Dataset Information

Hepatoprotective Effect of Citrus aurantium L. Against APAP-induced Liver Injury by Regulating Liver Lipid Metabolism and Apoptosis.

ABSTRACT: Acetaminophen (APAP) refers to a medication used to manage pain and fever symptoms, but it always causes liver injury when overdosed. Zhishi, dried young fruit of Citrus aurantium L., is a famous Citrus herbal medicine in Asian countries which is rich in dietary phenolic substances. In this study, the mechanism of Zhishi protected against APAP-induced liver injury was studied more deeply by metabolomic strategy and pharmacological study. The metabolomics results demonstrated that Zhishi can prevent the APAP-induced liver injury model by regulating liver metabolic disorders in glycerophospholipid metabolism, fatty acid biosynthesis and glycerolipid metabolism. Moreover, it is confirmed that Zhishi blocked apoptosis of APAP-induced BRL-3A cell by simultaneously regulating p53 up-regulated apoptosis regulator (PUMA), AMPK-SIRT1 and JNK1 signaling pathways. Our findings indicated that Zhishi exhibited a hepaprotective effect against APAP-induced liver necrosis by inhibiting the PUMA and reversing disorder of liver lipid metabolism which could assist in improving the clinical outcomes of chemical-induced liver injury.

SUBMITTER: Shu Y

PROVIDER: S-EPMC7019131 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Hepatoprotective Effect of Citrus aurantium L. Against APAP-induced Liver Injury by Regulating Liver Lipid Metabolism and Apoptosis.

Shu Yisong Y He Dan D Li Wen W Wang Menglei M Zhao Siyu S Liu Linlin L Cao Zhiwen Z Liu Rui R Huang Yujuan Y Li Hui H Yang Xueqing X Lu Cheng C Liu Yuanyan Y

International journal of biological sciences 20200114 5

Acetaminophen (APAP) refers to a medication used to manage pain and fever symptoms, but it always causes liver injury when overdosed. Zhishi, dried young fruit of Citrus aurantium L., is a famous Citrus herbal medicine in Asian countries which is rich in dietary phenolic substances. In this study, the mechanism of Zhishi protected against APAP-induced liver injury was studied more deeply by metabolomic strategy and pharmacological study. The metabolomics results demonstrated that Z ...[more]

PMID: 32071546

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Project description:As the current clinical treatment of acetaminophen (APAP)‑induced liver injury (AILI) has its limitations, new and effective treatment methods are required. Fingolimod (FTY720) is an immunosuppressive drug developed in recent years that has been shown to have a protective effect against ischemia/reperfusion liver injury. However, the role of FTY720 in AILI remains unclear. The aim of the present study was to determine whether FTY720 has a protective effect on AILI. AILI was induced using intraperitoneal injection of 300 mg/kg APAP in male C57BL/6J mice. Following APAP challenge, the mice were administered 5 mg/kg FTY720 for 30 min. Protein expression levels were measured using western blot analysis. Cell viability was examined using Cell Counting Kit‑8 assays. mRNA levels were measured using reverse transcription‑quantitative PCR. Inflammation levels were evaluated using immunohistochemistry. Cell death and reactive oxygen species levels were examined using immunofluorescence. Furthermore, laser scanning intravital microscopy was used to directly observe immune cell recruitment. APAP treatment increased the serum levels of alanine transaminase and aspartate transaminase at the 6‑ and 12‑h time‑points, suggesting liver tissue damage. However, FTY720 attenuated the liver injury induced by APAP by reducing the recruitment of immune cells and the release of pro‑inflammatory cytokines and chemokines. FTY720 activated JAK2/STAT3 signaling and regulated the expression of BAX, BCL‑2 and p65 to inhibit apoptosis and inflammation. In addition, compared with APAP treatment, the viability of primary hepatocytes treated with APAP and FTY720 was increased. Inhibition of JAK2/STAT3 signaling attenuated the protective, antioxidant effects of FTY720. In conclusion, FTY720 reduced liver injury by regulating the JAK2/STAT3 signaling pathway. This compound was capable of inhibiting oxidative stress to reduce hepatocyte death and the infiltration of neutrophils in the liver.

Project description: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.

Dataset Information

Hepatoprotective Effect of Citrus aurantium L. Against APAP-induced Liver Injury by Regulating Liver Lipid Metabolism and Apoptosis.

Publications

Hepatoprotective Effect of <i>Citrus aurantium L.</i> Against APAP-induced Liver Injury by Regulating Liver Lipid Metabolism and Apoptosis.

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