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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Curcumin in Liver Diseases: A Systematic Review of the Cellular Mechanisms of Oxidative Stress and Clinical Perspective</title><author><name sortKey="Farzaei, Mohammad Hosein" sort="Farzaei, Mohammad Hosein" uniqKey="Farzaei M" first="Mohammad Hosein" last="Farzaei">Mohammad Hosein Farzaei</name><affiliation><nlm:aff id="af1-nutrients-10-00855">Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran;<email>parvizi_70@yahoo.com</email></nlm:aff></affiliation></author><author><name sortKey="Zobeiri, Mahdi" sort="Zobeiri, Mahdi" uniqKey="Zobeiri M" first="Mahdi" last="Zobeiri">Mahdi Zobeiri</name><affiliation><nlm:aff id="af2-nutrients-10-00855">Internal Medicine Department, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran;<email>mehdizobeiri@yahoo.com</email> (M.Z.);<email>rnasseri.75@gmail.com</email> (R.N.)</nlm:aff></affiliation></author><author><name sortKey="Parvizi, Fatemeh" sort="Parvizi, Fatemeh" uniqKey="Parvizi F" first="Fatemeh" last="Parvizi">Fatemeh Parvizi</name><affiliation><nlm:aff id="af1-nutrients-10-00855">Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran;<email>parvizi_70@yahoo.com</email></nlm:aff></affiliation></author><author><name sortKey="El Senduny, Fardous F" sort="El Senduny, Fardous F" uniqKey="El Senduny F" first="Fardous F." last="El-Senduny">Fardous F. El-Senduny</name><affiliation><nlm:aff id="af3-nutrients-10-00855">Biochemistry division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt;<email>biobotany@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Marmouzi, Ilias" sort="Marmouzi, Ilias" uniqKey="Marmouzi I" first="Ilias" last="Marmouzi">Ilias Marmouzi</name><affiliation><nlm:aff id="af4-nutrients-10-00855">Laboratory of Pharmacology and Toxicology Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10100, Morocco;<email>ilias.marmouzi@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Coy Barrera, Ericsson" sort="Coy Barrera, Ericsson" uniqKey="Coy Barrera E" first="Ericsson" last="Coy-Barrera">Ericsson Coy-Barrera</name><affiliation><nlm:aff id="af5-nutrients-10-00855">Bioorganic Chemistry Laboratory, Facultad de Ciencias Básicas y Aplicadas, Universidad Militar Nueva Granada, Campus Nueva Granada, Cajicá 250247, Colombia;<email>ericsson.coy@unimilitar.edu.co</email></nlm:aff></affiliation></author><author><name sortKey="Naseri, Rozita" sort="Naseri, Rozita" uniqKey="Naseri R" first="Rozita" last="Naseri">Rozita Naseri</name><affiliation><nlm:aff id="af2-nutrients-10-00855">Internal Medicine Department, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran;<email>mehdizobeiri@yahoo.com</email> (M.Z.);<email>rnasseri.75@gmail.com</email> (R.N.)</nlm:aff></affiliation></author><author><name sortKey="Nabavi, Seyed Mohammad" sort="Nabavi, Seyed Mohammad" uniqKey="Nabavi S" first="Seyed Mohammad" last="Nabavi">Seyed Mohammad Nabavi</name><affiliation><nlm:aff id="af6-nutrients-10-00855">Applied Biotechnology Research Center, Baghyatollah University of Medical Sciences, Tehran 1435916471, Iran;<email>Nabavi208@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Rahimi, Roja" sort="Rahimi, Roja" uniqKey="Rahimi R" first="Roja" last="Rahimi">Roja Rahimi</name><affiliation><nlm:aff id="af7-nutrients-10-00855">Department of Persian Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran 1416663361, Iran;<email>rojarahimi@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Abdollahi, Mohammad" sort="Abdollahi, Mohammad" uniqKey="Abdollahi M" first="Mohammad" last="Abdollahi">Mohammad Abdollahi</name><affiliation><nlm:aff id="af8-nutrients-10-00855">Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS) and Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">29966389</idno><idno type="pmc">6073929</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073929</idno><idno type="RBID">PMC:6073929</idno><idno type="doi">10.3390/nu10070855</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">000312</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000312</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Curcumin in Liver Diseases: A Systematic Review of the Cellular Mechanisms of Oxidative Stress and Clinical Perspective</title><author><name sortKey="Farzaei, Mohammad Hosein" sort="Farzaei, Mohammad Hosein" uniqKey="Farzaei M" first="Mohammad Hosein" last="Farzaei">Mohammad Hosein Farzaei</name><affiliation><nlm:aff id="af1-nutrients-10-00855">Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran;<email>parvizi_70@yahoo.com</email></nlm:aff></affiliation></author><author><name sortKey="Zobeiri, Mahdi" sort="Zobeiri, Mahdi" uniqKey="Zobeiri M" first="Mahdi" last="Zobeiri">Mahdi Zobeiri</name><affiliation><nlm:aff id="af2-nutrients-10-00855">Internal Medicine Department, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran;<email>mehdizobeiri@yahoo.com</email> (M.Z.);<email>rnasseri.75@gmail.com</email> (R.N.)</nlm:aff></affiliation></author><author><name sortKey="Parvizi, Fatemeh" sort="Parvizi, Fatemeh" uniqKey="Parvizi F" first="Fatemeh" last="Parvizi">Fatemeh Parvizi</name><affiliation><nlm:aff id="af1-nutrients-10-00855">Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran;<email>parvizi_70@yahoo.com</email></nlm:aff></affiliation></author><author><name sortKey="El Senduny, Fardous F" sort="El Senduny, Fardous F" uniqKey="El Senduny F" first="Fardous F." last="El-Senduny">Fardous F. El-Senduny</name><affiliation><nlm:aff id="af3-nutrients-10-00855">Biochemistry division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt;<email>biobotany@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Marmouzi, Ilias" sort="Marmouzi, Ilias" uniqKey="Marmouzi I" first="Ilias" last="Marmouzi">Ilias Marmouzi</name><affiliation><nlm:aff id="af4-nutrients-10-00855">Laboratory of Pharmacology and Toxicology Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10100, Morocco;<email>ilias.marmouzi@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Coy Barrera, Ericsson" sort="Coy Barrera, Ericsson" uniqKey="Coy Barrera E" first="Ericsson" last="Coy-Barrera">Ericsson Coy-Barrera</name><affiliation><nlm:aff id="af5-nutrients-10-00855">Bioorganic Chemistry Laboratory, Facultad de Ciencias Básicas y Aplicadas, Universidad Militar Nueva Granada, Campus Nueva Granada, Cajicá 250247, Colombia;<email>ericsson.coy@unimilitar.edu.co</email></nlm:aff></affiliation></author><author><name sortKey="Naseri, Rozita" sort="Naseri, Rozita" uniqKey="Naseri R" first="Rozita" last="Naseri">Rozita Naseri</name><affiliation><nlm:aff id="af2-nutrients-10-00855">Internal Medicine Department, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran;<email>mehdizobeiri@yahoo.com</email> (M.Z.);<email>rnasseri.75@gmail.com</email> (R.N.)</nlm:aff></affiliation></author><author><name sortKey="Nabavi, Seyed Mohammad" sort="Nabavi, Seyed Mohammad" uniqKey="Nabavi S" first="Seyed Mohammad" last="Nabavi">Seyed Mohammad Nabavi</name><affiliation><nlm:aff id="af6-nutrients-10-00855">Applied Biotechnology Research Center, Baghyatollah University of Medical Sciences, Tehran 1435916471, Iran;<email>Nabavi208@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Rahimi, Roja" sort="Rahimi, Roja" uniqKey="Rahimi R" first="Roja" last="Rahimi">Roja Rahimi</name><affiliation><nlm:aff id="af7-nutrients-10-00855">Department of Persian Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran 1416663361, Iran;<email>rojarahimi@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Abdollahi, Mohammad" sort="Abdollahi, Mohammad" uniqKey="Abdollahi M" first="Mohammad" last="Abdollahi">Mohammad Abdollahi</name><affiliation><nlm:aff id="af8-nutrients-10-00855">Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS) and Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran</nlm:aff></affiliation></author></analytic><series><title level="j">Nutrients</title><idno type="eISSN">2072-6643</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Oxidative stress has been considered a key causing factor of liver damage induced by a variety of agents, including alcohol, drugs, viral infections, environmental pollutants and dietary components, which in turn results in progression of liver injury, non-alcoholic steatohepatitis, non-alcoholic liver disease, liver fibrosis and cirrhosis. During the past 30 years and even after the major progress in the liver disease management, millions of people worldwide still suffer from an acute or chronic liver condition. Curcumin is one of the most commonly used indigenous molecules endowed by various shielding functionalities that protects the liver. The aim of the present study is to comprehensively review pharmacological effects and molecular mechanisms, as well as clinical evidence, of curcumin as a lead compound in the prevention and treatment of oxidative associated liver diseases. For this purpose, electronic databases including “Scopus,” “PubMed,” “Science Direct” and “Cochrane library” were extensively searched with the keywords “curcumin or curcuminoids” and “hepatoprotective or hepatotoxicity or liver” along with “oxidative or oxidant.” Results showed that curcumin exerts remarkable protective and therapeutic effects of oxidative associated liver diseases through various cellular and molecular mechanisms. Those mechanisms include suppressing the proinflammatory cytokines, lipid perodixation products, PI3K/Akt and hepatic stellate cells activation, as well as ameliorating cellular responses to oxidative stress such as the expression of Nrf2, SOD, CAT, GSH, GPx and GR. Taking together, curcumin itself acts as a free radical scavenger over the activity of different kinds of ROS via its phenolic, β-diketone and methoxy group. Further clinical studies are still needed in order to recognize the structure-activity relationships and molecular mechanisms of curcumin in oxidative associated liver diseases.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Muriel, P" uniqKey="Muriel P">P. Muriel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cicho Lach, H" uniqKey="Cicho Lach H">H. Cichoż-Lach</name></author><author><name sortKey="Michalak, A" uniqKey="Michalak A">A. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nutrients</journal-id><journal-id journal-id-type="iso-abbrev">Nutrients</journal-id><journal-id journal-id-type="publisher-id">nutrients</journal-id><journal-title-group><journal-title>Nutrients</journal-title></journal-title-group><issn pub-type="epub">2072-6643</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29966389</article-id><article-id pub-id-type="pmc">6073929</article-id><article-id pub-id-type="doi">10.3390/nu10070855</article-id><article-id pub-id-type="publisher-id">nutrients-10-00855</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Curcumin in Liver Diseases: A Systematic Review of the Cellular Mechanisms of Oxidative Stress and Clinical Perspective</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Farzaei</surname><given-names>Mohammad Hosein</given-names></name><xref ref-type="aff" rid="af1-nutrients-10-00855">1</xref><xref rid="c1-nutrients-10-00855" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Zobeiri</surname><given-names>Mahdi</given-names></name><xref ref-type="aff" rid="af2-nutrients-10-00855">2</xref></contrib><contrib contrib-type="author"><name><surname>Parvizi</surname><given-names>Fatemeh</given-names></name><xref ref-type="aff" rid="af1-nutrients-10-00855">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-4572-2061</contrib-id><name><surname>El-Senduny</surname><given-names>Fardous F.</given-names></name><xref ref-type="aff" rid="af3-nutrients-10-00855">3</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-0121-8939</contrib-id><name><surname>Marmouzi</surname><given-names>Ilias</given-names></name><xref ref-type="aff" rid="af4-nutrients-10-00855">4</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-3553-9749</contrib-id><name><surname>Coy-Barrera</surname><given-names>Ericsson</given-names></name><xref ref-type="aff" rid="af5-nutrients-10-00855">5</xref></contrib><contrib contrib-type="author"><name><surname>Naseri</surname><given-names>Rozita</given-names></name><xref ref-type="aff" rid="af2-nutrients-10-00855">2</xref></contrib><contrib contrib-type="author"><name><surname>Nabavi</surname><given-names>Seyed Mohammad</given-names></name><xref ref-type="aff" rid="af6-nutrients-10-00855">6</xref></contrib><contrib contrib-type="author"><name><surname>Rahimi</surname><given-names>Roja</given-names></name><xref ref-type="aff" rid="af7-nutrients-10-00855">7</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-0123-1209</contrib-id><name><surname>Abdollahi</surname><given-names>Mohammad</given-names></name><xref ref-type="aff" rid="af8-nutrients-10-00855">8</xref><xref rid="c1-nutrients-10-00855" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-nutrients-10-00855"><label>1</label>Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran;<email>parvizi_70@yahoo.com</email></aff><aff id="af2-nutrients-10-00855"><label>2</label>Internal Medicine Department, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran;<email>mehdizobeiri@yahoo.com</email> (M.Z.);<email>rnasseri.75@gmail.com</email> (R.N.)</aff><aff id="af3-nutrients-10-00855"><label>3</label>Biochemistry division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt;<email>biobotany@gmail.com</email></aff><aff id="af4-nutrients-10-00855"><label>4</label>Laboratory of Pharmacology and Toxicology Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10100, Morocco;<email>ilias.marmouzi@gmail.com</email></aff><aff id="af5-nutrients-10-00855"><label>5</label>Bioorganic Chemistry Laboratory, Facultad de Ciencias Básicas y Aplicadas, Universidad Militar Nueva Granada, Campus Nueva Granada, Cajicá 250247, Colombia;<email>ericsson.coy@unimilitar.edu.co</email></aff><aff id="af6-nutrients-10-00855"><label>6</label>Applied Biotechnology Research Center, Baghyatollah University of Medical Sciences, Tehran 1435916471, Iran;<email>Nabavi208@gmail.com</email></aff><aff id="af7-nutrients-10-00855"><label>7</label>Department of Persian Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran 1416663361, Iran;<email>rojarahimi@gmail.com</email></aff><aff id="af8-nutrients-10-00855"><label>8</label>Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS) and Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran</aff><author-notes><corresp id="c1-nutrients-10-00855"><label>*</label>Correspondences: <email>mh.farzaei@gmail.com</email> (M.H.F.); <email>Mohammad@TUMS.Ac.Ir</email> (M.A.)</corresp></author-notes><pub-date pub-type="epub"><day>01</day><month>7</month><year>2018</year></pub-date><pub-date pub-type="collection"><month>7</month><year>2018</year></pub-date><volume>10</volume><issue>7</issue><elocation-id>855</elocation-id><history><date date-type="received"><day>28</day><month>5</month><year>2018</year></date><date date-type="accepted"><day>28</day><month>6</month><year>2018</year></date></history><permissions><copyright-statement>© 2018 by the authors.</copyright-statement><copyright-year>2018</copyright-year><license license-type="open-access"><license-p>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 (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Oxidative stress has been considered a key causing factor of liver damage induced by a variety of agents, including alcohol, drugs, viral infections, environmental pollutants and dietary components, which in turn results in progression of liver injury, non-alcoholic steatohepatitis, non-alcoholic liver disease, liver fibrosis and cirrhosis. During the past 30 years and even after the major progress in the liver disease management, millions of people worldwide still suffer from an acute or chronic liver condition. Curcumin is one of the most commonly used indigenous molecules endowed by various shielding functionalities that protects the liver. The aim of the present study is to comprehensively review pharmacological effects and molecular mechanisms, as well as clinical evidence, of curcumin as a lead compound in the prevention and treatment of oxidative associated liver diseases. For this purpose, electronic databases including “Scopus,” “PubMed,” “Science Direct” and “Cochrane library” were extensively searched with the keywords “curcumin or curcuminoids” and “hepatoprotective or hepatotoxicity or liver” along with “oxidative or oxidant.” Results showed that curcumin exerts remarkable protective and therapeutic effects of oxidative associated liver diseases through various cellular and molecular mechanisms. Those mechanisms include suppressing the proinflammatory cytokines, lipid perodixation products, PI3K/Akt and hepatic stellate cells activation, as well as ameliorating cellular responses to oxidative stress such as the expression of Nrf2, SOD, CAT, GSH, GPx and GR. Taking together, curcumin itself acts as a free radical scavenger over the activity of different kinds of ROS via its phenolic, β-diketone and methoxy group. Further clinical studies are still needed in order to recognize the structure-activity relationships and molecular mechanisms of curcumin in oxidative associated liver diseases.</p></abstract><kwd-group><kwd>curcumin</kwd><kwd>hepatotoxicity</kwd><kwd>liver diseases</kwd><kwd>oxidative stress</kwd><kwd>systematic review</kwd></kwd-group></article-meta></front><body><sec id="sec1-nutrients-10-00855"><title>1. Introduction</title><p>During the past 30 years and even after the major progress in the liver disease management, millions of people still suffer from an acute or chronic liver condition worldwide. Liver diseases affect more than 10% of the world population and its mortal end-stage generally follows cirrhosis and liver cancer [<xref rid="B1-nutrients-10-00855" ref-type="bibr">1</xref>]. Diverse etiologies characterize the disease to constitute about the fourth to the fifth cause of deaths worldwide. The Nonalcoholic Fatty Liver Disease (NAFLD) is the global leading cause of liver diseases with 40% frequently, followed by Hepatitis B virus (HBV), Hepatitis C virus (HCV) and harmful alcohol consumption, accounting for 30%, 15% and 11%, respectively [<xref rid="B1-nutrients-10-00855" ref-type="bibr">1</xref>].</p><p>Chronic liver diseases are often accompanied by increased oxidative stress, irrespective of the cause of the liver dysfunction [<xref rid="B2-nutrients-10-00855" ref-type="bibr">2</xref>]. Oxidative stress (indicating excessive reactive oxygen species (ROS) levels and an oxidant and antioxidant imbalance) can lead to cellular degradation of proteins, lipids and DNA. Reactive oxygen species (ROS) participates in the liver fibrogenic response and contributes to ischemia/regeneration, necrosis and apoptosis. These modifications result in altered gene expression and progressive liver damage [<xref rid="B2-nutrients-10-00855" ref-type="bibr">2</xref>].</p><p>Natural products provide a repertory for discovery of new leads that can be used in treating different types of diseases such as cancer, inflammation and liver diseases. More than half of all pharmaceutical products have been discovered from natural compounds or their derivatives [<xref rid="B3-nutrients-10-00855" ref-type="bibr">3</xref>]. In the United States and Europe, approximately 65% of patients use herbal medicines against liver disease, due to their wide availability, low toxicity, pharmacological activity and chemical diversity and low side effects compared to synthetic drugs [<xref rid="B4-nutrients-10-00855" ref-type="bibr">4</xref>,<xref rid="B5-nutrients-10-00855" ref-type="bibr">5</xref>,<xref rid="B6-nutrients-10-00855" ref-type="bibr">6</xref>,<xref rid="B7-nutrients-10-00855" ref-type="bibr">7</xref>,<xref rid="B8-nutrients-10-00855" ref-type="bibr">8</xref>]. Curcumin is the main constituent of turmeric, the rhizome of <italic>Curcuma longa</italic>. It is widely used due to its therapeutic effectiveness and acceptable safety specification [<xref rid="B9-nutrients-10-00855" ref-type="bibr">9</xref>,<xref rid="B10-nutrients-10-00855" ref-type="bibr">10</xref>]. Curcumin possesses several biological activities such as anti-inflammatory [<xref rid="B11-nutrients-10-00855" ref-type="bibr">11</xref>,<xref rid="B12-nutrients-10-00855" ref-type="bibr">12</xref>], anticancer [<xref rid="B13-nutrients-10-00855" ref-type="bibr">13</xref>], antioxidant [<xref rid="B14-nutrients-10-00855" ref-type="bibr">14</xref>] and the ability to heal wounds [<xref rid="B15-nutrients-10-00855" ref-type="bibr">15</xref>]. From these facts, the aim of this review is to compile and discuss the effects of curcumin for the prevention and treatment of oxidative associated liver diseases as well as to highlight its molecular mechanism of action.</p></sec><sec id="sec2-nutrients-10-00855"><title>2. Liver Disease: Pathophysiology and Epidemiology</title><p>The vitality of the human liver is mainly associated with the impressive processes attributed to this part of the entrails. Its nomination was even regarded as a synonym of life [<xref rid="B1-nutrients-10-00855" ref-type="bibr">1</xref>]. In fact, multiple functionalities are attributed to this triangular organ extending across the abdominal cavity below the diaphragm [<xref rid="B1-nutrients-10-00855" ref-type="bibr">1</xref>]. Its metabolic and secretory capacities can cause hepatocellular death and eventually liver disease by involving a prominent exposure to alcohol, dietary components and viral infections [<xref rid="B16-nutrients-10-00855" ref-type="bibr">16</xref>]. Apparently, this organ is extremely vulnerable to numerous pathologies mainly associated with its great number of functions, structural organization, strategic localization and cell sensitivities. A number of mechanisms such as direct damage, stimulation of immune response against cells, formation of reactive intermediates, cytoskeletal damage, disruption of normal cell metabolism, triggering of apoptosis and hypoxia are involved in hepatocellular injury.</p><p>Hepatitis is an inflammatory process caused by drugs, alcohol and often by a virus. This is commonly known as hepatitis A, B, C, D and E. For instance, it is estimated that between 130 and 150 million patients suffer from HCV infection globally [<xref rid="B1-nutrients-10-00855" ref-type="bibr">1</xref>]. Chronic hepatitis therefore occurs when the injury persists for more than 6 months, resulting in raising aminotransferase levels or viral markers [<xref rid="B17-nutrients-10-00855" ref-type="bibr">17</xref>]. On the other hand, the abnormal accumulation of lipids in hepatic cells (5% or more) is generally referred as steatosis. The macrovesicular steatosis generates the propitious environment of alcoholic and non-alcoholic steatohepatitis (ASH & NASH) lesion development [<xref rid="B18-nutrients-10-00855" ref-type="bibr">18</xref>,<xref rid="B19-nutrients-10-00855" ref-type="bibr">19</xref>]. NASH is associated with hepatic steatosis and inflammation [<xref rid="B17-nutrients-10-00855" ref-type="bibr">17</xref>], however ASH and NASH are hardly distinguished on single-handed histological grounds [<xref rid="B20-nutrients-10-00855" ref-type="bibr">20</xref>]. Their pathophysiology includes hepatocellular damage most severe in (or restricted to) perivenular areas, inflammation and fibrosis. In this sense, the nomenclatures alcoholic fatty liver disease (AFLD) and NAFLD are used to demonstrate a wide range of alterations between uncomplicated steatosis and cirrhosis [<xref rid="B21-nutrients-10-00855" ref-type="bibr">21</xref>]. NAFLD is a chronic liver disease in non-abusively alcohol-drinking patients. It is highly associated with obesity, type-II diabetes mellitus and hyperlipidemia (high levels of triglycerides, low-density lipoprotein cholesterol, cholesterol and low level of high-density lipoprotein cholesterol) [<xref rid="B22-nutrients-10-00855" ref-type="bibr">22</xref>]. NAFLD treatment mainly depends on the severity. Regardless whether it is treated or not, NAFLD may progress to fibrosis and cirrhosis in specific population and the risk increases with aging, diabetes and obesity [<xref rid="B23-nutrients-10-00855" ref-type="bibr">23</xref>,<xref rid="B24-nutrients-10-00855" ref-type="bibr">24</xref>,<xref rid="B25-nutrients-10-00855" ref-type="bibr">25</xref>]. Current treatments rely on increasing insulin sensitivity (thiazolidinediones and metformin), slow-rate lowering body weight, reducing lipid level (gemfibrozil) and protecting hepatocytes (ursodeoxycholic acid, betaine, <italic>N</italic>-acetylcysteine, vitamin E). Thiazolidinediones (TZD) increases insulin sensitivity and lipid oxidation; preventing their accumulation in the liver [<xref rid="B26-nutrients-10-00855" ref-type="bibr">26</xref>,<xref rid="B27-nutrients-10-00855" ref-type="bibr">27</xref>]. Unfortunately, TZD has adverse side effects leading to edema and increases the body weight [<xref rid="B26-nutrients-10-00855" ref-type="bibr">26</xref>,<xref rid="B28-nutrients-10-00855" ref-type="bibr">28</xref>]. Therefore, there is a need for new strategies to control those liver diseases such as NAFLD, cirrhosis and even liver cancer [<xref rid="B29-nutrients-10-00855" ref-type="bibr">29</xref>,<xref rid="B30-nutrients-10-00855" ref-type="bibr">30</xref>].</p></sec><sec id="sec3-nutrients-10-00855"><title>3. Role of Oxidative Stress in Development of Liver Disease</title><p>The pathogenesis of liver diseases integrates the oxidative stress processes and damages, including lipids, proteins and DNA alterations as well as modulation of functional signaling pathways. Oxidative stress is an imbalance between antioxidant capacity and the level of ROS in cells. ROS and reactive nitrogen species (RNS) are now being used to describe the free radicals derived from molecular oxygen and the oxidants derived from NO•, respectively [<xref rid="B31-nutrients-10-00855" ref-type="bibr">31</xref>,<xref rid="B32-nutrients-10-00855" ref-type="bibr">32</xref>]. Additionally, ROS can be produced by the endoplasmic reticulum in the liver via the cytochrome P450 enzymes at the macrophages and neutrophils levels [<xref rid="B2-nutrients-10-00855" ref-type="bibr">2</xref>]. One of the mechanisms leading to oxidative stress is the modulation of protein expression under H<sub>2</sub>O<sub>2</sub> stress. This alteration exposes the liver to severe oxidative stress, resulting in hepatocyte apoptosis. Oxidative stress induced liver diseases can also cause brain impairment and kidney failure [<xref rid="B33-nutrients-10-00855" ref-type="bibr">33</xref>,<xref rid="B34-nutrients-10-00855" ref-type="bibr">34</xref>].</p><p>Many etiological factors were associated with liver disease and are highly productive of ROS. In fact, studies have demonstrated that ethanol can result in a significant rising of mitochondrial ROS levels in hepatocytes [<xref rid="B35-nutrients-10-00855" ref-type="bibr">35</xref>]. Ethanol oxidation involves at least three distinct enzymatic pathways [<xref rid="B36-nutrients-10-00855" ref-type="bibr">36</xref>]. Alcohol dehydrogenase (ADH) firstly oxidizes ethanol to acetaldehyde and the latter is then oxidized to acetate by aldehyde dehydrogenases (ALDH) in the mitochondria. The ethanol oxidation is also promoted by the microsomal ethanol oxidizing system (MEOS), the cytochrome P450 enzyme Cytochrome P450 2E1 (CYP2E1) and the catalase in peroxisomes. An excessive consumption of alcohol results in a higher metabolic activity which elevates ROS and liver injury [<xref rid="B37-nutrients-10-00855" ref-type="bibr">37</xref>].</p><p>On the other hand, drug hepatotoxicity is linked to ROS and RNS productions [<xref rid="B38-nutrients-10-00855" ref-type="bibr">38</xref>]. Actually, the intake of medication can induce oxidative stress via increase of cellular oxidants and lipid peroxidation and depletion of antioxidants in the liver. For instance, sulfasalazine reduces superoxide dismutase (SOD) but increases catalase (CAT) activity. Zoledronic acid results in significantly elevated malondialdehyde (MDA) and nitric oxide levels, whereas reduced glutathione (GSH) levels [<xref rid="B39-nutrients-10-00855" ref-type="bibr">39</xref>]. Even paracetamol also increases MDA, nitrite and nitrate in the liver and reduces total SOD and Cu/Zn-SOD activities. In addition to these factors, exposure to heavy metals, microcystin, radiation and temperature have also been shown to cause oxidative damage in liver [<xref rid="B40-nutrients-10-00855" ref-type="bibr">40</xref>,<xref rid="B41-nutrients-10-00855" ref-type="bibr">41</xref>].</p></sec><sec id="sec4-nutrients-10-00855"><title>4. Curcumin and Oxidative Stress</title><p><italic>Curcuma longa</italic> (turmeric) is a widely used spice, coloring agent and source of curcumin [<xref rid="B42-nutrients-10-00855" ref-type="bibr">42</xref>]. Derivatives from <italic>Curcuma longa</italic> L. are including, Curcumin, Ar-turmerone, Methylcurcumin, Demethoxy curcumin, Bisdemethoxy curcumin and Sodium curcuminate. Curcumin that is in the most important fraction of <italic>Curcuma longa</italic> L., is one of the most commonly used indigenous molecules endowed by various protective functionalities [<xref rid="B42-nutrients-10-00855" ref-type="bibr">42</xref>,<xref rid="B43-nutrients-10-00855" ref-type="bibr">43</xref>]. The pharmacokinetic (PK) studies of curcumin have consistently reported that the bioavailability of curcumin is relatively low due to its instability, poor solubility and absorption and its rapid metabolic elimination by reduction and conjugation in the presence of mild temperature and light. Similar to rodent studies, the poor bioavailability of curcumin in humans causes a primary barrier to achieve adequate plasma levels with favorable pharmacological effects [<xref rid="B42-nutrients-10-00855" ref-type="bibr">42</xref>,<xref rid="B44-nutrients-10-00855" ref-type="bibr">44</xref>]. Hence curcumin derivatives are of great interest in biomedical research [<xref rid="B43-nutrients-10-00855" ref-type="bibr">43</xref>].</p><p>This bright-yellow curcuminoid contains a variety of functional antioxidant groups, including the β-diketo group, carbon-carbon double bonds and phenyl rings. Curcumin can thus eliminate lipid radicals in the cell membrane and become a phenoxyl radical, so it is considered a very strong lipid-soluble antioxidant [<xref rid="B45-nutrients-10-00855" ref-type="bibr">45</xref>]. Furthermore, curcumin was found to inhibit lipid peroxidation and neutralize ROS (superoxide, peroxyl, hydroxyl radicals) [<xref rid="B46-nutrients-10-00855" ref-type="bibr">46</xref>] and RNS (nitric oxide and peroxynitrite) [<xref rid="B47-nutrients-10-00855" ref-type="bibr">47</xref>]. The protective effect of curcumin against oxidative stress was previously described in vitro and in vivo [<xref rid="B48-nutrients-10-00855" ref-type="bibr">48</xref>,<xref rid="B49-nutrients-10-00855" ref-type="bibr">49</xref>,<xref rid="B50-nutrients-10-00855" ref-type="bibr">50</xref>,<xref rid="B51-nutrients-10-00855" ref-type="bibr">51</xref>]. For instance, its biomembrane-protective effect against peroxidative damage was mainly linked to its ROS scavenging ability [<xref rid="B52-nutrients-10-00855" ref-type="bibr">52</xref>]. The hydrogen donor capacity was also associated with its phenolic and/or central methylenic groups. The enol form of curcumin was demonstrated to be significantly more stable than the diketo form. This study also suggested that the hydrogen atom abstraction takes place in the phenolic group [<xref rid="B52-nutrients-10-00855" ref-type="bibr">52</xref>,<xref rid="B53-nutrients-10-00855" ref-type="bibr">53</xref>,<xref rid="B54-nutrients-10-00855" ref-type="bibr">54</xref>,<xref rid="B55-nutrients-10-00855" ref-type="bibr">55</xref>]. However, the activity of the radical and the reaction medium influenced the relative contribution of the phenolic group and the central methylenic group to the antioxidant activity [<xref rid="B52-nutrients-10-00855" ref-type="bibr">52</xref>,<xref rid="B56-nutrients-10-00855" ref-type="bibr">56</xref>]. In addition, curcumin degradation products can also claim for its antioxidant activities. It can degrade under basic pH after 30 min into ferulic acid and vanillin [<xref rid="B57-nutrients-10-00855" ref-type="bibr">57</xref>]. In addition, curcumin exhibited chelating activity and is able to capture ferrous ion through its functional carbonyl groups [<xref rid="B45-nutrients-10-00855" ref-type="bibr">45</xref>].</p></sec><sec id="sec5-nutrients-10-00855"><title>5. Study Design</title><p>Electronic databases including “Scopus,” “PubMed,” “Science Direct” and “Cochrane library” were searched for cellular, animal or human studies with the keywords “curcumin or curcuminoids” and “hepatoprotective or hepatotoxicity or liver” in title/abstract, along with “oxidative or oxidant” in the whole text. References of the final articles were also reviewed for more relevant articles. Data were collected from the inception date until 2018 (up to January). Only English language papers were included. Results from primary systematic search were screened by two independent investigators. All published articles as well as abstracts presented at meetings were evaluated. From a total of 1436 results, 707 were excluded because of duplication, 219 for being reviews and 392 being irrelevant judged on the title and/or abstract. From the 112 primarily selected papers, 47 were excluded based on the full texts. Finally, 65 articles were included in this review. <xref ref-type="fig" rid="nutrients-10-00855-f001">Figure 1</xref> illustrates a flow diagram of study selection process.</p></sec><sec id="sec6-nutrients-10-00855"><title>6. Cellular and Molecular Mechanisms of Curcumin in the Prevention of Oxidative Associated Liver Disease</title><sec id="sec6dot1-nutrients-10-00855"><title>6.1. Curcumin and Non-Alcoholic Steatohepatitis (NASH)</title><p>The relationship between steatosis and fibrosis, hepatic cell injury and lobular inflammation is recognized as NASH. On this context, curcumin (200 mg/kg/day for 3 weeks) likewise exerted a protective effect on CCl<sub>4</sub>-induced NASH. During the respective histopathological inspection, depletions of lipid accumulation and MDA deposition were observed in male Wistar-Albino rats [<xref rid="B58-nutrients-10-00855" ref-type="bibr">58</xref>]. Curcumin also restricted successfully the fibrosis (both development and progression) in mice with methionine+choline-deficiency (MCD)-induced steatohepatitis [<xref rid="B59-nutrients-10-00855" ref-type="bibr">59</xref>]. Reductions of tissue inhibitor metalloproteinase-1 (TIMP-1) secretion and inhibition of 8-OH-deoxyguanosine-mediated hepatic oxidative stress in cultured stellate cells from mice were recorded [<xref rid="B59-nutrients-10-00855" ref-type="bibr">59</xref>]. In this regard, the hepatic inflammation and steatosis was then decreased along with the diminished levels of serum biochemical markers and cytokines and enlarged levels of liver antioxidants [<xref rid="B60-nutrients-10-00855" ref-type="bibr">60</xref>]. Furthermore, the nuclear factor erythroid 2 related factor 2 (Nrf2) protein expression was significantly higher in curcumin-treated rats, so authors concluded this NASH prevention/amelioration can be related with Nrf2 activation [<xref rid="B60-nutrients-10-00855" ref-type="bibr">60</xref>] as described for heavy metals-induced hepatotoxicity. A study was designed to investigate the underlying mechanisms of curcumin-treating protection on NASH progression using an innovative NASH-hepatocellular carcinoma (HCC) mouse model [<xref rid="B61-nutrients-10-00855" ref-type="bibr">61</xref>]. As result of this model, curcumin reduced the steatosis and fibrosis conditions and, as previously mentioned in several studies, caused a prominent decrease of biomarkers in NASH mice. However, the most important finding of this study was that curcumin can modulate/inhibit the high-mobility group box 1 (HMGB1)-NF-κB translocation to prevent the NASH progression and liver injury [<xref rid="B61-nutrients-10-00855" ref-type="bibr">61</xref>].</p></sec><sec id="sec6dot2-nutrients-10-00855"><title>6.2. Curcumin and Alcoholic Liver Disease (ALD)</title><p>Morphological changes and clinical disorders in liver can be produced by the metabolism-related toxic effects of ethanol, since its oxidation affords apoptosis and cell injury-initiating products (e.g., acetaldehyde and ROS). These products can lead to fatty liver, hepatic inflammation, alcoholic hepatitis (necrosis) and progressive alcoholic cirrhosis (fibrosis). Aforementioned facts comprise the well-known alcoholic liver disease (ALD) [<xref rid="B62-nutrients-10-00855" ref-type="bibr">62</xref>]. Curcumin has been studied in several investigations for attenuating ALD effects and describing the respective mechanisms. Thus, inflammation and liver pathology can be improved in curcumin-administered (400 or 1200 mg/kg/day orally for 4 weeks) female Sprague-Dawley rats. Decreasing of hepatic MDA levels and inhibition of NF-κB activation were also observed for both doses but lower ones could avoid hepatocyte apoptosis [<xref rid="B63-nutrients-10-00855" ref-type="bibr">63</xref>]. Curcumin additionally modulated the antioxidant capacity, alcohol metabolic enzyme activity (i.e., CYP2E1 inhibition) and lipid metabolism (i.e., increasing activated protein kinase (AMPK) expression) after chronic alcohol intake-induced liver injury [<xref rid="B64-nutrients-10-00855" ref-type="bibr">64</xref>]. Curcumin was also related to hepatoprotection acting as a redox regulator and time/dose-dependent heme oxygenase-1 (HO-1) inducer against ethanol-induced oxidative injury in hepatocytes [<xref rid="B65-nutrients-10-00855" ref-type="bibr">65</xref>]. In balb/c mice, curcumin has been also suggested to defend liver from chronic-ethanol-induced damage. It also mitigated hepatohistopathological changes and lipid accumulation and amended levels of common biomarkers [<xref rid="B66-nutrients-10-00855" ref-type="bibr">66</xref>]. The attenuation of liver oxidative stress by curcumin has been described via induction/modulation of antioxidant signaling pathways such as Nrf2 activation and up-regulation of detoxifying genes expression (e.g., NQO1, HO-1 and GCLC) via ERK/p38-MAPK pathways [<xref rid="B67-nutrients-10-00855" ref-type="bibr">67</xref>]. Moreover, curcumin treatment (150 mg/kg/day for 8 weeks) exhibited health benefits in female Wistar-Furth rats through lipid metabolism modulation. Curcumin treatment alleviated the hepatosteatosis and suppressed the atherogenesis in ALD, even enhancing the antiatherogenic markers, that is, PON1/HTLase and GSH [<xref rid="B68-nutrients-10-00855" ref-type="bibr">68</xref>].</p><p>However, despite the potential of curcumin as an anti-inflammatory and antifibrotic agent against liver damage, some concentration-dependent negative effects were reported in male C57BL/6 mice. Based on those findings, curcumin seems to have dual impacts on alcoholic liver injury. The recognized hepatoprotective effect of curcumin was achieved at 0.1 mM, whereas an acceleration of liver injury and cellular edema was observed using 1 mM dose [<xref rid="B69-nutrients-10-00855" ref-type="bibr">69</xref>]. These facts can therefore be considered as a caution on using high doses of traditional medicines. In this sense, literature has a plethora of positive effects for more affordable therapeutics but negative ones are infrequently reported.</p></sec><sec id="sec6dot3-nutrients-10-00855"><title>6.3. Curcumin for the Prevention of the Oxidative Stress in Liver</title><p>The imbalance between the generation and degradation of ROS can cause oxidative stress and eventually the generation of free radicals and cellular damage. However, as will be explained later, it has been reported that curcumin can be used for the prevention of oxidative stress in the liver. Some of the important mechanisms of curcumin in the prevention of oxidative associated liver disease are shown in <xref ref-type="fig" rid="nutrients-10-00855-f002">Figure 2</xref>. Hydrogen peroxide was used by AL-Rubaei and colleagues as an agent that can damage liver cells. Their result showed that curcumin prevented liver toxicity and lower levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) enzymes could be measured [<xref rid="B70-nutrients-10-00855" ref-type="bibr">70</xref>]. The effect of the pre- and post-treatment of curcumin were examined in rats contacted with methotrexate (MTX) induced oxidative stress. The results showed that the amelioration of antioxidant enzymes, including glutathione <italic>S</italic>-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx), SOD and CAT, also the inhibition of ROS production can prevent oxidative stress in pre-treatment. Curcumin post-treatment can control the balance between oxidant and antioxidant [<xref rid="B71-nutrients-10-00855" ref-type="bibr">71</xref>]. In another work, the ability of curcumin was shown to treat hepatotoxicity caused by methotrexate [<xref rid="B72-nutrients-10-00855" ref-type="bibr">72</xref>]. AL-Harbi et al. found that administration of curcumin (60 mg/kg) have hepatoprotective effects on sodium fluoride induced oxidative stress. It can reduce hepatotoxicity and liver enzyme activities [<xref rid="B73-nutrients-10-00855" ref-type="bibr">73</xref>]. The effect of curcumin against oxidative stress induced by malathion (MAL), an organophosphorus insecticide (OPI), has been reported to reduce the MDA and nitric oxide (NO) levels and increased the GSH levels [<xref rid="B74-nutrients-10-00855" ref-type="bibr">74</xref>]. Excessive accumulation of iron overload (IOL) in the liver leads to oxidative stress as a result of cellular injury. The result of a study performed by Ali Hussein and colleagues indicated that treatment of rats with oxidative damage induced by IOL, significantly increased serum unsaturated iron binding capacity (UIBC), total protein, albumin, GSH, SOD and CAT activity accompanied by a reduction in serum iron, total iron-binding capacity (TIBC), transferrin (TF), ALT and AST activities, NO and MDA levels [<xref rid="B75-nutrients-10-00855" ref-type="bibr">75</xref>]. Similarly, in another study, the hepatoprotective effect of curcumin against oxidative stress created by IOL was confirmed [<xref rid="B76-nutrients-10-00855" ref-type="bibr">76</xref>]. Ciftci et al. in a rat model of oxidative stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental pollutant, noticed that the administration of 100 mg/kg/day curcumin reduced liver level of thiobarbituric acid reactive substances (TBARS). TCDD also increased liver levels of GSH, CuZn-SOD and GSH-Px [<xref rid="B77-nutrients-10-00855" ref-type="bibr">77</xref>]. Coneac et al. found that curcumin is able to reduce oxidative stress in acute experimental inflammation produced by Turpentine oil [<xref rid="B78-nutrients-10-00855" ref-type="bibr">78</xref>]. Dai et al. has confirmed that curcumin could ameliorate reduced L02 cell viability, prevent oxidative stress and inhibit the rises of SOD activity and GSH level. It could also be used as a prospective medical factor for quinocetone (QCT)-induced oxidative stress in human hepatocyte L02 cells [<xref rid="B79-nutrients-10-00855" ref-type="bibr">79</xref>]. In another in vitro study, the ability of curcumin to suppress oxidative stress in rat hepatic stellate cells (HSCs)-T6 was tested. Secretion of extracellular matrix (ECM) molecules and the levels of ROS and MDA were found to be decreased, whereas nuclear expression levels of Nrf2 and the levels of GSH were increased. Additionally, the expression of smooth muscle α-actin (α-SMA) was suppressed [<xref rid="B80-nutrients-10-00855" ref-type="bibr">80</xref>]. It has been demonstrated that curcumin possesses the ability to attenuate lipid peroxidation and increase GSH level in rats exposed to cadmium, an industrial pollutant [<xref rid="B81-nutrients-10-00855" ref-type="bibr">81</xref>]. An increase of GSH level and SOD, GPx, GR and CAT activities and decrease of MDA level were also observed with curcumin in an immobilization-induced stress rat model, which changes the activities of antioxidant enzymes [<xref rid="B82-nutrients-10-00855" ref-type="bibr">82</xref>]. In carbon tetrachloride (CCl<sub>4</sub>)-induced liver injury and fibrogenesis model, it was demonstrated that curcumin could be effective in protecting the liver by reducing oxidative stress. Activity of NF-κB, production of proinflammatory cytokines, structure of liver tissue and activation of HSC were then inhibited [<xref rid="B83-nutrients-10-00855" ref-type="bibr">83</xref>,<xref rid="B84-nutrients-10-00855" ref-type="bibr">84</xref>]. Singh et al. indicated that curcumin can be a potent protective agent against lindane as a pesticide that induces hepatotoxicity in rats. The presence of curcumin (pre- and post-treatment) with lindane significantly normalized the increased lipid peroxidation and decreased CAT, GPx, GR and SOD activities [<xref rid="B85-nutrients-10-00855" ref-type="bibr">85</xref>]. The possible protective role of curcumin was evaluated on cypermethrin-induced oxidative damage. A significant decrease in lipid peroxidation and the blood biochemical markers and decrease in CAT, GPx and GSH levels was observed in the liver of rats exposed to cypermethrin [<xref rid="B86-nutrients-10-00855" ref-type="bibr">86</xref>]. Watanab et al. determined the possibilities of curcumin in preventing or minimizing the oxidative stress induced by administration of trichloroethylene (TCE) in mouse liver. The activities of antioxidative enzymes were thus measured after curcumin protection [<xref rid="B87-nutrients-10-00855" ref-type="bibr">87</xref>].</p></sec><sec id="sec6dot4-nutrients-10-00855"><title>6.4. Curcumin and Liver Injury</title><p>Curcumin and related phenolics have been associated with the inhibition of lipid peroxidation, free radical formation and DNA damage under the role of radical scavengers and/or antioxidants. However, additional examination has been suggested to be explored in order to elucidate the mechanisms for the beneficial properties of curcumin on several oxidative stress-associated diseases such as liver injury. Thus, protective effects of curcumin on liver injury induced by different factors have been described by several studies using murine models. Association with the HO-1, an important mediator of cytoprotective events, might be considered as a plausible explanation about the way curcumin can act. Hepatoprotection of curcumin (single dose at 100 mg/kg intra peritoneal) against lipopolysaccharide-induced hepatitis in <sc>d</sc>-galactosamine-sensitized rats was clearly connected with the HO-1 up-regulation and the consequently bilirubin production. This protective effect accordingly impacted on nitric oxide synthase 2 (NOS-2) down-regulation and reduced the amounts of NO and lipid peroxidation products in liver [<xref rid="B88-nutrients-10-00855" ref-type="bibr">88</xref>].</p><p>Relatedly, prophylactic administration of curcumin to mice (300 mg/kg/day orally for 7 days) resulted in a reasonable chemopreventive capacity for protection of microcystins-induced liver injury [<xref rid="B89-nutrients-10-00855" ref-type="bibr">89</xref>]. The statistically significant reduction of ALT, lactate dehydrogenase (LDH) and GST levels in comparison to that of a microcystins-treated group were additionally observed. Positive MDA and negative SOD variations were also detected, so the authors concluded that curcumin can improve the hepatic antioxidative abilities in mice [<xref rid="B89-nutrients-10-00855" ref-type="bibr">89</xref>]. Comparable kind of reduction in oxidative stress and DNA damage was furthermore observed in Wistar albino rats (50 mg/kg/day orally for 14 days), since the biomarkers levels after biliary blocking were diminished in curcumin-treated rats. This result was a clear indication that curcumin assisted the recovery of liver function parameters, specifically on protecting the cholestasis-caused damages. In addition, curcumin generated a further reduction of ductal proliferation and portal inflammation in comparison with the induced group after histopathological evaluation. These facts indicated correspondingly a valuable decreasing of the inflammatory process. Similarly, after biliary duct ligation (BDL)-induced liver injury, curcumin promoted the statistically significant reduction of MDA, glutathione, NO and tumor necrosis factor-α (TNF-α) levels and enhancing the catalase, SOD and GST activities in liver [<xref rid="B90-nutrients-10-00855" ref-type="bibr">90</xref>]. Another study in liver tissue of Wistar rats also evidenced that curcumin can exert protection on BDL-induced hepatic damage through antioxidant action [<xref rid="B91-nutrients-10-00855" ref-type="bibr">91</xref>]. The down-regulation of Rho-related C3 botulinum toxin substrate (Rac1), NADPH oxidase-1 (NOX1) and Rac1-guanosine triphosphate (Rac1-GTP) and enhanced levels of hepatic enzymes (i.e., ALP, AST, ALT) and antioxidants (i.e., thiols, SOD and catalase) were also identified [<xref rid="B91-nutrients-10-00855" ref-type="bibr">91</xref>]. Additionally, hepatoprotective effect against ischemia/reperfusion (I/R)-promoted liver injury was found upon curcumin pretreatment (100 mg/kg IP 30 min prior to I/R) in Female Wistar Albino rat. Thus, the reduction of some liver injury indexes in blood (i.e., NO, TNF-α, methyl guabidine (MG), glutamic oxaloacetic transaminase (GOT), glutamate pyruvate transaminase (GPT) and LDH) were also described as an indication of the potential of curcumin against inflammatory responses and oxidative/nitrosative stress during reperfusion liver injury [<xref rid="B92-nutrients-10-00855" ref-type="bibr">92</xref>].</p><p>Discrepancy between ineffective antioxidant defense and enlarged free radical production in liver has been evidently linked with drugs exposure-related oxidative stress [<xref rid="B93-nutrients-10-00855" ref-type="bibr">93</xref>]. In this sense, curcumin (three doses at 200 mg/kg during 36 h) also triggered attenuated levels of biochemical parameters in liver damage induced by acetaminophen overdose toxicity (at 750 mg/kg orally) in albino western rats. Particularly, down-regulation of pro-apoptotic Bax and macrosialin cluster of differentiation 68 (CD68) protein expressions were observed through immunohistochemical evaluations [<xref rid="B94-nutrients-10-00855" ref-type="bibr">94</xref>]. The hepatoprotective results were increased whether curcumin was combined with thymoquinone, comprising fewer side effects in comparison to <italic>N</italic>-acetylcysteine (i.e., the best antidote for acetaminophen hepatotoxicity). Similar results were found on gentamicin-induced liver injury in male albino rats, since curcumin administration (20 mg/kg/every other day, oral for 21 days) exhibited a statistically significant reduction of levels of biochemical parameters, TNF-α and bilirubin. Liver histological alterations and apoptotic executioner caspase-3, the proapopototic Bax and antiapoptotic B-cell lymphoma-2 (Bcl-2) protein expressions were successfully amended in curcumin-treated animals [<xref rid="B95-nutrients-10-00855" ref-type="bibr">95</xref>].</p><p>Several reports have also recognized the protective capacity of curcumin on liver injury produced by some xenobiotics. Curcumin (100 or 200 mg/kg/day intra peritoneal) has been previously described to exhibit a significant hepatoprotective activity against liver damages induced by aflatoxin B1 [<xref rid="B96-nutrients-10-00855" ref-type="bibr">96</xref>], lambda cyhalothrin [<xref rid="B97-nutrients-10-00855" ref-type="bibr">97</xref>], CCl<sub>4</sub> [<xref rid="B98-nutrients-10-00855" ref-type="bibr">98</xref>,<xref rid="B99-nutrients-10-00855" ref-type="bibr">99</xref>], mercury [<xref rid="B100-nutrients-10-00855" ref-type="bibr">100</xref>] and other heavy metals [<xref rid="B101-nutrients-10-00855" ref-type="bibr">101</xref>] in adult rats. Levels of lipid peroxidation, serum biomarker enzymes, liver MDA, hydroxyproline and liver antioxidants (i.e., GSH, SOD, catalase) were correspondingly modified after curcumin treatment. DNA fragmentation preventing and mitochondrial functionalities preserving were also explained according to those findings.</p><p>Regarding protective ability of curcumin against heavy-metals (such as copper, cadmium, chromium, mercury, lead and arsenic), its free radical scavenging/reducing power/chelating capacities can restrain the heavy-metals-promoted hepatotoxicity by liver oxidative stress-related antagonism. These abilities were connected with the induction of the Nrf2/antioxidant response elements/Kelch-like ECH associated protein 1 (Nrf2/ARE/Keap1) pathway [<xref rid="B100-nutrients-10-00855" ref-type="bibr">100</xref>,<xref rid="B101-nutrients-10-00855" ref-type="bibr">101</xref>]. On the other hand, curcumin also exhibited a dose-dependent protection in CCl<sub>4</sub>-induced liver damage of Jian carp (<italic>Cyprinus carpio</italic> var. Jian). The up-regulation of the common antioxidative activities (SOD and GSH) and inhibition of cytokine production (e.g., Interleukin-1β (IL-1β), TNF-α, Interleukin 12 (IL-12)) were then observed and consequently correlated to the exhibited protective effect [<xref rid="B102-nutrients-10-00855" ref-type="bibr">102</xref>].</p><p>Despite the enormous, evidenced potential of curcumin to impede liver injury, the investigations are still quite scarce. The related studies are limited to evaluate the blood and liver levels of some biomarkers and examine liver histopathological/immunohistochemical results. Further studies on molecular, cellular and physiological mechanisms during curcumin hepatoprotection are accordingly needed prior a claim as a potential therapeutic agent against several oxidative stress-associated liver injuries.</p></sec><sec id="sec6dot5-nutrients-10-00855"><title>6.5. Curcumin and Hepatotoxicity</title><p>In terms of drug toxicity, the liver is often the targeted organ. More than 1000 drugs can cause toxicity in the liver and subsequently induce oxidative stress, steatosis and cell death. Most of anti-cancer, anti-analgesic and anti-inflammation drugs and antidepressants can be hepatotoxic. The production of ROS and RNS as the primary events, mitochondrial dysfunction and lipid dysmetabolism as the principal mechanisms of drug toxicity can be mentioned [<xref rid="B103-nutrients-10-00855" ref-type="bibr">103</xref>,<xref rid="B104-nutrients-10-00855" ref-type="bibr">104</xref>]. The main problem with these medications is the usage of high doses, which usually lead to hepatotoxicity in humans and experimental animals. Paracetamol (acetaminophen), commonly used as an antipyretic, is one of the most widespread drug-induced liver damage [<xref rid="B105-nutrients-10-00855" ref-type="bibr">105</xref>]. Manal et al. showed that curcumin supplementation at doses of 50 and 100 mg/kg/day to experimental rabbits with paracetamol-induced hepatotoxicity lowers the elevated aspartate transaminase, alkaline phosphatase and alanine transaminase levels and raises the total protein and albumin levels in plasma. In addition to these changes, curcumin increased the levels of red blood cells and platelets [<xref rid="B105-nutrients-10-00855" ref-type="bibr">105</xref>]. In another study, the efficacy of curcumin to manipulate the protein content, Succinate dehydrogenase (SDH), TBARS, Adenosine triphosphatase activity (ATPase), alkaline phosphatase activity (ALKase), acid phosphatase activity (ACPase), SOD and body weight of chloroquine phosphate (CQ)-induced hepatotoxicity was observed in a rat model [<xref rid="B106-nutrients-10-00855" ref-type="bibr">106</xref>]. Propanil (3,4-dichloropropioanilide), used to control weeds in wheat and rice products, is one of the most high-risking herbicide for humans. In a rat model of propanil-induced hepatotoxicity, curcumin improved the effects of propanil intoxication by decreasing lipid peroxidation levels and restored the levels of serum enzymes and reduced glutathione [<xref rid="B107-nutrients-10-00855" ref-type="bibr">107</xref>]. Although the liver has a high metabolic capacity, it is susceptible from a number of toxins such as thioacetamide (TAA) that causes the rise of ROS levels and the activation of HSCs [<xref rid="B104-nutrients-10-00855" ref-type="bibr">104</xref>]. Fazal et al. contributed to a study showing the protective effects of curcumin on liver toxicity in a rat TAA model by suppressing oxidative stress and angiotensin-converting enzyme (ACE) gene expression, protecting the liver tissue and anti-oxidant enzymes and restoring hepatocytes [<xref rid="B108-nutrients-10-00855" ref-type="bibr">108</xref>]. Additionally, Shapiro et al. confirmed the hepatoprotective effect of curcumin by reporting decreased levels of TBARS, minimized oxidative stress and inhibited inducible nitric oxide (iNOS) protein and NF-κB in acute thioacetamide hepatotoxicity rats supplemented with 200 and 400 mg/kg per day curcumin [<xref rid="B109-nutrients-10-00855" ref-type="bibr">109</xref>]. The increased production of reactive oxygen intermediates and lipid peroxidation, migration of activated PMNs into the liver, severe oxidative stress and eventually extensive damage to the liver are induced by lipopolysaccharides (LPS). Kaur et al. studied the effect of treatment of hepatotoxicity induced by LPS on enzymes and oxidative stress in rat liver. The results showed that the levels of ALT, AST and ALP as well as bilirubin in serum were significantly decreased, while the cytotoxic effects of NO, oxygen free radicals and cytokines were remarkably prevented [<xref rid="B110-nutrients-10-00855" ref-type="bibr">110</xref>]. Due to the accumulation of nanoparticles in different organs of experimental animals, including liver, spleen, brain and so forth, administration of NZnO (50 mg/kg/day) and treatment with curcumin (200 mg/kg/day) were measured in rats exposed to hepatotoxicity. The increased serum ALT, AST and ALP activity and MDA, decreased GPx and SOD levels suggests a link between NZnO and hepatic oxidative stress [<xref rid="B111-nutrients-10-00855" ref-type="bibr">111</xref>]. Although sodium fluoride is a substance that induces toxicity and oxidative stress, Moghaddam et al. showed that the protective effect of curcumin was related to its ability to adjust the imbalance of antioxidant enzymes and reduced lipid peroxidation levels in rat with fluoride-induced hepatotoxicity [<xref rid="B112-nutrients-10-00855" ref-type="bibr">112</xref>]. 60–70% of synthetic dyes are azo dyes that are soluble in processed food. It causes environmental contamination during food processing and can thus have harmful effects on human lymphocytes through direct interaction with genetic material such as DNA [<xref rid="B113-nutrients-10-00855" ref-type="bibr">113</xref>]. It has been reported that the azo dye tartrazine (Tz) can cause pathological changes in the liver and kidneys. EL-Desoky and colleagues administered doses of 1.0, 2.0, or 4.0 g of curcumin to a rat model of Tz-mediated hepatotoxicity and oxidative stress. They noticed that maximum improving effects on antioxidant enzyme activities were observed when 2.0 g of curcumin was used compared to those exposed to Tz alone [<xref rid="B101-nutrients-10-00855" ref-type="bibr">101</xref>]. Random or intentional intake of high doses of Cr compounds, such as potassium dichromate (K<sub>2</sub>Cr<sub>2</sub>O<sub>7</sub>), can lead to serious damage to the liver. This damage is generated by increasing lipid peroxidation and ROS levels and inhibiting structural tissue injury, antioxidant enzymes and mitochondrial damage [<xref rid="B114-nutrients-10-00855" ref-type="bibr">114</xref>,<xref rid="B115-nutrients-10-00855" ref-type="bibr">115</xref>]. García-Niño et al., in a model of liver oxidative stress induced by K<sub>2</sub>Cr<sub>2</sub>O<sub>7</sub>, remarked that 400 mg/kg curcumin could prevent the increased activities of plasma enzymes, while 15 mg/kg K<sub>2</sub>Cr<sub>2</sub>O<sub>7</sub> is unable to induce alterations in the oxidative stress markers [<xref rid="B115-nutrients-10-00855" ref-type="bibr">115</xref>]. Similarly, the protective effect of curcumin (400 mg/kg) was evaluated by García-Niño and colleagues on the hepatotoxicity provoked by K<sub>2</sub>Cr<sub>2</sub>O<sub>7</sub> (15 mg/kg) in rats. Prevention of histological damage, decrease in body weight gain, increase of liver weight, liver/body ratio and amelioration of the liver oxidative damage can be mentioned as their result [<xref rid="B114-nutrients-10-00855" ref-type="bibr">114</xref>].</p></sec><sec id="sec6dot6-nutrients-10-00855"><title>6.6. Curcumin and Liver Fibrosis and Cirrhosis</title><p>If the development of liver disease is not prevented, it can progress from simple steatosis to more severe disease forms, including hepatitis, fibrosis and cirrhosis [<xref rid="B103-nutrients-10-00855" ref-type="bibr">103</xref>]. Collagens are the most abundant protein in the extracellular matrix and HSCs are the main cells that produce collagen in the liver. Fibrosis is characterized by an excessive deposition of collagen between hepatocytes and sinusoids [<xref rid="B104-nutrients-10-00855" ref-type="bibr">104</xref>,<xref rid="B116-nutrients-10-00855" ref-type="bibr">116</xref>]. Chronic tissue injury, ROS, inflammatory cytokines and apoptotic signals activate the HSC [<xref rid="B104-nutrients-10-00855" ref-type="bibr">104</xref>,<xref rid="B116-nutrients-10-00855" ref-type="bibr">116</xref>]. Transforming growth factor beta (TGF-β) also has a critical role in initiating and the development of the HSC phenotypic activity [<xref rid="B117-nutrients-10-00855" ref-type="bibr">117</xref>]. In addition, oxidative stress increasingly activates HSCs [<xref rid="B118-nutrients-10-00855" ref-type="bibr">118</xref>]. If the imbalance between synthesis and destruction of collagen by membrane-bound metalloproteinase continues, the fibrosis advances to become cirrhosis. Cirrhosis is the end-stage of progressive fibrosis and is characterized by the degradation of the hepatic lobules structures and blood flow failure [<xref rid="B104-nutrients-10-00855" ref-type="bibr">104</xref>,<xref rid="B117-nutrients-10-00855" ref-type="bibr">117</xref>]. CCl<sub>4</sub> is one of the causative of liver damage, developing fibrosis and further cirrhosis. CCl<sub>4</sub> initiates cell damage by producing free radicals and increasing collagen synthesis through lipid peroxidation mechanism. Hence, the efficacy of curcumin has been examined in hepatic fibrosis induced by CCl<sub>4</sub> in rats. It was concluded that treatment with curcumin significantly reduced serum and tissue cholesterol profiles, GOT, GPT, ALP and TBARS [<xref rid="B119-nutrients-10-00855" ref-type="bibr">119</xref>]. Bruck et al. showed that curcumin inhibited the thioacetamide-induced cirrhosis in rats. They also found a decreasing of oxidative stress, hydroxyproline levels, liver histopathology and spleen weights (<italic>p</italic> < 0.001) [<xref rid="B117-nutrients-10-00855" ref-type="bibr">117</xref>]. Chenari et al. established that treatment with curcumin in the BDL fibrotic rat model significantly reduced low-density lipoprotein (LDL), total cholesterol (TC) and triglyceride (TG) levels, AMPK, carnitine palmitoyltransferase 1A (CPT-1A), isocitrate dehydrogenase 2 (IDH2) and manganese-dependent superoxide dismutase (MnSOD) gene expressions. In addition, it was observed that the level of HDL and protein/gene expression of the silent mating type information regulation type 2, homolog3 (SIRT3) in response to oxidative stress, by reducing ROS level, significantly increased [<xref rid="B118-nutrients-10-00855" ref-type="bibr">118</xref>]. Curcumin can also be effective in the treatment of chronic hepatic diseases and reducing levels of ALT, γ-GTP, TGF-β expression can be measured in a rat model of BDL-induced liver cirrhosis. 100 mg/kg of curcumin was also capable of decreasing oxidative stress by alterations of glutathione levels [<xref rid="B117-nutrients-10-00855" ref-type="bibr">117</xref>]. In another study, the effectiveness of curcumin in the treatment of BDL was shown by reducing liver damage and oxidative stress [<xref rid="B120-nutrients-10-00855" ref-type="bibr">120</xref>]. There is a work performed on a mouse model of LPS-induced acute liver injury by Zhong and colleagues who studied the hepatoprotective role of curcumin. This effect was then demonstrated through reduction of pro-inflammatory cytokines and oxidative stress, increase of liver antioxidant enzymes and decrease of liver apoptosis by inhibiting phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway [<xref rid="B121-nutrients-10-00855" ref-type="bibr">121</xref>]. Preclinical studies evaluating the effects of curcumin in the prevention/accelerating of oxidative associated liver diseases are listed in <xref rid="nutrients-10-00855-t001" ref-type="table">Table 1</xref>.</p></sec><sec id="sec6dot7-nutrients-10-00855"><title>6.7. Role of Epigenetic Pathway in Protective Effect of Curcumin against Oxidative Associated Liver Diseases</title><p>Epigenetics, reversible alterations in gene expression, regulates the chromatin structure modifications and the initiation of transcription by altering the gene transcription without changing the primary DNA sequence [<xref rid="B122-nutrients-10-00855" ref-type="bibr">122</xref>]. There is a link between oxidative stress, epigenetics and NAFLD through the mitochondria. Epigenetic mechanisms have a crucial role in the pathophysiology of NAFLD and epigenetic causes of oxidative stress contribute to NAFLD [<xref rid="B123-nutrients-10-00855" ref-type="bibr">123</xref>]. The most studied epigenetic mechanisms are: (a) DNA methylation; (b) histone modifications; and (c) microRNAs (miRs) [<xref rid="B122-nutrients-10-00855" ref-type="bibr">122</xref>].</p><p>DNA methylation, the first discovery of epigenetic regulation of gene expression, is a biochemical modification (methylation) of cytosine-phosphoguanine (CpG) dinucleotides in promoter regions that is regulated by DNA methyltransferases (DNMTs) [<xref rid="B124-nutrients-10-00855" ref-type="bibr">124</xref>,<xref rid="B125-nutrients-10-00855" ref-type="bibr">125</xref>]. Increasing the level of Methyl-CpG binding protein 2 (MECP2) activates HSCs and promotes fibrosis by repressing peroxisome proliferator-activated receptor γ (PPARγ) [<xref rid="B124-nutrients-10-00855" ref-type="bibr">124</xref>]. Also, epigenetic variations in mitochondrial DNA methylation can cause abnormal gene expression in NAFLD [<xref rid="B125-nutrients-10-00855" ref-type="bibr">125</xref>]. Among post-translational modifications of histones, acetylation that is usually associated with the activation of gene transcription affects the gene expression in NAFLD [<xref rid="B122-nutrients-10-00855" ref-type="bibr">122</xref>,<xref rid="B125-nutrients-10-00855" ref-type="bibr">125</xref>]. MiRs, small noncoding RNAs, regulate post-transcriptional gene expression through degradation or repression of mRNAs. Activation and inactivation of HSCs can be controlled by miRs [<xref rid="B124-nutrients-10-00855" ref-type="bibr">124</xref>]. In addition, several targets for treatment of NAFLD have been proposed by this mechanism [<xref rid="B125-nutrients-10-00855" ref-type="bibr">125</xref>]. Hence, among epigenetic machineries, miRs are the most widely investigated in NAFLD [<xref rid="B122-nutrients-10-00855" ref-type="bibr">122</xref>].</p><p>It has been demonstrated that curcumin can reduce the occurrence and/or delay the development of HCC by epigenetic mechanisms such as DNA demethylation and histone deacetylases (HDAC)-inhibitory effect [<xref rid="B126-nutrients-10-00855" ref-type="bibr">126</xref>]. Furthermore, Curcumin can modulate miRs in liver diseases [<xref rid="B127-nutrients-10-00855" ref-type="bibr">127</xref>]. A novel mechanism suppressing liver fibrosis by Zheng et al., resulted in the inhibition of cell proliferation and up-regulation of the Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression through microRNA-mediated control of DNA methylation after curcumin treatment [<xref rid="B128-nutrients-10-00855" ref-type="bibr">128</xref>]. Liu et al. showed that the administration of curcumin modulated the growth of human breast cancer cell line MDA-MB-361 and induced the Deleted in Liver Cancer 1 (DLC1) expression. In this study CpG demethylation of many tumor suppressor genes was conducted and inhibition of DNA methyltransferase 1 expression by decreasing the expression of transcription factor Sp1 was observed [<xref rid="B129-nutrients-10-00855" ref-type="bibr">129</xref>]. In another study, Yuan et.al. investigated the effect of the DNA methylation inhibitor 5-Aza-CdR and curcumin on DNA methylation of the PPAR-α gene in NAFLD pathogenesis. They found that gene expression was regulated through epigenetic modifications, DNA methylation levels were reversed and lipid accumulation was improved [<xref rid="B130-nutrients-10-00855" ref-type="bibr">130</xref>].</p></sec></sec><sec id="sec7-nutrients-10-00855"><title>7. Nanoformulations of Curcumin in Oxidative Associated Liver Diseases</title><p>The first report on the bioavailability of curcumin was in 1978 [<xref rid="B131-nutrients-10-00855" ref-type="bibr">131</xref>]. The study showed that traces of curcumin could be identified in the plasma of rats receiving 50 mg/kg intravenously. This fact indicated the poor absorption of curcumin. Another study showed that low levels of curcumin could be detected in the plasma after oral administration of high dose, representing the low absorption from the intestine [<xref rid="B132-nutrients-10-00855" ref-type="bibr">132</xref>]. More experiments have been performed in order to understand the reason behind the poor bioavailability and distribution of curcumin in liver, spleen and kidney or heart [<xref rid="B131-nutrients-10-00855" ref-type="bibr">131</xref>,<xref rid="B132-nutrients-10-00855" ref-type="bibr">132</xref>,<xref rid="B133-nutrients-10-00855" ref-type="bibr">133</xref>,<xref rid="B134-nutrients-10-00855" ref-type="bibr">134</xref>].</p><p>These circumstances opened another area of research with the aim of improving the bioavailability either by encapsulation of curcumin in phosphatidyl-choline (Meriva<sup>®</sup>) [<xref rid="B134-nutrients-10-00855" ref-type="bibr">134</xref>] or by nanoformulation to increase drug delivery. Phosphatidyl-choline coating increased the detectable level of curcumin and its metabolites in the plasma and the liver [<xref rid="B134-nutrients-10-00855" ref-type="bibr">134</xref>]. Zein, a corn protein, recently was used to improve the bioavailability of curcumin and liver targeting [<xref rid="B135-nutrients-10-00855" ref-type="bibr">135</xref>]. Zein has been used in many pharmaceutical products due to its low side effects, slow release of the drug and targeting the liver [<xref rid="B136-nutrients-10-00855" ref-type="bibr">136</xref>,<xref rid="B137-nutrients-10-00855" ref-type="bibr">137</xref>]. Algandaby et al. formulated curcumin-zein nanospheres and investigated the efficiency of the product in treating liver fibrosis in CCl<sub>4</sub>-treated mouse model. The study confirmed the increase in liver targeting (3.24 fold) by determination of curcumin level in liver and plasma. Curcumin-zein (cur-zein) form decreased aminotransferases and ALP levels. Additionally, absence of fibrosis and ballooning degeneration and fat accumulation reduction in liver sections were also observed. Therefore, cur-zein improved the curcumin antifibrotic activity in comparison to curcumin alone.</p><p>A report by Ahmad et al. 2018 [<xref rid="B138-nutrients-10-00855" ref-type="bibr">138</xref>] described the formation of nanocomposite of curcumin with chitosan. This material increased the hepatoprotective activity of curcumin. Pretreatment of mice with curcumin-chitosan nanospheres elevated the antioxidant enzymes (SOD, GSH, GST and catalase) and protected the mouse from cadmium toxicity. For improving the bioavailability of curcumin, Singh et al. evaluated the efficacy of curcumin-solid lipid nanoparticles (C-SLNs) on CCl<sub>4</sub>-induced hepatic injury in rats compared to curcumin alone. Microemulsification method was used to prepare C-SLNs with size of 147.6 mm. Using of C-SLNs (12.5 mg/kg) was more effective and reduced oxidative stress, histopathological alterations as well as TNF-α, serum ALT and AST [<xref rid="B139-nutrients-10-00855" ref-type="bibr">139</xref>].</p></sec><sec id="sec8-nutrients-10-00855"><title>8. Clinical Studies Supporting the Efficacy of Curcumin in Oxidative Associated Liver Diseases</title><p>The animal studies confirmed the ability of curcumin in lowering lipogenesis, oxidative stress and increasing insulin sensitivity [<xref rid="B140-nutrients-10-00855" ref-type="bibr">140</xref>,<xref rid="B141-nutrients-10-00855" ref-type="bibr">141</xref>]. On the other hand, human clinical studies on the bioavailability and efficacy of curcumin have been mainly performed on patients with cancer or diabetes. The results showed that curcumin is characterized by low systemic bioavailability with rapid metabolism in liver and excretion [<xref rid="B142-nutrients-10-00855" ref-type="bibr">142</xref>].</p><p>Two recent articles that investigated the role of curcumin in prevention and treatment of NAFLD, are listed in <xref rid="nutrients-10-00855-t002" ref-type="table">Table 2</xref> [<xref rid="B143-nutrients-10-00855" ref-type="bibr">143</xref>,<xref rid="B144-nutrients-10-00855" ref-type="bibr">144</xref>]. Panahi et al. performed a randomized controlled study with 87 individuals, 44 patients (20 females and 24 males) were diagnosed with NAFLD and categorized into grades from 1 to 3 according to the liver ultrasonography. Patients group received two doses of curcumin (1000 mg/day) in phytosomal capsules. After 8 weeks, liver aminotransferases and ultrasonography with anthropometric parameters were evaluated in patients and the placebo group. Panahi et al. showed the ability of curcumin phytosomal to reduce the body mass index (−0.99 ± 1.25) <italic>versus</italic> the placebo group (−0.15 ± 1.31). Curcumin-receiving group showed a remarkable decrease in liver enzymes AST, ALT, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate-pyruvate transaminase (SGPT) levels. Moreover, liver sonography was improved within patients treated with curcumin where the portal vein diameter decreased and vein flow was increased. Curcumin also decreased the NAFLD severity by decreasing the fat content in the liver. The aforementioned results by Panahi et al. confirmed the efficacy of curcumin supplementation for short period in treating NAFLD [<xref rid="B144-nutrients-10-00855" ref-type="bibr">144</xref>].</p><p>Another randomized double-blinded placebo study was carried out to investigate the ability of curcumin in treating NAFLD [<xref rid="B143-nutrients-10-00855" ref-type="bibr">143</xref>]. This study used a lower dose of curcumin (500 mg/day) in amorphous form and for the same short period (8 weeks). Total 80 subjects participated in the clinical study. Only 40 patients received curcumin daily. Rahmani et al. evaluated the anthropometric measurements, liver aminotransferases, low-density lipoprotein-cholesterol (LDL-C), triglyceride, glucose, cholesterol, high-density lipoprotein-cholesterol (HDL-C) and glycated hemoglobin (HbA1c). After 8 weeks of supplementation with curcumin, the waist circumference, Body mass index (BMI) and weight were significantly reduced. In addition, total cholesterol and LDL-C were decreased while HDL-C was elevated. The other biochemical parameters such as aminotransferases (ALT and AST) were reduced by the end of the trial. In order to confirm the ability and efficacy of curcumin in treating NAFLD, a histological sample of liver should be collected but this is an invasive procedure and holds a risk of morbidity. Liver sonography with biochemical parameters is an excellent alternative technique to show the improvement [<xref rid="B145-nutrients-10-00855" ref-type="bibr">145</xref>]. In this clinical trial, liver sonography showed that curcumin improved the NAFLD sonography grade to 78.9%, where grade 3 was not detected in the participants, grade 2 was detected in only 13.2% of patients and 15.8% were completely improved.</p><p>As discussed previously, curcumin has low bioavailability. However, several clinical trials as well as preclinical studies confirmed the protective and therapeutic effects of curcumin in different oxidative associated diseases including liver disorders. Different evidences have suggested that the therapeutic activities of this natural molecule, despite its undesirable pharmacokinetic properties, is mainly due to the main metabolites of curcumin, which may have a key role in the biological function [<xref rid="B146-nutrients-10-00855" ref-type="bibr">146</xref>,<xref rid="B147-nutrients-10-00855" ref-type="bibr">147</xref>].</p></sec><sec id="sec9-nutrients-10-00855"><title>9. Conclusions</title><p>Curcumin is able to protect and treat liver diseases and to alter different cellular pathways. For instance, curcumin induce the expression of heme oxygenase-1 [<xref rid="B148-nutrients-10-00855" ref-type="bibr">148</xref>] which cleaves heme and produces CO, biliverdien and bilirubin and other antioxidant molecules [<xref rid="B149-nutrients-10-00855" ref-type="bibr">149</xref>]. Regarding the reported effects on cellular responses, curcumin inhibits activation and proliferation of HSC, leading to a decrease in production of extracellular matrix collagen and protecting liver from fibrogenesis [<xref rid="B83-nutrients-10-00855" ref-type="bibr">83</xref>]. This effect on HSC was found to be through the down-regulation of PDGF-βR, EGFR and TGF-β coupled with the reduction of mRNA level of PPAR-γ [<xref rid="B150-nutrients-10-00855" ref-type="bibr">150</xref>,<xref rid="B151-nutrients-10-00855" ref-type="bibr">151</xref>]. Curcumin induced the synthesis of reduced glutathione [<xref rid="B152-nutrients-10-00855" ref-type="bibr">152</xref>] leading to a marked decrease in lipid peroxidation products such as lipid hydroperoxide and MDA [<xref rid="B83-nutrients-10-00855" ref-type="bibr">83</xref>,<xref rid="B84-nutrients-10-00855" ref-type="bibr">84</xref>]. The increase in GSH level is due to the ability of curcumin in elevating the gene expression of the rate-limiting enzyme in glutathione synthesis and glutamate cysteine ligase (GCL) [<xref rid="B83-nutrients-10-00855" ref-type="bibr">83</xref>]. Curcumin treatment leads to a marked decrease in the level of proinflammatory cytokines such as TNF-α, INF-γ, IL-1β and IL-6 [<xref rid="B84-nutrients-10-00855" ref-type="bibr">84</xref>,<xref rid="B153-nutrients-10-00855" ref-type="bibr">153</xref>]. The decrease in proinflammatory cytokines was due to the inhibition of NF-κB translocation to the nucleus and decreasing its DNA binding activity [<xref rid="B84-nutrients-10-00855" ref-type="bibr">84</xref>].</p><p>Curcumin increased the expression of SIRT3, a NAD<sup>+</sup>-dependent deacetylase and ADP-ribosyltransferase. SIRT3 activation by curcumin led to the decrease in lipid deposition through AMPK and the mitochondrial CPT-1A. Moreover, SIRT3 caused a decrease in ROS level by upregulating the expression of MnSOD and the mitochondrial IDH2 [<xref rid="B118-nutrients-10-00855" ref-type="bibr">118</xref>]. Another signaling cellular pathway attenuated in the liver by curcumin treatment is PI3K/Akt. Hence, curcumin inhibited and decreased the level of apoptotic markers such as Bad, Bcl-xL, cytochrome <italic>c</italic>, Apaf-1, cleaved caspase-9, -3 and -6. p38 mitogen-activated protein kinase/JUN was also downregulated and protected the liver cells from death [<xref rid="B121-nutrients-10-00855" ref-type="bibr">121</xref>]. Also, curcumin downregulated the expression of ACE [<xref rid="B108-nutrients-10-00855" ref-type="bibr">108</xref>].</p><p>A wide variety of preclinical studies support the effectiveness of dietary curcumin in the management of oxidative associated liver diseases. However, there are few RCTs assessing the efficacy of curcumin in liver disorders. <xref rid="nutrients-10-00855-t002" ref-type="table">Table 2</xref> exhibits the evidence of curcumin in the prevention and treatment of oxidative associated liver diseases in humans. Further well-designed RCTs are therefore required to confirm the dietary and adjunctive role of curcumin as promising protective or curative agent in the management of oxidative associated liver diseases.</p><p>To conclude, the results obtained from the present review revealed that curcumin can be effective in various types of oxidative associated liver disorders. This potentiality attributes to curcumin effects on hepatotoxicity, non-alcoholic steatohepatitis, alcoholic liver disease, liver fibrosis and cirrhosis as well as hepatic injury. Experimental evidences indicate that curcumin exhibits its preventive and curative effect against oxidative associated liver diseases through various cellular signaling pathways. Those pathways include ERK/p38/MAPK pathway, hepatic Nrf2/ARE/Keap1 signaling, up-regulation of detoxifying genes expression, TIMP signaling, AMPK pathway and lipid metabolism, as well as down-regulation of Rac1, NOX1 and Rac1-GTP transduction. Regarding the above mentioned biological activities of curcumin in either protecting or treating liver, it is highly recommended to consider curcumin as a safe and effective natural product for oxidative associated liver diseases. Among the studies that were conducted in various oxidative models associated liver disease, some investigated the protective effects of curcumin [<xref rid="B83-nutrients-10-00855" ref-type="bibr">83</xref>,<xref rid="B84-nutrients-10-00855" ref-type="bibr">84</xref>,<xref rid="B85-nutrients-10-00855" ref-type="bibr">85</xref>,<xref rid="B86-nutrients-10-00855" ref-type="bibr">86</xref>,<xref rid="B97-nutrients-10-00855" ref-type="bibr">97</xref>,<xref rid="B98-nutrients-10-00855" ref-type="bibr">98</xref>,<xref rid="B105-nutrients-10-00855" ref-type="bibr">105</xref>,<xref rid="B106-nutrients-10-00855" ref-type="bibr">106</xref>,<xref rid="B107-nutrients-10-00855" ref-type="bibr">107</xref>]. According to these articles, curcumin as a dietary supplement has a protective role against the onset of liver diseases. The intake of a significant content of curcumin in the daily regimen or as dietary supplementation along with restricted therapeutic options can provide perfect prevention and treatment for liver disorders. Present review revealed that further in vitro and preclinical studies are encouraged to recognize the exact bioavailability, bioefficacy and cellular transduction signaling pathways of curcumin in managing oxidative associated liver diseases.</p></sec></body><back><ack><title>Acknowledgments</title><p>This article is the outcome of an in-house financially non-supported study.</p></ack><notes><title>Author Contributions</title><p>M.H.F. and M.Z. designed the structure of the paper and drafted the manuscript. F.P., F.F.E.-S., I.M., E.C.-B. and R.N. performed the literature search and contributed in writing the manuscript. S.M.N., R.R. and M.A. reviewed and revised the manuscript. All authors have seen and approved the final version of the manuscript.</p></notes><notes><title>Funding</title><p>This research received no external funding.</p></notes><notes notes-type="COI-statement"><title>Conflicts of Interest</title><p>The authors declare no conflicts of interest.</p></notes><ref-list><title>References</title><ref id="B1-nutrients-10-00855"><label>1.</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Muriel</surname><given-names>P.</given-names></name></person-group><article-title>The Liver: General Aspects and Epidemiology</article-title><source>Liver Pathophysiology</source><publisher-name>Elsevier</publisher-name><publisher-loc>Amsterdam, The Netherlands</publisher-loc><year>2017</year><fpage>3</fpage><lpage>22</lpage></element-citation></ref><ref id="B2-nutrients-10-00855"><label>2.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cichoż-Lach</surname><given-names>H.</given-names></name><name><surname>Michalak</surname><given-names>A.</given-names></name></person-group><article-title>Oxidative Stress as a Crucial Factor in Liver Diseases</article-title><source>World J. 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Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), reactive oxygen species (ROS), sulfasalazine reduces superoxide dismutase (SOD), glutathione (GSH), glutathione reductase (GR), malondialdehyde (MDA), catalase (CAT), inducible nitric oxide (iNOS), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), extracellular signal-regulated kinases (ERK), mitogen-activated protein kinase (MAPK).</p></caption><graphic xlink:href="nutrients-10-00855-g002"></graphic></fig><table-wrap id="nutrients-10-00855-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">nutrients-10-00855-t001_Table 1</object-id><label>Table 1</label><caption><p>Preclinical studies evaluating the effects of curcumin in the prevention/accelerating of oxidative associated liver diseases.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Liver Disease Type</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Experimental Model Used (Animal, Strain, Genetic or Dietary Liver Injury)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Curcumin Source</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Dose and Formulation (Injection)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Duration of Treatment</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Reference</th></tr></thead><tbody><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Non-Alcoholic Steatohepatitis (NASH)</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ccl<sub>4</sub> 0.5 mL/kg/every other day/SC/3 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Albino Wistar rat</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma, St. Louis, MO, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 mg/kg/day in olive oil (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B58-nutrients-10-00855" ref-type="bibr">58</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Methionine and choline deficient diet (MCD diet)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male C57BL/6 mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma, St. Louis, MO, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">25 µg/every other day/in DMSO (IP)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4, 8 or 10 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B59-nutrients-10-00855" ref-type="bibr">59</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">High fat diet (HFD)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Adult Sprague-Dawley rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma, St. Louis, MO, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50 mg/kg/day/suspended in 0.5% CMC</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B60-nutrients-10-00855" ref-type="bibr">60</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 μg STZ/single dose/SC/2 days after birth<break></break>(HFD 32)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">C57BL/6 J mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma-Aldrich, Tokyo, Japan</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg/day in 1% gum Arabic (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">14 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B61-nutrients-10-00855" ref-type="bibr">61</xref>]</td></tr><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Alcoholic Liver Disease</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50% ethanol (7.5 g/kg/day/4 weeks/oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Female Sprague-Dawley rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cayman Chemical Company, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">400 or 600 mg/kg/twice a day/in 50% ethanol</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B63-nutrients-10-00855" ref-type="bibr">63</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">25% ethanol (5 g/kg/day/6 weeks/oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male ICR mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma, St. Louis, MO, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">19.7 or 47.5 mg/kg/day (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B64-nutrients-10-00855" ref-type="bibr">64</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mm ethanol for 8 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Primary rat hepatocytes from male Sprague–Dawley rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">diferuloylmethane; CAS No. 458-37-7, Sigma, St. Louis, MO, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5–50 M/dissolved in 0.5 N NaOH then diluted in PBS</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0–5 h before ethanol treatment</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B65-nutrients-10-00855" ref-type="bibr">65</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.4 g/kg/day ethanol for the initial 4 weeks and 4 g/kg/day for another 2 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Balb/c mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Diferuloylmethane; CAS No. 458-37-7), Sigma, St. Louis, MO, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">75 mg/kg/day/in DMSO (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6 weeks along with ethanol intake</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B66-nutrients-10-00855" ref-type="bibr">66</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.4 g/kg/day ethanol/daily/6 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Adult Male Balb/C mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Purity >98.0%, from the National Institute for Food and Drug Control (Beijing, China)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">75 or 150 mg/kg/in olive oil/(oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 h before ethanol administration for 6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B67-nutrients-10-00855" ref-type="bibr">67</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Low <italic>ω</italic>-3 poly unsaturated fatty acids (PUFA) diet + ethanol<break></break>High 𝜔 − 3 PUFA + ethanol</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Female Wistar-Furth rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">150 mg/kg/day</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B68-nutrients-10-00855" ref-type="bibr">68</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5% ethanol/IV, 5 times a week/100 µL/mouse/for 2 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male C57BL/6 mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma-Aldrich, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 mM or 1 mM/100 µL/mouse (IV) dissolved in 0.5 N NaOH then diluted in PBS</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5 times a week for 2 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B69-nutrients-10-00855" ref-type="bibr">69</xref>]</td></tr><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Oxidative Stress Inducers</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H<sub>2</sub>O<sub>2</sub> 0.5% (<italic>v</italic>/<italic>v</italic>)/day/for 60 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Crude curcumin was purchased from local wet market in Baghdad, Iraq</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 mg/kg/day</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1st model = 30 days after induction of oxidative stress<break></break>2nd model = 15 days then followed by receiving H<sub>2</sub>O<sub>2</sub> for 60 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B70-nutrients-10-00855" ref-type="bibr">70</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Methotrexate 20 mg/kg/I.P./single dose</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Rat</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg/day (I.P.)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B72-nutrients-10-00855" ref-type="bibr">72</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melathion (MAL) 200 mg/kg/oral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Female Sprague Dawley rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Curcuma longa</italic> Turmeric, Sigma, St. Louis, MO, USA (C1386)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 g/kg (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B76-nutrients-10-00855" ref-type="bibr">76</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Iron overload (Haemojet<sup>®</sup>) containing ferric hydroxide polymaltose<break></break>100 mg/Kg/I.P./3 doses per week/for 2 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male albino rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Purity~95%, Indian production, purchased from El-Goumhoria Co., Cairo-Egypt</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg/day/dissolved in DMSO</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3, 4 or 5 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B75-nutrients-10-00855" ref-type="bibr">75</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2,3,7,8-tetrachlorodibenzo-p-dioxin 2 mg/kg/week/oral diluted in corn oil</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Female Sprague Dawley rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Chemical Co., St. Louis, Missouri, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg/day/dissolved in corn oil</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">30 and 60 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B77-nutrients-10-00855" ref-type="bibr">77</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Turpentine oil 0.6 mL/kg/I.M.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Wistar Bratislava albino rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Purity >98%, Abcam (Cambridge, United Kingdom)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">150 mg/kg/dissolved in 0.5% CMC (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1st model = 60 min prior Turpentine injection<break></break>2nd model = 120 min after Turpentine injection</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B78-nutrients-10-00855" ref-type="bibr">78</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cdcl<sub>2</sub> 0.025 mmol/kg to rats and 0.03 mmol/kg to mice/S.C.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Adult male Wistar rats and male CD mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma–Aldrich, St. Louis, MO, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50 mg/kg/day/dispersed in 0.25% methylcellulose</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B81-nutrients-10-00855" ref-type="bibr">81</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immobilization-induced stress, rats kept in the restrainers for 1 h every day, for 21 consecutive days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Wistar albino rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma-Aldrich Chemical (St. Louis, USA)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10 or 20 or 30 mg/kg/day/IP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">21 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B82-nutrients-10-00855" ref-type="bibr">82</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ccl<sub>4</sub> 1 mL/kg (1:1) in olive oil/every other day for 8 weeks./I.P.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Sprague-Dawley rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 or 400 mg/kg/suspended in PBS</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B83-nutrients-10-00855" ref-type="bibr">83</xref>,<xref rid="B84-nutrients-10-00855" ref-type="bibr">84</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lindane<break></break>1st model = 60 mg/kg/for 24 h/oral<break></break>2nd model = 30 mg/kg/for 14 d</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Aldrich (St. Louis, MO, USA)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 or 200 mg/kg/day/dissolved in DMSO (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1st model = pretreatment for 14 days<break></break>2nd model = posttreatment for 14 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B85-nutrients-10-00855" ref-type="bibr">85</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cypermethrin 25 mg/kg/day/for 28 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Adult male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Chemicals, USA and SRL Chemicals, India.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">28 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B86-nutrients-10-00855" ref-type="bibr">86</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Trichloroethylene (TCE) 1.2 mmol/kg/diluted in corn oil/24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male ddY mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10, 50 or 100 µM/dissolved in DMSO (I.P.)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B87-nutrients-10-00855" ref-type="bibr">87</xref>]</td></tr><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>In Vitro Study</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Quinocetone (QCT)-</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Human hepatocyte L02 cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Purity 98%, Aladdin Reagent Co., Ltd. (Shanghai, China)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.5 or 5 mM/0.1% DMSO</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2 h pretreatment then incubated for 4 or 24 h with QCT</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B79-nutrients-10-00855" ref-type="bibr">79</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glucose oxidase (GO) 100 mu/mL/2 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Rat HSCs-6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma-Aldrich (St. Louis, MO, USA)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.15 µM</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3 h pretreatment then incubated with GO for 2 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B80-nutrients-10-00855" ref-type="bibr">80</xref>]</td></tr><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Liver Injury</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LPS (10 μg/kg/I.P.)/D-galactosamine (400 mg/kg/I.P.)/24 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma-Aldrich (Prague, Czech Republic)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg (I.P.)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pretreatment for 1 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B88-nutrients-10-00855" ref-type="bibr">88</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Microcystins 38.11 μg/kg/3 h/I.P.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Swiss mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">300 mg/kg (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">7 days pretreatment</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B89-nutrients-10-00855" ref-type="bibr">89</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Biliary duct ligation (BDL)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar albino rats (<italic>Rattus novegiccus</italic>)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">curcumin (97%, purity) from Sigma Chemicals</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50 mg/kg/day in corn oil (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">14 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B90-nutrients-10-00855" ref-type="bibr">90</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Curcumin (purity >80%) from Sigma Chemicals</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg/day in Carboxymethyl cellulose (CMC) (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">28 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B91-nutrients-10-00855" ref-type="bibr">91</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ischemia/reperfusion (I/R)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Female Wistar Albino rat</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Chemical Co., USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg (I.P.)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">30 min pretreatment before I/R</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B92-nutrients-10-00855" ref-type="bibr">92</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Acetaminophen (APAP) (750 mg/kg/single dose/oral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Albino Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Armal company</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 mg/kg in corn oil (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1st = 24 h before APA<break></break>2nd = 2 h after APAP<break></break>3rd = 12 h after APAP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B94-nutrients-10-00855" ref-type="bibr">94</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Gentamicin (100 mg/kg/I.P.)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male albino rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Chemical Co.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">20 mg/kg/every other day in 1% CMC (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">21 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B95-nutrients-10-00855" ref-type="bibr">95</xref>]</td></tr><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Xenobiotics</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Aflatoxin B1 (25 μg/kg)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Fischer rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Chemical Company</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 mg/kg</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">90 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B96-nutrients-10-00855" ref-type="bibr">96</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lambda cyhalothrin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male albino rats (<italic>Rattus norvegicus</italic>)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma-Aldrich Chemical Co</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 mg/kg/day suspended in PBS (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B97-nutrients-10-00855" ref-type="bibr">97</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hg (0.6, 1.2, or 2.4 mg/kg in saline/IP/daily/3 days)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male and female Adult Wistar rat</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Curcumin (98%) was provided by Sigma, Saint Louis, Missouri, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg/in DMSO (SC)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2 h pretreatment before Hg</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B100-nutrients-10-00855" ref-type="bibr">100</xref>]</td></tr><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>CCl<sub>4</sub></bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">(1:1 in olive oil) 1 mL/kg/every other day/IP/4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Sprague-Dawley rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Curcuma longa</italic> L. (CLL, turmeric)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 mg/kg/day in PBS (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B98-nutrients-10-00855" ref-type="bibr">98</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1st model = 0.2 mL/kg/24 h<break></break>2nd model = 1 mL/kg (1:1 in corn oil)/2 times per week, oral/4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Sprague-Dawley rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Curcuma longa</italic> L. (<italic>Zingiberaceae</italic>)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50, 100 or 200 mg kg/day in corn oil (oral) orally for 4 consecutive days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1st = 4 days before CCl<sub>4</sub> treatment<break></break>2nd = during CCl<sub>4</sub> treatment for 4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B99-nutrients-10-00855" ref-type="bibr">99</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">30% CCl4 in olive oil (0.05 mL/10 g/IP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fish <italic>Cyprinus carpio</italic> var. Jian (Jian carp)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma-Aldrich Chemical Co</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.1%, 0.5%, or 1.0%</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">60 days before CCl<sub>4</sub> treatment</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B102-nutrients-10-00855" ref-type="bibr">102</xref>]</td></tr><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Hepatotoxicity</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Propanil 20 mg/kg/3 times a week/in olive oil (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Albino rat</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Chemical, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50 mg/kg/3 times a week/in olive oil</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">28 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B95-nutrients-10-00855" ref-type="bibr">95</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Paracetamol 500 mg/kg/day for 15 days (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Adult male rabbits</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Chemical</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50 and 100 mg/kg/in corn oil (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">15 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B105-nutrients-10-00855" ref-type="bibr">105</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine phosphate (CQ) 100, 200 or 300/daily/45 d</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Swiss Albino mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">80 mg/kg/day (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">45 days during CQ treatment</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B107-nutrients-10-00855" ref-type="bibr">107</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TAA 200 mg/kg/I.P. for 12 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar albino rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">75 mg/kg (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">12 weeks after discontinuation of TAA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B108-nutrients-10-00855" ref-type="bibr">108</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TAA 300 mg/kg/2 days/I.P./dissolved in a solution of glycerol formal, chremaphore and H<sub>2</sub>O (5:2:2)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Chemical</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 or 400 mg/kg/day dissolved in glycerol formal, chremaphore and H<sub>2</sub>O (5:2:2) (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">48 h before TAA administration then continued during the two days of TAA injection</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B109-nutrients-10-00855" ref-type="bibr">109</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LPS 1 mg/kg/I.P.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Aldrich Chemicals Private Ltd., New Delhi, India</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5, 30 or 60 mg/kg/suspended in 0·5% CMC (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6 days before LPS injection and sacrificed after 6 h post LPS injection</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B110-nutrients-10-00855" ref-type="bibr">110</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nzno 50 mg/kg/on 7th day of saline administration (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">200 mg/kg/day/in corn oil (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">7 days prior NZnO and continued for 21 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B111-nutrients-10-00855" ref-type="bibr">111</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Naf 600 ppm via drinking water/7 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma-Aldrich Chemical, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10 or 20 mg/kg/dissolved in 5% DMSO (I.P.)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">7 days then exposed for 7 days NaF</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B112-nutrients-10-00855" ref-type="bibr">112</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">(Tz, azo dye) 7.5 mg/kg/diet/90 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar Albino rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Local markets, Saudi Arabia</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1, 2 or 4 g/kg</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">90 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B113-nutrients-10-00855" ref-type="bibr">113</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">K<sub>2</sub>Cr<sub>2</sub>O<sub>7</sub> 15 mg/kg/I.P./single dose</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma-Aldrich (St. Louis, MO, USA).</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">400 mg/kg/suspended in 0.5% CMC (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10 days prior single dose of K<sub>2</sub>Cr<sub>2</sub>O<sub>7</sub> for 24 h or 48 h</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B114-nutrients-10-00855" ref-type="bibr">114</xref>,<xref rid="B115-nutrients-10-00855" ref-type="bibr">115</xref>]</td></tr><tr><td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Fibrosis and Cirrhosis</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TAA 200 mg/kg/I.P./twice a week for 12 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">300 mg/kg/day/in solvent/2 mL per rat<break></break>(intragingival)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">12 weeks along with TAA or 4 or 6 weeks after TAA discontinuation</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B116-nutrients-10-00855" ref-type="bibr">116</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Biliary duct ligation</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar Albino rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma-Aldrich, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg/day (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1st dose = 3 days before BDL and terminated after 14 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B120-nutrients-10-00855" ref-type="bibr">120</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar Albino rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Chemicals Co Purity (HPLC) >80%, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg/day/suspended in 5% CMC (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">28 days after BDL surgery</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B118-nutrients-10-00855" ref-type="bibr">118</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Chemicals Co, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg/day/suspended in 0.7% CMC (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">28 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B117-nutrients-10-00855" ref-type="bibr">117</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CCl<sub>4</sub> 0.4 g/kg/3 times per week/dissolved in mineral oil/for 3 months</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male Wistar rats</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sigma Chemicals Co, USA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100 mg/kg/day (oral)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2 months</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B117-nutrients-10-00855" ref-type="bibr">117</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LPS 5 mg/kg/I.P.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Male C57BL/6 mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">20, 40 or 80 mg/kg/day (oral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B121-nutrients-10-00855" ref-type="bibr">121</xref>]</td></tr></tbody></table></table-wrap><table-wrap id="nutrients-10-00855-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">nutrients-10-00855-t002_Table 2</object-id><label>Table 2</label><caption><p>Clinical studies of curcumin used in the treatment of oxidative associated liver diseases.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Dose</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Study Design</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">No. of Patients</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Duration of Treatment</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Result</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Reference</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1000 mg/day</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Patients with NAFLD were randomly assigned to the curcumin (<italic>n</italic> = 44) or placebo group (<italic>n</italic> = 43)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">87</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ the body mass index, AST, ALT, SGOT, SGPT</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B144-nutrients-10-00855" ref-type="bibr">144</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">500 mg/day</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Patients with NAFLD were randomly assigned to the curcumin (<italic>n</italic> = 40) or placebo group (<italic>n</italic> = 40)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">80</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">↓ Total cholesterol, LDL-C, ALT, AST<break></break>↑ HDL-C</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B143-nutrients-10-00855" ref-type="bibr">143</xref>]</td></tr></tbody></table></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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