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

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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.

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Untargeted Metabolomics Strategies—Challenges and Emerging Directions

Stacy D Sherrod, John A. McLean, Alexandra C. Schrimpe-Rutledge … (2016)

Metabolites are building blocks of cellular function. These species are involved in enzyme-catalyzed chemical reactions and are essential for cellular function. Upstream biological disruptions result in a series of metabolomic changes, and as such the metabolome holds a wealth of information that is thought to be most predictive of phenotype. Uncovering this knowledge is a work in progress. The field of metabolomics is still maturing; the community has leveraged proteomics experience when applicable and developed a range of sample preparation and instrument methodology along with myriad data processing and analysis approaches. Research focuses have now shifted toward a fundamental understanding of the biology responsible for metabolomic changes. There are several types of metabolomics experiments including both targeted and untargeted analyses. While untargeted, hypothesis generating, workflows exhibit many valuable attributes, challenges inherent to the approach remain. This Critical Insight comments on these challenges, focusing on the identification process of LC-MS based untargeted metabolomics studies – specifically in mammalian systems. Biological interpretation of metabolomics data hinges on the ability to accurately identify metabolites. The range of confidence associated with identifications that is often overlooked is reviewed, and opportunities for advancing the metabolomics field are described.

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A comprehensive review of the health perspectives of resveratrol.

Abdur Rauf, Muhammad Imran, Hafiz Ansar Rasul Suleria … (2017)

Many natural products present in our diet, including flavonoids, can prevent the progression of cancer and other diseases. Resveratrol, a natural polyphenol present in various fruits and vegetables, plays an important role as a therapeutic and chemopreventive agent used in the treatment of various illnesses. It exhibits effects against different types of cancer through different pathways. It additionally exerts antidiabetic, anti-inflammatory, and anti-oxidant effects in a variety of cell types. Furthermore, the cardiovascular protective capacities of resveratrol are associated with multiple molecular targets and may lead to the development of novel therapeutic strategies for atherosclerosis, ischemia/reperfusion, metabolic syndrome, and heart failure. Accordingly, this article presents an overview of recent developments in the use of resveratrol for the prevention and treatment of different diseases along with various mechanisms. In addition, the present review summarizes the most recent literature pertaining to resveratrol as a chemotherapeutic agent against multiple diseases and provides an assessment of the potential of this natural compound as a complementary or alternative medicine.

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c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity.

Chieko Saito, John Lemasters, Hartmut Jaeschke (2010)

Acetaminophen (APAP) overdose, which causes liver injury in animals and humans, activates c-jun N-terminal kinase (JNK). Although it was shown that the JNK inhibitor SP600125 effectively reduced APAP hepatotoxicity, the mechanisms of protection remain unclear. C57Bl/6 mice were treated with 10mg/kg SP600125 or vehicle (8% dimethylsulfoxide) 1h before 600mg/kg APAP administration. APAP time-dependently induced JNK activation (detected by JNK phosphorylation). SP600125, but not the vehicle, reduced JNK activation, attenuated mitochondrial Bax translocation and prevented the mitochondrial release of apoptosis-inducing factor at 4-12h. Nuclear DNA fragmentation, nitrotyrosine staining, tissue GSSG levels and liver injury (plasma ALT release and necrosis) were partially attenuated by the vehicle (-65%) and completely eliminated by SP600125 (-98%) at 6 and 12h. Furthermore, SP600125 attenuated the increase of inducible nitric oxide synthase (iNOS) mRNA and protein. However, APAP did not enhance plasma nitrite+nitrate levels (NO formation); SP600125 had no effect on this parameter. The iNOS inhibitor L-NIL did not reduce NO formation or injury after APAP but prevented NO formation caused by endotoxin. Since SP600125 completely eliminated the increase in hepatic GSSG levels, an indicator of mitochondrial oxidant stress, it is concluded that the inhibition of peroxynitrite was mainly caused by reduced superoxide formation. Our data suggest that the JNK inhibitor SP600125 protects against APAP-induced liver injury in part by attenuation of mitochondrial Bax translocation but mainly by preventing mitochondrial oxidant stress and peroxynitrite formation and thereby preventing the mitochondrial permeability transition pore opening, a key event in APAP-induced cell necrosis. 2010 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Biol Sci

Journal ID (iso-abbrev): Int. J. Biol. Sci

Journal ID (publisher-id): ijbs

Title: International Journal of Biological Sciences

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1449-2288

Publication date Collection: 2020

Publication date (Electronic): 14 January 2020

Volume: 16

Issue: 5

Pages: 752-765

Affiliations

[1 ]Beijing University of Chinese Medicine, Beijing, 100029, China

[2 ]Patent Examination Cooperation (Tianjin) Center of the Patent Office, Tianjin, 300304, China

[3 ]Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

Author notes

✉ Corresponding authors: Dr. Xueqin Yang, Beijing Key Laboratory of Health-cultivation, Beijing University of Chinese Medicine, Beijing, 100029, China. Tel: +86 10 64286989, Fax: +86 10 84738611. E-mail address: yangxq0721@ 123456126.com . Dr. Cheng Lu, Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China. Tel.: +86 10 64014411-3403, Fax: +86 10 84032881. E-mail address: lv_cheng0816@ 123456163.com . Dr. Yuanyan Liu, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China. Tel: +86 10 84738658, Fax: +86 10 84738611. E-mail address: yyliu_1980@ 123456163.com .

* Yisong Shu and Dan He contributed equally to this work.

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: ijbsv16p0752

DOI: 10.7150/ijbs.40612

PMC ID: 7019131

PubMed ID: 32071546

SO-VID: 0b55e09a-1d21-47ae-b30e-1507bbdf4cfa

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This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

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

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Cancer Metabolism

Most cited references 36

Untargeted Metabolomics Strategies—Challenges and Emerging Directions

A comprehensive review of the health perspectives of resveratrol.

c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity.

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