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Protective Effects of Crocetin on Arsenic Trioxide-Induced Hepatic

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Protective Effects of Crocetin on Arsenic Trioxide-Induced Hepatic Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Protective Effects of Crocetin on Arsenic Trioxide-Induced Hepatic Injury: Involvement of Suppression in Oxidative Stress and Inflammation Through Activation of Nrf2 Signaling Pathway in Rats This article was published in the following Dove Press journal: Drug Design, Development and Therapy Yanshuang Liu, 1,2,* Purpose: Arsenic trioxide (ATO) has been shown to induce hepatic injury. Crocetin is Yingran Liang,3,* a primary constituent of saffron, which has been verified to have antioxidant and anti- Bin Zheng,3 Li Chu,3 inflammatory effects. In the current experiment, we evaluated the efficacy of crocetin against Donglai Ma, 3 ATO-induced hepatic injury and explored the potential molecular mechanisms in rats. Hongfang Wang,3 Xi Chu,4 Methods: Rats were pretreated with 25 or 50 mg/kg crocetin 6 h prior to treating with 5 mg/ kg ATO to induce hepatic injury daily for 7 days. Jianping Zhang2,5 Results: Treatment with crocetin attenuated ATO-induced body weight loss, decreases in 1 Department of Diagnostics, School of food and water consumption, and improved ATO-induced hepatic pathological damage. Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Crocetin significantly inhibited ATO-induced alanine aminotransferase (ALT), aspartate ’ Shijiazhuang, Hebei, 050200, People s aminotransferase (AST), and alkaline phosphatase (ALP) increases. Crocetin prevented Republic of China; 2Hebei Key Laboratory of Integrative Medicine on Liver-Kidney ATO-induced liver malondialdehyde (MDA) and reactive oxygen species (ROS) levels. Patterns, Shijiazhuang 050200, Hebei, People’s Republic of China; 3Department of Crocetin abrogated the ATO-induced decrease of catalase (CAT) and superoxide dismutase Pharmaceutics, School of Pharmacy, Hebei (SOD) activity. Crocetin was found to significantly restore the protein levels of interleukin 6 University of Chinese Medicine, Shijiazhuang, β β α Hebei, 050200, People’s Republic of China; (IL-6), interleukin 1 (IL-1 ), and tumor necrosis factor-alpha (TNF- ). Furthermore, cro- 4Department of Pharmacy, The Fourth cetin promoted the expression of nuclear factor erythroid 2 related factor 2 (Nrf2), heme Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s oxygenase-1 (HO-1), and NADP(H): quinone oxidoreductase 1 (NQO1). Republic of China; 5Department of Conclusion: These findings suggest that crocetin ameliorates ATO-induced hepatic injury in Pharmacology, School of Basic Medicine, Hebei University of Chinese Medicine, rats. In addition, the effect of crocetin might be related to its role in antioxidant stress, as an Shijiazhuang, Hebei, 050200, People’s anti-inflammatory agent, and in regulating the Nrf2 signaling pathway. Republic of China Keywords: crocetin, arsenic trioxide, hepatotoxicity, oxidative stress, inflammation, Nrf2 *These authors contributed equally to this signaling pathway work Correspondence: Xi Chu The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei, Introduction People’s Republic of China Arsenic trioxide (ATO) is widely used as an effective component of traditional Tel/Fax +86 311 86095324 Email [email protected] Chinese medicine that produces significant remission in individuals with refractory or relapsed acute promyelocytic leukemia (APL).1 The United States (US) Food Jianping Zhang School of Basic Medicine, Hebei and Drug Administration approved ATO for APL in September 2000.2 However, University of Chinese Medicine, Shijiazhuang 050200, Hebei, People’s ATO is a known environmental toxicant that has become a widespread health Republic of China concern because of its toxicity.3,4 Epidemiological studies have also confirmed an Tel/Fax +86 311 89926719 Email [email protected] obvious association between the excess intake of inorganic arsenic and various submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 1921–1931 1921 DovePress © 2020 Liu et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php – http://doi.org/10.2147/DDDT.S247947 and incorporate the Creative Commons Attribution Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Liu et al Dovepress Figure 1 Chemical structure of crocetin. hazardous effects in humans, including hepatotoxicity, heme oxygenase-1 (HO-1) and NADP(H): quinone oxidor- nephrotoxicity, neurotoxicity, as well as dermatosis, eductase 1 (NQO1).21,22 The activation of these proteins is which limit its clinical application.3,5,6 now recognized as a strategy for cellular defense against As the main organ for the metabolism of poisonous the adverse effects of excessive ROS generation.22 substances, the liver is the primary target for ATO.7 A variation in the redox state means a variation in ROS Arsenic is absorbed into the body and distributed to tissues production or metabolism.23 Furthermore, ATO produces and viscera, especially into the liver.5 In experimental excess ROS by combining with nearby mercaptans, causes research, arsenic induces liver injuries that result in lipid peroxidation, and promotes apoptosis.24 Nrf2 confers changes in the biochemical indexes of liver functions, a protective effect against ROS and xenobiotics in healthy such as elevations of serum enzymes.7 Many investigators cells.25 have also confirmed that ATO was able to cause serious Crocetin (CRO) (C20H24O4; molecular weight 328.4g/ histopathological changes in the liver.8 mol, Figure 1) is a primary constituent of saffron, which Hepatic injury induced by arsenicals is closely related has been known to exert many kinds of pharmacological to oxidative stress by triggering the production of intracel- effects, including antioxidative stress,26 anti- lular reactive oxygen species (ROS), which can play a key inflammatory,27 anti-cancer, anti-apoptotic,28,29 heart dis- role in the toxic effect of arsenic and its compounds.9,10 ease preventive,30 and neuroprotective effects.31,32 These Oxidative stress is a state of an imbalance between oxida- properties of CRO, especially its ability to reduce oxida- tion and antioxidation involved in cellular damage.11,12 tive stress and inflammation, propose that it might be Excessive accumulation of ROS leads to cellular injuries, a significant candidate to attenuate liver injury. such as lipid peroxidation, DNA oxidative disruption, and Accordingly, we supposed that CRO could effectively enzyme inactivation.13,14 Synthetic or natural scavengers block hepatotoxicity induced by ATO. To test this predic- of ROS and antioxidants could attenuate ATO-induced tion, we investigated the effects of CRO on ATO-induced toxicity, thereby enabling full exploitation of the therapeu- hepatic injuries and explored the potential mechanisms of tic potential of ATO.15 The imbalance between the gen- oxidative stress and inflammation through activation of the eration of ROS and the antioxidant systems is usually Nrf2 signaling pathway in rats. Thus, safe and effective maintained by critical enzymes, for example, superoxide drugs for decreasing ATO-induced hepatotoxicity will pro- dismutase (SOD) and catalase (CAT).13 vide novel opportunities for the clinical use of ATO. Exposure of arsenic to individuals involved in the production of pro-inflammatory cytokines.16,17 Materials and Methods Interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor Materials necrosis factor-alpha (TNF-α) are important mediators of Crocetin with HPLC purity of ≥ 98% and arsenic triox- the inflammatory response and are involved with many ide (ATO, MW:197.84) were procured from Shanghai early systemic inflammation events.18 Yuanye Biotechnology Co., Ltd. (Shanghai, China). Nuclear factor erythroid 2 related factor 2 (Nrf2) plays Alanine aminotransferase (ALT), aspartate aminotrans- a dominant role as a central transcription factor in protect- ferase (AST), alkaline phosphatase (ALP), malondialde- ing against increased oxidative damage and toxic injury.19 hyde (MDA), glutathione (GSH), catalase (CAT), and Nrf2 is located in the cytoplasm of the resting cells.19,20 superoxide dismutase (SOD) detection kits were pro- Upon stimulation, Nrf2 translocates to the nucleus and cured from Jiancheng Bioengineering Institute of initiates transcription of its target genes, for instance, Nanjing (Nanjing, Jiangsu, China). The ROS detection 1922 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 DovePress Dovepress Liu et al kit was procured from Wuhan Servicebio Technology, Sample Preparations Co., Ltd (Wuhan, China). Antibodies specificforNrf2 During the period of feeding, body weights were recorded and NQO1 were procured from Bioworld Technology, at the beginning and end of the experiment, food and water Co., Ltd. (Nanjing, Jiangsu, China). HO-1 antibodies consumption were recorded daily in the morning before were obtained from Wuhan Sanying Biotechnology Co., supplemental diet. Ltd (Wuhan, China). β-actin was procured from Beijing On the 8th day, rats were starved overnight and
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