Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans

Yu, Dianke; Wu, Leihong; Gill, Pritmohinder; Tolleson, William H.; Chen, Si; Sun, Jinchun; Knox, Bridgett; Jin, Yichen; Xiao, Wenming; Hong, Huixiao; Wang, Yong; Ren, Zhen; Guo, Lei; Mei, Nan; Guo, Yongli; Yang, Xi; Shi, Leming; Chen, Yinting; Zeng, Linjuan; Dreval, Kostiantyn; Tryndyak, Volodymyr; Pogribny, Igor P.; Fang, Hong; Shi, Tieliu; McCullough, Sandra; Bhattacharyya, Sudeepa; Schnackenberg, Laura K.; Mattes, William B.; Beger, Richard D.; James, Laura P.; Ning, Baitang

doi:10.1007/s00204-017-2090-y

Cited by 44 publications

(39 citation statements)

References 42 publications

(62 reference statements)

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“…Additionally, miR-149-3p inhibits the proliferation, migration, and invasion of bladder cancer cells by targeting the S100A4 protein, which is involved with cellular differentiation, motility, and regulating transcription [ 46 ]. Upregulation of miR-224-5p has been found to occur as part of the protective adaptive response of hepatocytes during acetaminophen-induced toxicity, and this upregulation of miR-224-5p was associated with suppression of drug metabolizing enzyme levels [ 47 ]. Using a streptozotocin-induced diabetic rat model, Mohan et al demonstrated the utility of urinary exosomal miR-451-5p as an early biomarker of diabetes-associated nephropathy, and the elevated levels of miR-451-5p appeared to be protective against kidney fibrosis [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex

Fay

Alt

Ryba

et al. 2018

Toxics

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Cadmium (Cd) is a nephrotoxic environmental pollutant that causes a generalized dysfunction of the proximal tubule characterized by polyuria and proteinuria. Even though the effects of Cd on the kidney have been well-characterized, the molecular mechanisms underlying these effects have not been fully elucidated. MicroRNAs (miRNAs) are small non-coding RNAs that regulate cellular and physiologic function by modulating gene expression at the post-transcriptional level. The goal of the present study was to determine if Cd affects renal cortex miRNA expression in a well-established animal model of Cd-induced kidney injury. Male Sprague-Dawley rats were treated with subcutaneous injections of either isotonic saline or CdCl2 (0.6 mg/kg) 5 days a week for 12 weeks. The 12-week Cd-treatment protocol resulted in kidney injury as determined by the development of polyuria and proteinuria, and a significant increase in the urinary biomarkers Kim-1, β2 microglobulin and cystatin C. Total RNA was isolated from the renal cortex of the saline control and Cd treated animals, and differentially expressed miRNAs were identified using µParafloTM microRNA microarray analysis. The microarray results demonstrated that the expression of 44 miRNAs were significantly increased and 54 miRNAs were significantly decreased in the Cd treatment group versus the saline control (t-test, p ≤ 0.05, N = 6 per group). miR-21-5p, miR-34a-5p, miR-146b-5p, miR-149-3p, miR-224-5p, miR-451-5p, miR-1949, miR-3084a-3p, and miR-3084c-3p demonstrated more abundant expression and a significant two-fold or greater increased expression in the Cd-treatment group versus the saline control group. miR-193b-3p, miR-455-3p, and miR-342-3p demonstrated more abundant expression and a significant two-fold or greater decreased expression in the Cd-treatment group versus the saline control group. Real-time PCR validation demonstrated (1) a significant (t-test, p ≤ 0.05, N = 6 per group) increase in expression in the Cd-treated group for miR-21-5p (2.7-fold), miR-34a-5p (10.8-fold), miR-146b-5p (2-fold), miR-224-5p (10.2-fold), miR-3084a-3p (2.4-fold), and miR-3084c-3p (3.3-fold) and (2) a significant (t-test, p ≤ 0.05, N = 6 per group) 52% decrease in miR-455-3p expression in the Cd-treatment group. These findings demonstrate that Cd significantly alters the miRNA expression profile in the renal cortex and raises the possibility that dysregulated miRNA expression may play a role in the pathophysiology of Cd-induced kidney injury. In addition, these findings raise the possibility that Cd-dysregulated miRNAs might be used as urinary biomarkers of Cd exposure or Cd-induced kidney injury.

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Section: Discussionmentioning

confidence: 99%

Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex

Fay

Alt

Ryba

et al. 2018

Toxics

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“…6 ). Furthermore, it has been shown that hsa-miR-224 expression induced in acetaminophen-induced hepatotoxicity 55 . Thus, environmental toxins-induce miR-224 expression during liver injury.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-224 down-regulates Glycine N-methyltransferase gene expression in Hepatocellular Carcinoma

Hung

Yeh

et al. 2018

Sci Rep

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Glycine N-methyltransferase (GNMT) is a tumor suppressor for HCC. It is down-regulated in HCC, but the mechanism is not fully understood. MicroRNA-224 (miR-224) acts as an onco-miR in HCC. This study is the first to investigate miR-224 targeting the coding region of GNMT transcript. The GNMT-MT plasmid containing a miR-224 binding site silent mutation of the GNMT coding sequence can escape the suppression of miR-224 in HEK293T cells. Expression of both exogenous and endogenous GNMT was suppressed by miR-224, while miR-224 inhibitor enhanced GNMT expression. miR-224 counteracts the effects of GNMT on the reduction of cell proliferation and tumor growth. The levels of miR-224 and GNMT mRNA showed a significant inverse relationship in tumor specimens from HCC patients. Utilizing CCl4-treated hepatoma cells and mice as a cell damage of inflammatory or liver injury model, we observed that the decreased expression levels of GNMT were accompanied with the elevated expression levels of miR-224 in hepatoma cells and mouse liver. Finally, hepatic AAV-mediated GNMT also reduced CCl4-induced miR-224 expression and liver fibrosis. These results indicated that AAV-mediated GNMT has potential liver protection activity. miR-224 can target the GNMT mRNA coding sequence and plays an important role in GNMT suppression during liver tumorigenesis.

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“…We referred to the miRNA array data from GEO nos. GSE42181 and GSE42182 and a reference 39 to determine the Fig. 4 miR-185-5p participates in the regulation of p66Shc expression.…”

Section: Mir-185-5p Participates In the Regulation Of P66shc Expressionmentioning

confidence: 99%

circ-CBFB upregulates p66Shc to perturb mitochondrial dynamics in APAP-induced liver injury

et al. 2020

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p66Shc, a master regulator of mitochondrial reactive oxygen species (mtROS), is a crucial mediator of hepatocyte oxidative stress. However, its functional contribution to acetaminophen (APAP)-induced liver injury and the mechanism by which it is modulated remain unknown. Here, we aimed to assess the effect of p66Shc on APAP-induced liver injury and to evaluate if circular RNA (circRNA) functions as a competitive endogenous RNA (ceRNA) to mediate p66Shc in APAP-induced liver injury. p66Shc-, miR-185-5p-, and circ-CBFB-silenced mice were injected with APAP. AML12 cells were transfected with p66Shc, miR-185-5p, and circ-CBFB silencing or overexpression plasmids or siRNAs prior to APAP stimulation. p66Shc was upregulated in liver tissues in response to APAP, and p66Shc silencing in vivo protected mice from APAP-induced mitochondrial dynamics perturbation and liver injury. p66Shc knockdown in vitro attenuated mitochondrial dynamics and APAP-induced hepatocyte injury. Mechanically, p66Shc perturbs mitochondrial dynamics partially by inhibiting OMA1 ubiquitination. miR-185-5p, which directly suppressed p66Shc translation, was identified by microarray and bioinformatics analyses, and its overexpression attenuated mitochondrial dynamics and hepatocyte injury in vitro. Furthermore, luciferase, pull-down and RNA immunoprecipitation assays demonstrated that circ-CBFB acts as a miRNA sponge of miR-185-5p to mediate p66Shc in APAP-induced liver injury. circ-CBFB knockdown also alleviated APAP-induced mitochondrial dynamics perturbation and hepatocyte injury. More importantly, we found that the protective effects of circ-CBFB knockdown on p66Shc, mitochondrial dynamics and liver injury were abolished by miR-185-5p inhibition both in vivo and in vitro. In conclusion, p66Shc is a key regulator of APAP-induced liver injury that acts by triggering mitochondrial dynamics perturbation. circ-CBFB functions as a ceRNA to regulate p66Shc during APAP-induced liver injury, which may provide a potential therapeutic target.

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Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans

Cited by 44 publications

References 42 publications

Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex

Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex

MicroRNA-224 down-regulates Glycine N-methyltransferase gene expression in Hepatocellular Carcinoma

circ-CBFB upregulates p66Shc to perturb mitochondrial dynamics in APAP-induced liver injury

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