os was also highly expressed in artificial and in vitro decidualization. A microarray experiment reported that Gdap10 was highly expressed in acetaminopheninduced liver injury (Kim et al 2017). Hepatocyte chromosome polyploidization is an important response to liver injury.…”

Section: Discussionmentioning

confidence: 99%

Progesterone-induced RNA Hand2os1 regulates decidualization in mice uteri

Jia

Cai

et al. 2020

Reproduction

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Decidualization is a critical process for successful embryo implantation and subsequent placenta formation. The characterization and physiological function of lncRNA during decidualization remain largely unknown. In the present study, we conducted RNA-sequencing analysis to compare gene expression between decidua of days 6 and 8, and normal pregnant endometrium (day 4). A total of 2332 high-confidence putative lncRNA transcripts were expressed. Functional clustering analysis of cis and trans lncRNA targets showed that differentially expressed lncRNAs may regulate multiple gene ontology terms and pathways that have important functions in decidualization. Subsequent analyses using qRT-PCR validated that eight of all lncRNAs were differentially regulated in mice uteri during decidualization, both in vivo and in vitro. Furthermore, we showed that differentially expressed lncRNA of Hand2os1 was specifically detected in stromal cells on days 2 to 5 of pregnancy and was strongly upregulated in decidual cells on days 6–8 of pregnancy. Similarly, Hand2os1 expression was also strongly expressed in decidualized cells following artificial decidualization, both in vivo and in vitro. In uterine stromal cells, P4 was able to significantly upregulate the expression of Hand2os1, but upregulation was impeded by RU486, whereas E2 appeared to have no regulating effect on Hand2os1 expression. Concurrently, Hand2os1 significantly promoted the decidual process in vitro and dramatically increased decidualization markers Prl8a2 and Prl3c1. Our results provide a valuable catalog for better understanding of the functional roles of lncRNAs in pregnant mouse uteri, as it relates to decidualization.

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Section: Discussionmentioning

confidence: 99%

Progesterone-induced RNA Hand2os1 regulates decidualization in mice uteri

Jia

Cai

et al. 2020

Reproduction

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“…However, APAP overdose is one of the leading causes of DILI globally accounting for >50% of cases (5). It has proven difficult to elucidate the specific pathogenesis of DILI due to the differing severity of symptoms between patients resulting from individual differences (6).…”

Section: Introductionmentioning

confidence: 99%

CXCL9 regulates acetaminophen‑induced liver injury via CXCR3

et al. 2019

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Drug-induced liver injury has become a serious public health problem. Although the mechanism of acetaminophen (APAP)-induced liver injury has been studied for decades it has not been fully elucidated. In-depth study into the mechanisms underlying APAP-induced liver injury may provide useful information for more effective prevention and treatment. In the present study, the role of C-X-C motif chemokine ligand-9 (CXCL9) in APAP-induced liver injury was investigated thus providing a novel direction for the prevention and treatment of drug hepatitis. A total of 20 fasting male patients ingested APAP tablets at Nanjing First Hospital. In addition, wild type (WT) mice were treated with 250 mg/kg APAP or isodose PBS for 1, 3, 6 and 12 h, respectively. Results from reverse-transcription-quantitative polymerase chain reaction analyses demonstrated that CXCL9 mRNA levels were increased in the blood of patients who took APAP in a fasting state and in the livers of APAP-treated WT mice, compared with their respective controls. Hepatocyte apoptosis in the liver tissue of APAP-treated mice decreased following administration of a CXCL9 neutralizing antibody. Caspase-3, caspase-8 and phosphorylated-AKT (S437) were activated in primary hepatocytes isolated from WT mice following CXCL9 treatment. However, no significant differences in expression of caspase-3, caspase-8 and p-AKT (S437) were detected in hepatocytes isolated from C-X-C motif chemokine receptor 3 (CXCR3)−/− mice following CXCL9 treatment. After CXCL9 administration, WT mice exhibited higher serum levels of aspartate transaminase and increased caspase-3 and caspase-8 activity in liver tissue compared with controls. The same trends were not observed in CXCR3−/− mice. In conclusion, CXCL9 regulated APAP-induced liver injury through stimulation of hepatocyte apoptosis via binding to CXCR3. These findings provide a novel prevention and treatment strategy for DILI.

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“…Liver histology in zebrafish: Zebrafish larvae were collected and fixed in 10% neutral buffered formalin at room temperature overnight and were then subjected to paraffin embedding and sectioning. Hematoxylin and eosin staining was performed to histologically examine hepatotoxicity as described previously ( Jeong et al ., 2017a ; Kim et al ., 2017 ).…”

Section: Methodsmentioning

confidence: 99%

Fasiglifam (TAK-875), a G Protein-Coupled Receptor 40 (GPR40) Agonist, May Induce Hepatotoxicity through Reactive Oxygen Species Generation in a GPR40-Dependent Manner

Kim

Koh

et al. 2018

Biomolecules & Therapeutics

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Fasiglifam (TAK-875) a G-protein coupled receptor 40 (GPR40) agonist, significantly improves hyperglycemia without hypoglycemia and weight gain, the major side effects of conventional anti-diabetics. Unfortunately, during multi-center Phase 3 clinical trials, unexpected liver toxicity resulted in premature termination of its development. Here, we investigated whether TAK-875 directly inflicts toxicity on hepatocytes and explored its underlying mechanism of toxicity. TAK-875 decreased viability of 2D and 3D cultures of HepG2, a human hepatocarcinoma cell line, in concentration- (>50 μM) and time-dependent manners, both of which corresponded with ROS generation. An antioxidant, N-acetylcysteine, attenuated TAK-875-mediated hepatotoxicity, which confirmed the role of ROS generation. Of note, knockdown of GPR40 using siRNA abolished the hepatotoxicity of TAK-875 and attenuated ROS generation. In contrast, TAK-875 induced no cytotoxicity in fibroblasts up to 500 μM. Supporting the hepatotoxic potential of TAK-875, exposure to TAK-875 resulted in increased mortality of zebrafish larvae at 25 μM. Histopathological examination of zebrafish exposed to TAK-875 revealed severe hepatotoxicity as manifested by degenerated hypertrophic hepatocytes with cytoplasmic vacuolation and acentric nuclei, confirming that TAK-875 may induce direct hepatotoxicity and that ROS generation may be involved in a GPR40-dependent manner.

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Expression Levels of GABA-A Receptor Subunit Alpha 3, Gabra3 and Lipoprotein Lipase, Lpl Are Associated with the Susceptibility to Acetaminophen-Induced Hepatotoxicity

Cited by 9 publications

References 42 publications

Progesterone-induced RNA Hand2os1 regulates decidualization in mice uteri

Progesterone-induced RNA Hand2os1 regulates decidualization in mice uteri

CXCL9 regulates acetaminophen‑induced liver injury via CXCR3

Fasiglifam (TAK-875), a G Protein-Coupled Receptor 40 (GPR40) Agonist, May Induce Hepatotoxicity through Reactive Oxygen Species Generation in a GPR40-Dependent Manner

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