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      Hepatoprotective Effect of Baicalein Against Acetaminophen-Induced Acute Liver Injury in Mice

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          Abstract

          Baicalein (BAI), one of the main components of Scutellaria baicalensis Georgi, possesses numerous pharmacological properties, including anti-cancer, anti-oxidative, anti-virus and anti-bacterial activities. The purpose of this study was to evaluate the hepatoprotective effect of baicalein against acetaminophen (APAP)-exposed liver injury in mice, and elucidate the underlying hepatoprotective mechanism. Baicalein pretreatment significantly alleviated the elevation of IL-6, IL-1β and TNF-α in serum and hepatic in a dose-dependent manner. It also dose-dependently reduced the hepatic malondialdehyde (MDA) concentration, as well as the depletion of hepatic superoxide dismutase (SOD), hepatic glutathione (GSH) and hepatic catalase (CAT). Moreover, pretreatment with baicalein significantly ameliorated APAP-exposed liver damage and histological hepatocyte changes. Baicalein also relieved APAP-induced autophagy by regulating AKT/mTOR pathway, LC3B and P62 expression. Furthermore, the hepatoprotective effect of baicalein to APAP-induced liver injury involved in Jak2/Stat3 and MAPK signaling pathway. Taken together, our findings suggested that baicalein exhibits the ability to prevent liver from APAP-induced liver injury and provided an underlying molecular basis for potential applications of baicalein to cure liver injuries.

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          Most cited references44

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          p62 in Cancer: Signaling Adaptor Beyond Autophagy.

          Adaptor proteins participate in selective autophagy, which is critical for cellular detoxification and stress relief. However, new evidence supports an autophagy-independent key role of the adaptor p62 (encoded by the gene Sqstm1) in signaling functions central to tumor initiation in the epithelium and suppression of tumor progression in the stroma.
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            Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential

            Acetaminophen (APAP) hepatotoxicity is characterized by an extensive oxidative stress. However, its source, pathophysiological role and possible therapeutic potential if targeted, have been controversially described. Earlier studies argued for cytochrome P450-generated reactive oxygen species (ROS) during APAP metabolism, which resulted in massive lipid peroxidation and subsequent liver injury. However, subsequent studies convincingly challenged this assumption and the current paradigm suggests that mitochondria are the main source of ROS, which impair mitochondrial function and are responsible for cell signaling resulting in cell death. Although immune cells can be a source of ROS in other models, no reliable evidence exists to support a role for immune cell-derived ROS in APAP hepatotoxicity. Recent studies suggest that mitochondrial targeted antioxidants can be viable therapeutic agents against hepatotoxicity induced by APAP overdose, and re-purposing existing drugs to target oxidative stress and other concurrent signaling events can be a promising strategy to increase its potential application in patients with APAP overdose.
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              Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity.

              Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                31 December 2018
                January 2019
                : 24
                : 1
                : 131
                Affiliations
                College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; zhouhongchao813716@ 123456126.com (H.-C.Z.); wanghui813716@ 123456126.com (H.W.); sk1981521@ 123456jlau.edu.cn (K.S.); lijianming4773@ 123456163.com (J.-M.L.)
                Author notes
                [* ]Correspondence: yz449@ 123456msstate.edu (Y.Z.); durui71@ 123456126.com (R.D.); Tel./Fax: +86-431-84-532-981 (R.D.)
                [†]

                These authors contributed equally to this work.

                Article
                molecules-24-00131
                10.3390/molecules24010131
                6337302
                30602693
                5b4321d6-3706-4918-b089-2b1a42e5f14b
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 November 2018
                : 26 December 2018
                Categories
                Article

                baicalein,acetaminophen,liver injury,inflammation,autophagy
                baicalein, acetaminophen, liver injury, inflammation, autophagy

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