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      In Vivo Hepatoprotective Effects of a Peptide Fraction from Krill Protein Hydrolysates against Alcohol-Induced Oxidative Damage

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          Abstract

          Background: Krill ( Euphausia superba) represent the largest animal biomass on earth, and are a rich source of high-quality protein with essential amino acids. Krill-derived peptides are renowned for their antioxidant activities. Hence, these peptides may have protective effects against oxidative stress. Alcoholic liver disease is a prevalent cause of death worldwide. The present study explores the hepatoprotective effects of krill peptide hydrolysate fractions against ethanol-induced liver damage in BALB/c mice. Methods: Hydrolysis was carried out by mimicking the gastrointestinal digestion environment and the filtrate was fractionated based on molecular weight (<1 kDa, 1–3 kDa, and >3 kDa). The 1–3 kDa fraction (KPF), which indicated the highest antioxidant effect, was further investigated for its effect on weight and survival rate increase in mice and its influence on serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and liver cholesterol levels. Moreover, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) levels were measured, followed by Nrf2 and HO-1 expression. Histopathology studies were conducted to assess hepatic tissue damage. Results: KPF enhanced the weight and survival rate of mice while reducing serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and liver cholesterol levels. Moreover, KPF upregulated SOD, CAT, and GPx in liver tissues, while downregulating tumor necrosis factor α and interleukin-6 mRNA expression. KPF further increased Nrf2 and HO-1 expression and suppressed ethanol-induced apoptotic proteins in the liver. Histopathology of KPF-treated mice showed less hepatic tissue damage compared to ethanol-treated mice. Conclusions: Hydrolysates and bioactive peptides prepared from krill can be employed as functional foods to enhance liver function and health. Further investigations of KPF could lead to the development of functional foods.

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          Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model.

          The use of many halogenated alkanes such as carbon tetrachloride (CCl4), chloroform (CHCl3) or iodoform (CHI3), has been banned or severely restricted because of their distinct toxicity. Yet CCl4 continues to provide an important service today as a model substance to elucidate the mechanisms of action of hepatotoxic effects such as fatty degeneration, fibrosis, hepatocellular death, and carcinogenicity. In a matter of dose,exposure time, presence of potentiating agents, or age of the affected organism, regeneration can take place and lead to full recovery from liver damage. CCl4 is activated by cytochrome (CYP)2E1, CYP2B1 or CYP2B2, and possibly CYP3A, to form the trichloromethyl radical, CCl3*. This radical can bind to cellular molecules (nucleic acid, protein, lipid), impairing crucial cellular processes such as lipid metabolism, with the potential outcome of fatty degeneration (steatosis). Adduct formation between CCl3* and DNA is thought to function as initiator of hepatic cancer. This radical can also react with oxygen to form the trichloromethylperoxy radical CCl3OO*, a highly reactive species. CCl3OO* initiates the chain reaction of lipid peroxidation, which attacks and destroys polyunsaturated fatty acids, in particular those associated with phospholipids. This affects the permeabilities of mitochondrial, endoplasmic reticulum, and plasma membranes, resulting in the loss of cellular calcium sequestration and homeostasis, which can contribute heavily to subsequent cell damage. Among the degradation products of fatty acids are reactive aldehydes, especially 4-hydroxynonenal, which bind easily to functional groups of proteins and inhibit important enzyme activities. CCl4 intoxication also leads to hypomethylation of cellular components; in the case of RNA the outcome is thought to be inhibition of protein synthesis, in the case of phospholipids it plays a role in the inhibition of lipoprotein secretion. None of these processes per se is considered the ultimate cause of CCl4-induced cell death; it is by cooperation that they achieve a fatal outcome, provided the toxicant acts in a high single dose, or over longer periods of time at low doses. At the molecular level CCl4 activates tumor necrosis factor (TNF)alpha, nitric oxide (NO), and transforming growth factors (TGF)-alpha and -beta in the cell, processes that appear to direct the cell primarily toward (self-)destruction or fibrosis. TNFalpha pushes toward apoptosis, whereas the TGFs appear to direct toward fibrosis. Interleukin (IL)-6, although induced by TNFalpha, has a clearly antiapoptotic effect, and IL-10 also counteracts TNFalpha action. Thus, both interleukins have the potential to initiate recovery of the CCl4-damaged hepatocyte. Several of the above-mentioned toxication processes can be specifically interrupted with the use of antioxidants and mitogens, respectively, by restoring cellular methylation, or by preserving calcium sequestration. Chemicals that induce cytochromes that metabolize CCl4, or delay tissue regeneration when co-administered with CCl4 will potentiate its toxicity thoroughly, while appropriate CYP450 inhibitors will alleviate much of the toxicity. Oxygen partial pressure can also direct the course of CCl4 hepatotoxicity. Pressures between 5 and 35 mmHg favor lipid peroxidation, whereas absence of oxygen, as well as a partial pressure above 100 mmHg, both prevent lipid peroxidation entirely. Consequently, the location of CCl4-induced damage mirrors the oxygen gradient across the liver lobule. Mixed halogenated methanes and ethanes, found as so-called disinfection byproducts at low concentration in drinking water, elicit symptoms of toxicity very similar to carbon tetrachloride, including carcinogenicity.
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            CYP2E1 and oxidative liver injury by alcohol.

            Ethanol-induced oxidative stress seems to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway seems to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide and, in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This review article summarizes some of the biochemical and toxicological properties of CYP2E1 and briefly describes the use of cell lines developed to constitutively express CYP2E1 and CYP2E1 knockout mice in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help us to understand the actions of CYP2E1 and its role in alcoholic liver injury.
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              Alcohol, Oxidative Stress, and Free Radical Damage

              Reactive oxygen species (ROS) are small, highly reactive, oxygen-containing molecules that are naturally generated in small amounts during the body’s metabolic reactions and can react with and damage complex cellular molecules such as fats, proteins, or DNA. Alcohol promotes the generation of ROS and/or interferes with the body’s normal defense mechanisms against these compounds through numerous processes, particularly in the liver. For example, alcohol breakdown in the liver results in the formation of molecules whose further metabolism in the cell leads to ROS production. Alcohol also stimulates the activity of enzymes called cytochrome P450s, which contribute to ROS production. Further, alcohol can alter the levels of certain metals in the body, thereby facilitating ROS production. Finally, alcohol reduces the levels of agents that can eliminate ROS (i.e., antioxidants). The resulting state of the cell, known as oxidative stress, can lead to cell injury. ROS production and oxidative stress in liver cells play a central role in the development of alcoholic liver disease.
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                Author and article information

                Journal
                Mar Drugs
                Mar Drugs
                marinedrugs
                Marine Drugs
                MDPI
                1660-3397
                07 December 2019
                December 2019
                : 17
                : 12
                : 690
                Affiliations
                [1 ]Department of Marine Bio-Food Sciences, Chonnam National University, Yeosu 59626, Korea; soo6683@ 123456naver.com (S.Y.P.); shanurabru@ 123456gmail.com (I.P.S.F.); dskang@ 123456jnu.ac.kr (D.-S.K.)
                [2 ]Department of Food Technology and Nutrition, Chonnam National University, Yeosu 59626, Korea; iosu5772@ 123456naver.com (E.J.H.); mijoo92@ 123456naver.com (M.J.K.); 9321@ 123456jnu.ac.kr (C.-B.A.)
                [3 ]Biomaterials Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 181 Ipsin-gil, Jeongeup-si, Jeonbuk 56212, Korea; jungks@ 123456kribb.re.kr
                Author notes
                [* ]Correspondence: gnahn@ 123456jnu.ac.kr or gnahn@ 123456chonnam.ac.kr ; Tel.: +82-61-659-7213
                Article
                marinedrugs-17-00690
                10.3390/md17120690
                6950056
                31817914
                0d3e3275-7bda-4692-a3f6-7798785d7b6e
                © 2019 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
                : 09 November 2019
                : 05 December 2019
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                alcoholic liver disease,euphausia superba,protein hydrolysate,antioxidant peptides,ultrafiltration,glutamic oxaloacetic transaminase,glutamic pyruvic transaminase

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