CCR2 and CCR5 promote diclofenac-induced hepatotoxicity in mice

He, Zhanke; Wei, Guoquan; Li, Na; Niu, Mengwei; Gong, Shenhai; Wu, Guangyan; Wang, Teng; Chen, Peng

doi:10.1007/s00210-018-1576-3

Cited by 7 publications

(2 citation statements)

References 38 publications

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“…In addition, CCR2 suppression alleviated hepatic ischemia/reperfusion injury and blocked hepatic in ltration of in ammatory monocytes [19,20]. In the present research, the expression of CCR2 gene was increased by 1.50 and 1.20 times on the 3rd and 5th day after Mn exposure which corroborated previous ndings that the expression of CCR2 was increased in liver damage induced by diclofenac, and CCR2 inhibition could alleviate the diclofenac-induced liver injury [21].…”

Section: Discussionsupporting

confidence: 91%

Unveiling the Hub Genes Associated with Manganese-Induced Hepatotoxicity

Yang

Wang

et al. 2023

Preprint

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Excessive exposure to manganese (Mn) can cause severe toxicity in human and animal organs, particularly the liver. However, the specific mechanisms of Mn-induced hepatotoxicity remain unclear. Thus, the objective of this study was to identify the key genes associated with hepatotoxicity caused by Mn administration. We obtained the gene expression data set GSE59923 from the Gene Expression Omnibus, which included liver samples treated with manganese chloride (MnCl2) as well as control samples. Through our analysis, we identified 222, 351, and 494 differentially expressed genes (DEGs) in the livers treated with MnCl2 at 700 mg/kg on the 1st, 3rd, and 5th day, respectively. Notably, we found a total of 27 overlapping DEGs in the liver samples. Biological process analysis revealed that these common DEGs were associated with the response to xenobiotic stimulus, cellular calcium ion homeostasis, and ion transmembrane transport. Pathway analysis further indicated the involvement of cAMP, p53, PI3K-Akt, MAPK, and AMPK signaling pathways in Mn-induced hepatotoxicity. Furthermore, we identified several important genes, including CCR2, CDKN1A, CELSR2, LCN2, and PER2, which appeared to play a role in Mn-induced hepatotoxicity. Taken together, this study sheds light on the molecular mechanisms underlying Mn-induced hepatotoxicity, contributing to our overall understanding of this condition.

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Section: Discussionsupporting

confidence: 91%

Unveiling the Hub Genes Associated with Manganese-Induced Hepatotoxicity

Yang

Wang

et al. 2023

Preprint

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“…In a study on rats with Dicl-IDILI, serum miR-122 was found to be a more specific biomarker of hepatotoxicity than liver transaminases ( Sharapova et al, 2016 ). Another study reported that chemokine receptors CCR2 and CCR5 promoted the pathophysiological process of Dicl-IDILI ( He et al, 2019 ). Furthermore, levels of IL-10 and IL-4 gene polymorphism can increase susceptibility to Dicl-IDILI ( Aithal et al, 2004 ).…”

Section: Discussionmentioning

confidence: 99%

Screening for Susceptibility-Related Biomarkers of Diclofenac-Induced Liver Injury in Rats Using Metabolomics

Gao²,

Song³

et al. 2021

Front. Pharmacol.

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Early identification of individuals susceptible to idiosyncratic drug-induced liver injury (IDILI) is a challenging unmet demand. Diclofenac, one of the most widely available over-the-counter drugs for pain management worldwide, may induce liver dysfunction, acute liver failure, and death. Herein, we report that diclofenac-related hepatobiliary adverse reactions occurred more frequently in cases with immune activation. Furthermore, experiments with rats demonstrated divergent hepatotoxicity responses in individuals exposed to diclofenac, and modest inflammation potentiated diclofenac-induced liver injury. Susceptible rats had unique plasma metabolomic characteristics, and as such, the metabolomic approach could be used to distinguish susceptible individuals. The 23 identified susceptibility-related metabolites were enriched by several metabolic pathways related to acute-phase reactions of immunocytes and inflammatory responses, including sphingolipid, tyrosine, phenylalanine, tryptophan, and lipid metabolism pathways. This finding implies a mechanistic role of metabolic and immune disturbances affects susceptibility to diclofenac-IDILI. Further nine metabolite biomarkers with potent diagnostic capabilities were identified using receiver operating characteristic curves. These findings elucidated the potential utility of metabolomic biomarkers to identify individuals susceptible to drug hepatotoxicity and the underlying mechanism of metabolic and immune disturbances occurring in IDILI.

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