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Haddadi Y, Chahlaoui A, Taouraout A, Ichennarn I. Zinc bioaccumulation in house sparrows (Passer domesticus) across urban and rural areas of Meknes, Morocco: a bioindicator of environmental pollution. ENVIRONMENTAL MONITORING AND ASSESSMENT 2025; 197:362. [PMID: 40047948 DOI: 10.1007/s10661-025-13772-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 02/19/2025] [Indexed: 04/11/2025]
Abstract
This study investigates zinc (Zn) bioaccumulation in house sparrows (Passer domesticus) across urban and rural areas of Meknes, Morocco, to evaluate their effectiveness as bioindicators of environmental pollution. Fifty sparrows were sampled from five locations: an industrial zone, town center, bus station, main road, and a rural reference site. Zinc concentrations, measured on a dry weight basis using Inductively Coupled Plasma Mass Spectrometry (ICP-MS), revealed significant differences between sites for the liver (111.43 ± 4.25 µg/g), kidneys (56.68 ± 3.50 µg/g), blood (1.638 ± 0.652 µg/g), bones (21.36 ± 6.10 µg/g), and heart (16.87 ± 5.15 µg/g) at the most polluted site, Sidi Bouzekri industrial zone, according to ANOVA results (p < 0.05). No significant differences were found for feathers (9.85 ± 4.65 µg/g), lungs (12.02 ± 4.58 µg/g), and brain (9.49 ± 6.23 µg/g) across the study locations. The rural site, despite its distance from industrial sources, exhibited elevated zinc levels, likely due to agricultural activities. These findings highlight the effectiveness of house sparrows as bioindicators for monitoring zinc contamination, capturing pollution impacts from both urban and rural sources. Ongoing monitoring of zinc pollution in diverse environments remains essential for managing heavy metal exposure risks.
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Affiliation(s)
- Youssef Haddadi
- Natural Resources Management and Development Team, Environment and Health Laboratory, Department of Biology, Faculty of Sciences, Moulay Ismaïl University, B.P.11201, Zitoune, Meknes, Morocco.
| | - Abdelkader Chahlaoui
- Natural Resources Management and Development Team, Environment and Health Laboratory, Department of Biology, Faculty of Sciences, Moulay Ismaïl University, B.P.11201, Zitoune, Meknes, Morocco
| | - Aziz Taouraout
- Natural Resources Management and Development Team, Environment and Health Laboratory, Department of Biology, Faculty of Sciences, Moulay Ismaïl University, B.P.11201, Zitoune, Meknes, Morocco
| | - Imane Ichennarn
- Plant Ecology Unit, Department of Plant Protection and Environment, National School of Agriculture, 50001, Meknes, Morocco
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El-Nekeety AA, Hassan MA, Abdel-Aziem SH, Hassan NS, Abdel-Wahhab MA. Zinc citrate-coated whey protein nanoparticles alleviate kidney damage and the disturbances in inflammatory gene expression in rats. J Biochem Mol Toxicol 2023; 37:e23495. [PMID: 37577756 DOI: 10.1002/jbt.23495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 06/22/2023] [Accepted: 07/31/2023] [Indexed: 08/15/2023]
Abstract
This work was conducted to synthesize whey protein nanoparticles (WPNPs) for the coating of zinc citrate (Zn CITR) at three levels and to study their protective role against CCl4 -induced kidney damage and inflammatory gene expression disorder in rats. Seventy male Sprague-Dawley rats were divided into seven groups and treated orally for 4 weeks as follows; the control group, the group treated twice a week with CCl4 (5 mL/kg b.w), the groups received CCl4 plus WPNPs (300 mg/kg b.w); the group received 50 mg/kg b.w of Zn CITR or the three formulas of Zn CITR-WPNPs at low, medium and high doses (LD, MD, and HD). Blood and kidney samples were collected for different assays and histological analyses. The fabricated particles were semispherical, with an average size of 160 ± 2.7, 180 ± 3.1, and 200 ± 2.6 nm and ζ potential of -126, -93, and -84 mV for ZN CITR-WPNPs (LD), Zn CITR-WPNPs (MD), and ZN CITR-WPNPs (HD), respectively. CCl4 significantly increased (p ≤ 0.05) kidney function indices, oxidative stress markers, messenger RNA expression of transforming growth factor-β1, interleukin (IL)-1β, IL-10, IL-6, inducible nitric oxide synthase, and tumor necrosis factor-α and significantly decreased (p ≤ 0.05) renal superoxide dismutase, catalase, and glutathione peroxidase along with the histological changes in the kidney tissues. WPNPs, Zn CITR, and Zn CITR loaded WPNPS showed a protective effect against these complications and Zn CITR-WPNPs (LD) was more effective. WPNPs can be used effectively for coating Zn CITR at a level of 7 mg/g WPNPs to be used as a supplement for the protection of the kidney against different toxicants to enhance immunity and avoid harm of excess Zn.
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Affiliation(s)
- Aziza A El-Nekeety
- Food Toxicology and Contaminants Department, National Research Center, Cairo, Egypt
| | - Mona A Hassan
- Food Evaluation and Food Science Department, National Organization for Drug Control and Research, Giza, Egypt
| | | | - Nabila S Hassan
- Pathology Department, National Research Center, Cairo, Egypt
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Gheitasi I, Doustimotlagh AH, Kokhdan EP, Akbari G, Barmak MJ. Renoprotective effects of zinc sulfate against transient liver ischemia/reperfusion injury in rats. Heliyon 2023; 9:e15505. [PMID: 37153414 PMCID: PMC10160695 DOI: 10.1016/j.heliyon.2023.e15505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 03/29/2023] [Accepted: 04/11/2023] [Indexed: 05/09/2023] Open
Abstract
Objectives Liver ischemia/reperfusion damage frequently occurs in setting of hepatic resection and liver transplantation. It leads to disturbance in remote organs such as heart, lung and kidneys. This study explored the consequences of hepatic ischemia/reperfusion on the oxidative stress parameters, biochemical factors, and histopathological alterations in the kidney's rats, as well as evaluated the role of zinc sulfate on above-mentioned parameters. Materials and methods Twenty-eight male Wistar rats were accidently assigned into four groups (n = 7). They were Sham, ischemia/reperfusion, zinc sulfate pretreatment, and zinc sulfate pretreatment + ischemia/reperfusion groups. Sham group: obtained normal saline (2 ml/day, seven consecutive days), intraperitoneally, zinc sulfate pretreatment group: obtained zinc sulfate (5 mg/kg, seven consecutive days, intraperitoneally). Ischemia/reperfusion group: obtained normal saline as mentioned previous, then rats experienced the partial ischemia (%70) for 45 min followed by 60 min reperfusion. Zinc sulfate pretreatment group: obtained zinc sulfate as mentioned previous, then rats experience the partial ischemia/reperfusion as presented earlier. At the end of investigation, blood was withdrawn, liver and renal tissues were removed. Then, biochemical and oxidative stress parameters, and histological changes were evaluated in the mentioned tissues. Results The findings of this experiment indicated that zinc sulfate markedly reduced the serum levels of liver and kidney function tests in relative to ischemia/reperfusion group. Also, antioxidant enzymes activity, ferric reducing antioxidant power, and nitric oxide significantly increased, while malondialdehyde level declined in the renal tissue of zinc sulfate + ischemia/reperfusion group compared to ischemia/reperfusion rats. Furthermore, zinc sulfate alleviated the liver and kidneys histopathological alterations following ischemia/reperfusion. Conclusion Zinc sulfate ameliorated liver and kidney function, and improved oxidant-antioxidant balance in favor of antioxidants. It is suggested that zinc sulfate may be beneficial effects on hepato-renal injury after ischemia/reperfusion.
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Affiliation(s)
- Izadpanah Gheitasi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | | | | | - Ghaidafeh Akbari
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
- Corresponding author. Medical Physiology, Yasuj University of Medical Sciences, Yasuj, Iran.
| | - Mehrzad Jafari Barmak
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
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Zinc-glutathione in Chinese Baijiu prevents alcohol-associated liver injury. Heliyon 2023; 9:e13722. [PMID: 36873153 PMCID: PMC9975285 DOI: 10.1016/j.heliyon.2023.e13722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 02/01/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Zinc depletion is associated with alcohol-associated liver injury. We tested the hypothesis that increasing zinc availability along with alcohol consumption prevents alcohol-associated liver injury. Zinc-glutathione (ZnGSH) was synthesized and directly added to Chinese Baijiu. Mice were administered a single gastric dose of 6 g/kg ethanol in Chinese Baijiu with or without ZnGSH. ZnGSH in Chinese Baijiu did not change the likeness of the drinkers but significantly reduced the recovery time from drunkenness along with elimination of high-dose mortality. ZnGSH in Chinese Baijiu decreased serum AST and ALT, suppressed steatosis and necrosis, and increased zinc and GSH concentrations in the liver. It also increased alcohol dehydrogenase and aldehyde dehydrogenase in the liver, stomach, and intestine and reduced acetaldehyde in the liver. Thus, ZnGSH in Chinese Baijiu prevents alcohol-associated liver injury by increasing alcohol metabolism timely with alcohol consumption, providing an alternative approach to the management of alcohol-associated drinking.
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Nicoll R, Gerasimidis K, Forrest E. The Role of Micronutrients in the Pathogenesis of Alcohol-Related Liver Disease. Alcohol Alcohol 2021; 57:275-282. [PMID: 34491307 DOI: 10.1093/alcalc/agab060] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/27/2021] [Accepted: 08/03/2021] [Indexed: 11/13/2022] Open
Abstract
AIMS Chronic alcohol consumption may result in liver injury and chronic liver disease, but other factors are likely to influence disease progression. Malnutrition, specifically micronutrient deficiency, is frequently associated with both alcohol use disorder and chronic liver disease. We hypothesize that micronutrient deficiencies may affect the progression of liver disease in this population. METHODS Systematic integrative review of the medical literature; electronic search of MEDLINE 1950-2021; studies investigating role of any micronutrient in the acceleration of alcohol-related liver injury in humans or animals. Studies which specifically related to alcoholic hepatitis were excluded. Outcomes were extracted and recorded in tabulated form and discussed narratively. RESULTS We identified 46 studies investigating the role of micronutrient deficiencies in the pathogenesis of alcohol-related liver disease. Specific micronutrients which were identified included folic acid or related B vitamins (n = 9 studies), Vitamin D (n = 9 studies), magnesium (n = 8 studies), zinc (n = 8 studies) and selenium (n = 12 including one systematic review). Observational evidence suggests a potential role of magnesium deficiency in accelerating alcohol-related liver injury with weak or negative evidence for other micronutrients. CONCLUSIONS Magnesium deficiency may increase the risk of alcohol-related liver injury and adverse liver outcomes. However, currently, there is insufficient evidence to support magnesium supplementation except for clinically relevant magnesium deficiency. Long-term prospective cohort studies assessing the impact of micronutrients on liver disease progression in patients with alcohol use disorder are lacking and may help determine whether there is a causal role for micronutrient deficiencies in alcohol-related liver injury.
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Affiliation(s)
- Ruairidh Nicoll
- Department of Gastroenterology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK
| | - Konstantinos Gerasimidis
- Department of Human Nutrition, School of Medicine, College of Medicine, Veterinary and Life Sciences, University of Glasgow, New Lister Building, Glasgow Royal Infirmary, Glasgow G31 2ER, UK
| | - Ewan Forrest
- Department of Gastroenterology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK
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Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction, and Fatty Liver Disease. Antioxidants (Basel) 2021; 10:antiox10030384. [PMID: 33806556 PMCID: PMC8000766 DOI: 10.3390/antiox10030384] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
Emerging data demonstrate the important roles of altered gut microbiomes (dysbiosis) in many disease states in the peripheral tissues and the central nervous system. Gut dysbiosis with decreased ratios of Bacteroidetes/Firmicutes and other changes are reported to be caused by many disease states and various environmental factors, such as ethanol (e.g., alcohol drinking), Western-style high-fat diets, high fructose, etc. It is also caused by genetic factors, including genetic polymorphisms and epigenetic changes in different individuals. Gut dysbiosis, impaired intestinal barrier function, and elevated serum endotoxin levels can be observed in human patients and/or experimental rodent models exposed to these factors or with certain disease states. However, gut dysbiosis and leaky gut can be normalized through lifestyle alterations such as increased consumption of healthy diets with various fruits and vegetables containing many different kinds of antioxidant phytochemicals. In this review, we describe the mechanisms of gut dysbiosis, leaky gut, endotoxemia, and fatty liver disease with a specific focus on the alcohol-associated pathways. We also mention translational approaches by discussing the benefits of many antioxidant phytochemicals and/or their metabolites against alcohol-mediated oxidative stress, gut dysbiosis, intestinal barrier dysfunction, and fatty liver disease.
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Chen Z, Wu A, Jin H, Liu F. β-Sitosterol attenuates liver injury in a rat model of chronic alcohol intake. Arch Pharm Res 2020; 43:1197-1206. [PMID: 33155166 DOI: 10.1007/s12272-020-01271-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 10/13/2020] [Indexed: 12/17/2022]
Abstract
Liver disease associated with long-term drinking is one of the leading causes of death. There is an urgent need for more effective drugs to reduce alcoholic liver damage. Yin Chen Hao, a traditional Chinese herbal medicine, is widely used for liver diseases. Here, we aimed to explore the protective effect of β-sitosterol (the active ingredient of Artemisia spp.) on alcoholic liver injuries. We treated the rats with alcohol and different dosages of β-sitosterol to detect the expression levels of liver function indicators in serum. The functions of β-sitosterol were evaluated based on variations in histology, liver function indicators and DNA oxidative damages. The underlying mechanism was investigated by measuring lipid peroxidation, the antioxidant, the expression of cytochrome P450 2E1 and the expression of apoptosis related genes. The results showed that β-sitosterol could improve liver histology and suppress biochemical indicators caused by alcohol in serum. In addition, β-sitosterol alleviates alcohol-induced oxidative stress, such as restoring erythrocyte membrane fluidity, reducing glutathione depletion, restoring antioxidant enzyme activity and reducing malondialdehyde overproduction. Furthermore, β-sitosterol downregulated the expression of apoptosis-related genes through the PI3K/Akt pathway. In conclusion, β-sitosterol has a protective effect on chronic alcoholism and has broad clinical application prospects in the treatment of alcohol-induced liver damage.
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Affiliation(s)
- Zhenjuan Chen
- Hepatology Department, Qingdao No.6 People's Hospital, No.9, Fushun Road, Shibei District, Qingdao, Shandong, 266033, People's Republic of China
| | - Ancheng Wu
- Hepatology Department, Qingdao No.6 People's Hospital, No.9, Fushun Road, Shibei District, Qingdao, Shandong, 266033, People's Republic of China
| | - Hongmei Jin
- Hepatology Department, Qingdao No.6 People's Hospital, No.9, Fushun Road, Shibei District, Qingdao, Shandong, 266033, People's Republic of China
| | - Fuhui Liu
- Hepatology Department, Qingdao No.6 People's Hospital, No.9, Fushun Road, Shibei District, Qingdao, Shandong, 266033, People's Republic of China.
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Ma J, Cao H, Rodrigues RM, Xu M, Ren T, He Y, Hwang S, Feng D, Ren R, Yang P, Liangpunsakul S, Sun J, Gao B. Chronic-plus-binge alcohol intake induces production of proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via ASK1/p38MAPKα-dependent mechanisms. JCI Insight 2020; 5:136496. [PMID: 32544093 DOI: 10.1172/jci.insight.136496] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 06/05/2020] [Indexed: 12/14/2022] Open
Abstract
Alcohol-associated liver disease is a spectrum of liver disorders with histopathological changes ranging from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Recent data suggest that chronic-plus-binge ethanol intake induces steatohepatitis by promoting release by hepatocytes of proinflammatory mitochondrial DNA-enriched (mtDNA-enriched) extracellular vesicles (EVs). The aim of the present study was to investigate the role of the stress kinase apoptosis signal-regulating kinase 1 (ASK1) and p38 mitogen-activated protein kinase (p38) in chronic-plus-binge ethanol-induced steatohepatitis and mtDNA-enriched EV release. Microarray analysis revealed the greatest hepatic upregulation of metallothionein 1 and 2 (Mt1/2), which encode 2 of the most potent antioxidant proteins. Genetic deletion of the Mt1 and Mt2 genes aggravated ethanol-induced liver injury, as evidenced by elevation of serum ALT, neutrophil infiltration, oxidative stress, and ASK1/p38 activation in the liver. Inhibition or genetic deletion of Ask1 or p38 ameliorated ethanol-induced liver injury, inflammation, ROS levels, and expression of phagocytic oxidase and ER stress markers in the liver. In addition, inhibition of ASK1 or p38 also attenuated ethanol-induced mtDNA-enriched EV secretion from hepatocytes. Taken together, these findings indicate that induction of hepatic mtDNA-enriched EVs by ethanol is dependent on ASK1 and p38, thereby promoting alcoholic steatohepatitis.
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Affiliation(s)
- Jing Ma
- State Key Laboratory of Organ Failure Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA
| | - Haixia Cao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA
| | - Robim M Rodrigues
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA
| | - Mingjiang Xu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA
| | - Tianyi Ren
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA
| | - Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA
| | - Ruixue Ren
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA
| | - Peixin Yang
- Department of Obstetrics and Gynecology Science, University of Maryland, School of Medicine, Baltimore, Maryland, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, and.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA
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Akbari G. Role of Zinc Supplementation on Ischemia/Reperfusion Injury in Various Organs. Biol Trace Elem Res 2020; 196:1-9. [PMID: 31828721 DOI: 10.1007/s12011-019-01892-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 09/04/2019] [Indexed: 12/13/2022]
Abstract
Ischemia-reperfusion (I/R) injury is a serious condition which is associated with myocardial infarction, stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease, and sleep apnea and can lead to high morbidity and mortality. Salts of zinc (Zn) are commonly used by humans and have protective effects against gastric, renal, hepatic, muscle, myocardial, or neuronal ischemic injury. The present review evaluates molecular mechanisms underlying the protective effects of Zn supplement against I/R injury. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, and Scientific Information Database from 1991 to 2019. Zn supplementation increased the decreased parameters including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione (GSH), metallothionein (MT), protein sulfhydryl (P-SH), and nuclear factor-erythroid 2-related factor-2 (Nrf2) expression and decreased the increased elements such as endoplasmic reticulum (ER) stress, mitochondrial permeability transition pore (mPTP) opening, malondialdehyde (MDA), serum level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and microRNAs-(122 and 34a), apoptotic factors, and histopathological changes. Zn also increases phosphatidylinositol 3-kinase (PI3K)/Akt and glycogen synthase kinase-3β (GSK-3β) phosphorylation and preserves protein kinase C isoforms. It is suggested that Zn can be administered before elective surgeries for prevention of side effects of I/R injury.
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Affiliation(s)
- Ghaidafeh Akbari
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
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Ali H, Assiri MA, Shearn CT, Fritz KS. Lipid peroxidation derived reactive aldehydes in alcoholic liver disease. CURRENT OPINION IN TOXICOLOGY 2018; 13:110-117. [PMID: 31263795 DOI: 10.1016/j.cotox.2018.10.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Lipid peroxidation is a known consequence of oxidative stress and is thought to play a key role in numerous disease pathologies, including alcoholic liver disease (ALD). The overaccumulation of lipid peroxidation products during chronic alcohol consumption results in pathogenic lesions on protein, DNA, and lipids throughout the cell. Molecular adducts due to secondary end products of lipid peroxidation impact a host of biochemical processes, including inflammation, antioxidant defense, and metabolism. The aggregate burden of lipid peroxidation which occurs due to chronic alcohol metabolism, including downstream signaling events, contributes to the development and progression of ALD. In this current opinion we highlight recent studies and approaches relating cellular mechanisms of lipid peroxidation to the pathogenesis of alcoholic liver disease.
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Affiliation(s)
- Hadi Ali
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Mohammed A Assiri
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Colin T Shearn
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Kristofer S Fritz
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
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Cui R, Li R, Guo X, Jia X, Yan M. RNA interference against stromal interacting molecule-1 (STIM1) ameliorates ethanol-induced hepatotoxicity. Chem Biol Interact 2018; 289:47-56. [PMID: 29704510 DOI: 10.1016/j.cbi.2018.04.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 04/17/2018] [Accepted: 04/24/2018] [Indexed: 11/16/2022]
Abstract
Previously we have demonstrated that stromal interacting molecule-1 (STIM1) was involved in ethanol induced liver injury. However, the exact pathogenic mechanism of STIM1 in alcoholic liver disease (ALD) is still unknown. We constructed plasmid vectors encoding short-hairpin RNA against STIM1 to investigate its role in ALD in the rat liver cell line BRL and in Sprague-Dawley rats. The results showed that STIM1 targeted sh-RNA (Sh-STIM1) significantly ameliorated ethanol-induced BRL cells injury and liver injury in rats with 20 weeks-induced alcoholic liver disease. Inhibition of STIM1 also reduced intracellular calcium ion concentration, reactive oxygen species (ROS) production, lipid peroxidation, NF-kappa B activation and TNF-α production under ethanol exposure. STIM1 may play an important role in the pathogenesis of alcoholic liver disease. Silencing STIM1 may be effective in preventing alcoholic liver disease.
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Affiliation(s)
- Ruibing Cui
- Department of Geriatric Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012, PR China
| | - Rong Li
- Department of Geriatric Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012, PR China
| | - Xiaolan Guo
- Department of Geriatric Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012, PR China
| | - Xiaoqing Jia
- Department of Geriatric Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012, PR China
| | - Ming Yan
- Department of Geriatric Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012, PR China.
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Zinc deficiency as a mediator of toxic effects of alcohol abuse. Eur J Nutr 2017; 57:2313-2322. [PMID: 29177978 DOI: 10.1007/s00394-017-1584-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 11/20/2017] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To review data on the role of ethanol-induced alteration of Zn homeostasis in mediation of adverse effects of alcohol abuse. METHODS The scholarly published articles on the association between Zn metabolism and alcohol-associated disorders (liver, brain, lung, gut dysfunction, and fetal alcohol syndrome) have been reviewed. RESULTS It is demonstrated that alcohol-induced modulation of zinc transporters results in decreased Zn levels in lungs, liver, gut, and brain. Zn deficiency in the gut results in increased gut permeability, ultimately leading to endotoxemia and systemic inflammation. Similarly, Zn deficiency in lung epithelia and alveolar macrophages decreases lung barrier function resulting in respiratory distress syndrome. In turn, increased endotoxemia significantly contributes to proinflammatory state in alcoholic liver disease. Finally, impaired gut and liver functions may play a significant role in alcoholic brain damage, being associated with both increased proinflammatory signaling and accumulation of neurotoxic metabolites. It is also hypothesized that ethanol-induced Zn deficiency may interfere with neurotransmission. Similar changes may take place in the fetus as a result of impaired placental zinc transfer, maternal zinc deficiency, or maternal Zn sequestration, resulting in fetal alcoholic syndrome. Therefore, alcoholic Zn deficiency not only mediates the adverse effects of ethanol exposure, but also provides an additional link between different alcohol-induced disorders. CONCLUSIONS Generally, current findings suggest that assessment of Zn status could be used as a diagnostic marker of metabolic disturbances in alcohol abuse, whereas modulation of Zn metabolism may be a potential tool in the treatment of alcohol-associated disorders.
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Hamarneh SR, Kim BM, Kaliannan K, Morrison SA, Tantillo TJ, Tao Q, Mohamed MMR, Ramirez JM, Karas A, Liu W, Hu D, Teshager A, Gul SS, Economopoulos KP, Bhan AK, Malo MS, Choi MY, Hodin RA. Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice. Dig Dis Sci 2017; 62:2021-2034. [PMID: 28424943 PMCID: PMC5684583 DOI: 10.1007/s10620-017-4576-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 04/06/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease. METHODS Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis ± IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease. RESULTS Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes. CONCLUSIONS IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.
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Affiliation(s)
- Sulaiman R Hamarneh
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Byeong-Moo Kim
- Gastrointestinal Unit, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA
| | - Kanakaraju Kaliannan
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Sara A Morrison
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Tyler J Tantillo
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Qingsong Tao
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Mussa M Rafat Mohamed
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Juan M Ramirez
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Aaron Karas
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Wei Liu
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Dong Hu
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Abeba Teshager
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Sarah Shireen Gul
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Konstantinos P Economopoulos
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Atul K Bhan
- Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Madhu S Malo
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA
| | - Michael Y Choi
- Gastrointestinal Unit, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA.
| | - Richard A Hodin
- Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA.
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Boudreault F, Pinilla-Vera M, Englert JA, Kho AT, Isabelle C, Arciniegas AJ, Barragan-Bradford D, Quintana C, Amador-Munoz D, Guan J, Choi KM, Sholl L, Hurwitz S, Tschumperlin DJ, Baron RM. Zinc deficiency primes the lung for ventilator-induced injury. JCI Insight 2017; 2:86507. [PMID: 28570269 DOI: 10.1172/jci.insight.86507] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 04/25/2017] [Indexed: 01/13/2023] Open
Abstract
Mechanical ventilation is necessary to support patients with acute lung injury, but also exacerbates injury through mechanical stress-activated signaling pathways. We show that stretch applied to cultured human cells, and to mouse lungs in vivo, induces robust expression of metallothionein, a potent antioxidant and cytoprotective molecule critical for cellular zinc homeostasis. Furthermore, genetic deficiency of murine metallothionein genes exacerbated lung injury caused by high tidal volume mechanical ventilation, identifying an adaptive role for these genes in limiting lung injury. Stretch induction of metallothionein required zinc and the zinc-binding transcription factor MTF1. We further show that mouse dietary zinc deficiency potentiates ventilator-induced lung injury, and that plasma zinc levels are significantly reduced in human patients who go on to develop acute respiratory distress syndrome (ARDS) compared with healthy and non-ARDS intensive care unit (ICU) controls, as well as with other ICU patients without ARDS. Taken together, our findings identify a potentially novel adaptive response of the lung to stretch and a critical role for zinc in defining the lung's tolerance for mechanical ventilation. These results demonstrate that failure of stretch-adaptive responses play an important role in exacerbating mechanical ventilator-induced lung injury, and identify zinc and metallothionein as targets for lung-protective interventions in patients requiring mechanical ventilation.
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Affiliation(s)
- Francis Boudreault
- Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA
| | - Miguel Pinilla-Vera
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Joshua A Englert
- Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State Wexner Medical Center, Columbus, Ohio, USA
| | - Alvin T Kho
- Boston Children's Hospital Informatics Program, Boston, Massachusetts, USA
| | - Colleen Isabelle
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Antonio J Arciniegas
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Diana Barragan-Bradford
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Carolina Quintana
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Diana Amador-Munoz
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jiazhen Guan
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kyoung Moo Choi
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | - Shelley Hurwitz
- Center for Clinical Investigation, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Daniel J Tschumperlin
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
| | - Rebecca M Baron
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Ghorbani Z, Hajizadeh M, Hekmatdoost A. Dietary supplementation in patients with alcoholic liver disease: a review on current evidence. Hepatobiliary Pancreat Dis Int 2016; 15:348-360. [PMID: 27498574 DOI: 10.1016/s1499-3872(16)60096-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Alcoholic liver disease (ALD) is one of the main causes of liver disease worldwide. Although the pathogenesis of ALD has not yet been well elucidated, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species play a pivotal role in the clinical and pathological spectrum of the disease. This review summarizes the existing evidences on dietary supplements considered to have antioxidant, and/or anti-inflammatory properties, and their role in the management of ALD and the proposed mechanisms. DATA SOURCES The present study reviewed all studies published in PubMed, ScienceDirect and Scopus, from 1959 to 2015, indicating the role of different dietary supplementation in attenuation of many pathophysiological processes involved in development and progression of ALD. Full-texts of citations were used except for those that were published in languages other than English. RESULTS Significant progress has been made to understand the key events and molecular players for the onset and progression of ALD from both experimental and clinical studies; however, there is no successful treatment currently available. The present review discussed the role of a variety of dietary supplements (e.g. vitamin A, carotenoids, vitamins B3, C and E, in addition to antioxidants and anti-inflammatory agents) in treating ALD. It has been shown that supplementation with some carotenoids, vitamin B3, vitamin C, silymarin, curcumin, probiotics, zinc, S-adenosylmethionine and garlic may have potential beneficial effects in animal models of ALD; however, the number of clinical studies is very limited. In addition, supplementation should be accompanied with alcohol cessation. CONCLUSIONS Since oxidative stress and inflammation are involved in the pathogenesis of ALD, dietary supplements that can modulate these pathologies could be useful in the treatment of ALD. In addition to alcohol cessation, these supplements have shown beneficial effects on animal models of ALD. Clinical trials are needed to validate the beneficiary role of these supplements in patients with ALD.
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Affiliation(s)
- Zeinab Ghorbani
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology, Research Institute Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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16
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Altered oxidative stress/antioxidant status in blood of alcoholic subjects is associated with alcoholic liver disease. Drug Alcohol Depend 2014; 143:112-9. [PMID: 25107314 DOI: 10.1016/j.drugalcdep.2014.07.013] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 07/08/2014] [Accepted: 07/11/2014] [Indexed: 01/01/2023]
Abstract
BACKGROUND Oxidative stress is implicated in pathogenesis of alcoholic liver disease (ALD). This study investigated the possible correlation among the erythrocyte indices of oxidative stress, the leukocyte panels of antioxidant proteins (metallothioneins), the serum biochemical parameters and the liver steatosis grade. METHODS A total of 118 cases including 60 alcoholic subjects and 58 controls were enrolled. All the alcoholic subjects were screened for body mass index (BMI), liver steatosis, and blood chemistry and serology. The level of oxidative stress and oxidative stress-related parameters were measured in the blood and correlated with clinical findings. RESULTS Alcoholic subjects showed higher BMI, moderate/severe hepatic steatosis, increase in the levels of triglycerides, cholesterol, glucose, γ-glutamyl-transpeptidase (GGT), alanine aminotransferase (ALT), bilirubin, alpha 1 and beta 2 globulins, iron and a decrease in the levels of aspartate aminotransferase (AST) and beta 1 globulin with respect to the reference values. Moreover, alcoholic subjects showed: (i) an increase in Thiobarbituric Acid Reactive Substance (TBARS) content representing a good estimation of global oxidative stress; (ii) a stimulation of the activities of the antioxidant enzymes catalase and SOD; (iii) a modulation of expression of metallothioneins, with a down-regulation of MT-1A and an up-regulation of MT-1E isoforms. CONCLUSIONS Our data suggest that alcoholism is strongly associated with altered pattern of blood metallothioneins; this parameter combined with the score calculated by an ad hoc implemented algorithm (HePaTest) could offer a non-invasive alternative approach for evaluating alcohol-related damages and could be used in follow-up of alcoholic patients.
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17
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Williams JA, Manley S, Ding WX. New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases. World J Gastroenterol 2014; 20:12908-12933. [PMID: 25278688 PMCID: PMC4177473 DOI: 10.3748/wjg.v20.i36.12908] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/07/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.
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18
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Stefanson AL, Bakovic M. Dietary regulation of Keap1/Nrf2/ARE pathway: focus on plant-derived compounds and trace minerals. Nutrients 2014; 6:3777-801. [PMID: 25244368 PMCID: PMC4179188 DOI: 10.3390/nu6093777] [Citation(s) in RCA: 170] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Revised: 08/13/2014] [Accepted: 08/14/2014] [Indexed: 01/10/2023] Open
Abstract
It has become increasingly evident that chronic inflammation underpins the development of many chronic diseases including cancer, cardiovascular disease and type 2 diabetes. Oxidative stress is inherently a biochemical dysregulation of the redox status of the intracellular environment, which under homeostatic conditions is a reducing environment, whereas inflammation is the biological response to oxidative stress in that the cell initiates the production of proteins, enzymes, and other compounds to restore homeostasis. At the center of the day-to-day biological response to oxidative stress is the Keap1/Nrf2/ARE pathway, which regulates the transcription of many antioxidant genes that preserve cellular homeostasis and detoxification genes that process and eliminate carcinogens and toxins before they can cause damage. The Keap1/Nrf2/ARE pathway plays a major role in health resilience and can be made more robust and responsive by certain dietary factors. Transient activation of Nrf2 by dietary electrophilic phytochemicals can upregulate antioxidant and chemopreventive enzymes in the absence of actual oxidative stress inducers. Priming the Keap1/Nrf2/ARE pathway by upregulating these enzymes prior to oxidative stress or xenobiotic encounter increases cellular fitness to respond more robustly to oxidative assaults without activating more intense inflammatory NFκB-mediated responses.
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Affiliation(s)
- Amanda L Stefanson
- Department of Human Health and Nutritional Sciences, University of Guelph, 50 Stone Road E, Guelph, Ontario, Canada N1G 2W1.
| | - Marica Bakovic
- Department of Human Health and Nutritional Sciences, University of Guelph, 50 Stone Road E, Guelph, Ontario, Canada N1G 2W1.
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19
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Effects of binge ethanol on lipid homeostasis and oxidative stress in a rat model of nonalcoholic fatty liver disease. J Physiol Biochem 2014; 70:341-53. [PMID: 24481563 DOI: 10.1007/s13105-013-0308-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 12/10/2013] [Indexed: 02/06/2023]
Abstract
Excess fat accumulation renders the liver more vulnerable to ethanol, but it is still unclear how alcohol enhances lipid dysmetabolism and oxidative stress in a pre-existing steatosis condition. The effects produced by binge ethanol consumption in the liver of male Wistar rats fed a standard (Ctrl) or a high-fat diet HFD were compared. The liver status was checked through tissue histology and standard serum parameters. Alteration of hepatic lipid homeostasis and consequent oxidative unbalance were assessed by quantifying the mRNA expression of the lipid-regulated peroxisome proliferator-activated receptors (PPARs), of the cytochromes CYP2E1 and CYP4A1, and of some antioxidant molecules such as the metallothionein isoforms MT1 and MT2 and the enzymes catalase and superoxide dismutase. The number of adipose differentiation-related protein (ADRP)-positive lipid droplets (LDs) was evaluated by immunohistochemical staining. As a response to the double insult of diet and ethanol the rat liver showed: (1) a larger increase in fat accumulation within ADRP-positive LDs; (2) stimulation of lipid oxidation in the attempt to limit excess fat accumulation; (3) induction of antioxidant proteins (MT2, in particular) to protect the liver from the ethanol-induced overproduction of oxygen radicals. The data indicate an increased susceptibility of fatty liver to ethanol and suggest that the synergistic effect of diet and ethanol on lipid dysmetabolism might be mediated, at least in part, by PPARs and cytochromes CYP4A1 and CYP2E1.
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20
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Kumar SD, Vijaya M, Samy RP, Dheen ST, Ren M, Watt F, Kang YJ, Bay BH, Tay SSW. Zinc supplementation prevents cardiomyocyte apoptosis and congenital heart defects in embryos of diabetic mice. Free Radic Biol Med 2012; 53:1595-606. [PMID: 22819979 DOI: 10.1016/j.freeradbiomed.2012.07.008] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2011] [Revised: 07/02/2012] [Accepted: 07/08/2012] [Indexed: 12/14/2022]
Abstract
Oxidative stress induced by maternal diabetes plays an important role in the development of cardiac malformations. Zinc (Zn) supplementation of animals and humans has been shown to ameliorate oxidative stress induced by diabetic cardiomyopathy. However, the role of Zn in the prevention of oxidative stress induced by diabetic cardiac embryopathy remains unknown. We analyzed the preventive role of Zn in diabetic cardiac embryopathy by both in vivo and in vitro studies. In vivo study revealed a significant decrease in lipid peroxidation, superoxide ions, and oxidized glutathione and an increase in reduced glutathione, nitric oxide, and superoxide dismutase in the developing heart at embryonic days (E) 13.5 and 15.5 in the Zn-supplemented diabetic group when compared to the diabetic group. In addition, significantly down-regulated protein and mRNA expression of metallothionein (MT) in the developing heart of embryos from diabetic group was rescued by Zn supplement. Further, the nuclear microscopy results showed that trace elements such as phosphorus, calcium, and Zn levels were significantly increased (P<0.001), whereas the iron level was significantly decreased (P<0.05) in the developing heart of embryos from the Zn-supplemented diabetic group. In vitro study showed a significant increase in cellular apoptosis and the generation of reactive oxygen species (ROS) in H9c2 (rat embryonic cardiomyoblast) cells exposed to high glucose concentrations. Supplementation with Zn significantly decreased apoptosis and reduced the levels of ROS. In summary, oxidative stress induced by maternal diabetes could play a role in the development and progression of cardiac embryopathy, and Zn supplementation could be a potential therapy for diabetic cardiac embryopathy.
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MESH Headings
- Animals
- Apoptosis/drug effects
- Blood Glucose/metabolism
- Blotting, Western
- Cells, Cultured
- Diabetes Complications/etiology
- Diabetes Complications/pathology
- Diabetes Complications/prevention & control
- Diabetes Mellitus, Experimental/physiopathology
- Dietary Supplements
- Embryo, Mammalian/cytology
- Embryo, Mammalian/drug effects
- Embryo, Mammalian/metabolism
- Female
- Glutathione/genetics
- Glutathione/metabolism
- Heart Defects, Congenital/etiology
- Heart Defects, Congenital/pathology
- Heart Defects, Congenital/prevention & control
- Immunoenzyme Techniques
- Lipid Peroxidation/drug effects
- Metallothionein/genetics
- Metallothionein/metabolism
- Mice
- Myocytes, Cardiac/cytology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Nuclear Microscopy
- Oxidative Stress
- RNA, Messenger/genetics
- Rats
- Reactive Oxygen Species/metabolism
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Superoxide Dismutase/genetics
- Superoxide Dismutase/metabolism
- Zinc/administration & dosage
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Affiliation(s)
- Srinivasan Dinesh Kumar
- Department of Anatomy, National University Health System, National University of Singapore, Singapore 117597.
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21
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Zhou JY, Jiang ZA, Zhao CY, Zhen Z, Wang W, Nanji AA. Long-term binge and escalating ethanol exposure causes necroinflammation and fibrosis in rat liver. Alcohol Clin Exp Res 2012; 37:213-22. [PMID: 23009062 DOI: 10.1111/j.1530-0277.2012.01936.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2011] [Accepted: 06/10/2012] [Indexed: 01/17/2023]
Abstract
BACKGROUND To investigate whether "binge" and escalating alcohol exposure in the rat influences the development of pathological liver injury. METHODS Time courses for the formation of eicosanoids by cyclooxygenase (COX), oxidative stress and nitrosative stress production, expression of hypoxia-inducible factor 1 (HIF-1), cytokines, hepatic tissue necroinflammation, and fibrosis were assessed in rats during 16 weeks of daily alcohol gavage. RESULTS In this model of binge and escalating levels of alcohol, hepatic steatosis, necrosis, and inflammation as well as fibrosis were increased over the 16-week period. The levels of COX-2, oxidative stress, nitrosative stress, HIF-1, proinflammatory mediators (tumor necrosis factor-α, interleukin 1(β) [IL-1(β) ], IL-6), and procollagen-I were increased over the 16-week period. The content of IL-10 in rat serum increased at the end of 4 and 8 weeks but decreased thereafter and was significantly decreased at 12 and 16 weeks. CONCLUSIONS A rat model of alcoholic liver disease (ALD) with long-term binge and escalating ethanol exposure was developed. Our data support the hypothesis that enhanced eicosanoid production by COX, oxidative stress and nitrosative stress, HIF-1, and the imbalance between pro- and anti-inflammatory cytokines plays an important role in the pathogenesis of ALD.
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Affiliation(s)
- Jun-Ying Zhou
- Department of Infectious Disease , Third Hospital, Hebei Medical University, Shijiazhuang, China.
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22
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ZHU H, JIA Z, MISRA H, LI YR. Oxidative stress and redox signaling mechanisms of alcoholic liver disease: updated experimental and clinical evidence. J Dig Dis 2012; 13:133-142. [PMID: 22356308 PMCID: PMC3297983 DOI: 10.1111/j.1751-2980.2011.00569.x] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the United States and Europe. The spectrum of ALD ranges from fatty liver to alcoholic hepatitis and cirrhosis, which may eventually lead to hepatocellular carcinoma. In developed countries as well as developing nations, ALD is a major cause of end-stage liver disease that requires liver transplantation. The most effective therapy for ALD is alcohol abstinence; however, for individuals with severe ALD and those in whom alcohol abstinence is not achievable, targeted therapies are absolutely necessary. In this context, advances of our understanding of the pathophysiology of ALD over the past two decades have contributed to the development of therapeutic modalities (e.g., pentoxifylline and corticosteroids) for the disease although the efficacy of the available treatments remains limited. This article is intended to succinctly review the recent experimental and clinical findings of the involvement of oxidative stress and redox signaling in the pathophysiology of ALD and the development of mechanistically based antioxidant modalities targeting oxidative stress and redox signaling mechanisms. The biochemical and cellular sources of reactive oxygen and nitrogen species (ROS/RNS) and dysregulated redox signaling pathways associated with alcohol consumption are particularly discussed to provide insight into the molecular basis of hepatic cell dysfunction and destruction as well as tissue remodeling underlying ALD.
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Affiliation(s)
- Hong ZHU
- Department of Pharmacology, Edward Via College of Osteopathic Medicine, Virginia Tech Corporate Research Center, Blacksburg, Virginia, USA,Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA,Correspondence should be addressed to: Y. Robert Li, MD, PhD, Professor and Department Chair, Phone: (540) 231-1465, Fax: (540) 231-8846, or H. Zhu, MD, MPH, Assistant Professor, Phone: (540) 231-1468, Fax: (540) 231-8846,
| | - Zhenquan JIA
- Department of Biology, University of North Carolina at Greensboro, Greensboro, North Carolina, USA
| | - Hara MISRA
- Department of Pharmacology, Edward Via College of Osteopathic Medicine, Virginia Tech Corporate Research Center, Blacksburg, Virginia, USA,Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
| | - Y. Robert LI
- Department of Pharmacology, Edward Via College of Osteopathic Medicine, Virginia Tech Corporate Research Center, Blacksburg, Virginia, USA,Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA,Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences,, Blacksburg, Virginia, USA,Correspondence should be addressed to: Y. Robert Li, MD, PhD, Professor and Department Chair, Phone: (540) 231-1465, Fax: (540) 231-8846, or H. Zhu, MD, MPH, Assistant Professor, Phone: (540) 231-1468, Fax: (540) 231-8846,
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23
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Alcohol metabolizing and antioxidant activities of complex herbal extracts from medicinal plants. Food Sci Biotechnol 2011. [DOI: 10.1007/s10068-011-0184-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022] Open
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Kojima-Yuasa A, Kamatani K, Tabuchi M, Akahoshi Y, Kennedy DO, Matsui-Yuasa I. Zinc deficiency enhances sensitivity to carbon tetrachloride-induced hepatotoxicity in rats. J Trace Elem Med Biol 2011; 25:103-8. [PMID: 21514806 DOI: 10.1016/j.jtemb.2011.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Revised: 02/01/2011] [Accepted: 02/28/2011] [Indexed: 11/17/2022]
Abstract
Zinc (Zn) is an essential nutrient that is required in humans and animals for many physiological functions, including immune and antioxidant functions, growth and reproduction. The present study was conducted to examine the influence of Zn deficiency on the protective action against mild oxidative stress induced by a low dose of carbon tetrachloride (CCl(4)) in rats. Male Wistar rats were administered 125 or 250 μL/kg body weight CCl(4), which caused mild or no elevation of serum LDH, AST and ALT enzyme levels in rats fed a diet with adequate Zn. Treatment with CCl(4) (125 μL/kg) caused a significant release of these enzymes into the serum of rats fed a Zn-deficient diet but not in those given a diet with adequate Zn. Furthermore, no histological abnormalities were observed in CCl(4)-untreated rats fed either a diet with adequate Zn or a Zn-deficient diet or in CCl(4) (125 μL/kg)-treated rats fed a diet with adequate Zn. In CCl(4) (125 μL/kg)-treated rats fed a Zn-deficient diet, however, we observed associated collagen accumulation in the liver and hepatic necrosis. The degree of fibrosis was also more severe in CCl(4) (250 μL/kg)-treated rats fed a Zn-deficient diet. These results show that zinc deficiency during an oxidative stress injury negates the protective actions of certain treatments that normally block oxidative damage. The present study suggests that Zn plays an important role in regulating the antioxidative defense system under mild CCl(4) toxic conditions.
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Affiliation(s)
- Akiko Kojima-Yuasa
- Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, Sumiyoshi-ku, Osaka, Japan.
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25
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Abstract
Zinc deficiency is one of the most consistent nutritional/biochemical observations in alcoholic liver disease (ALD). The objectives of our research are to determine how alcohol interferes with cellular zinc homeostasis and if zinc deficiency is a causal factor in the development of ALD. Metallothionein (MT) is a major protein responsible for cellular zinc homeostasis. MT-transgenic (MT-TG) mice with hepatic overexpression of MT and elevation of zinc level were resistant to ethanol-induced liver injury. MT-knockout (MT-KO) mice with a reduction of hepatic zinc were more susceptible to alcohol toxicity. However, zinc treatment also provided beneficial effects on alcohol hepatoxicity in MT-KO mice, suggesting a MT-independent action. Dietary zinc supplementation normalized hepatic zinc level and attenuated the pathological changes in the liver of mice chronically fed alcohol. Several mechanisms were involved in zinc action against alcoholic cytotoxicity. Zinc enhanced cellular antioxidant capacity and corrected alcohol metabolic switch from alcohol dehydrogenase to cytochrome P4502E1. Zinc attenuated cytokine production and TNF-α receptor- and Fas-mediated cell death pathways. Zinc restored activities of hepatocyte nuclear factor-4α (HNF-4α) and peroxisome proliferation activator-α (PPAR-α), and enhanced hepatic fatty acid β-oxidation and lipid secretion. Hepatoma cell cultures showed that zinc deprivation induces lipid accumulation via inactivating HNF-4α and PPAR-α. These results suggest that alcohol exposure interferes with hepatic zinc homeostasis, leading to cellular zinc deprivation. Inactivation of zinc proteins due to zinc release is likely an important molecular mechanism in the pathogenesis of ALD.
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Affiliation(s)
- Zhanxiang Zhou
- University of North Carolina at Greensboro, Greensboro, N.C., USA.
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Yu X, Guo J, Fang H, Peng S. Basal metallothionein-I/II protects against NMDA-mediated oxidative injury in cortical neuron/astrocyte cultures. Toxicology 2011; 282:16-22. [PMID: 21215786 DOI: 10.1016/j.tox.2010.12.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Accepted: 12/24/2010] [Indexed: 10/18/2022]
Abstract
N-Methyl-D-aspartate (NMDA) receptor overactivation-mediated oxidative stress has been proposed to contribute to brain injury. Metallothionein-I/II (MT-I/II), a member of cysteine-rich metalloproteins, has been found to express in the central nervous system primarily in cortical tissues and be upregulated following brain injury. To address the role of MT-I/II on NMDA-mediated oxidative injury, we established primary cortical neuron/astrocyte cultures from neonatal MT-I/II deficient (MT⁻/⁻) and wild type (MT+/+) mice to test whether basal MT-I/II protects cortical cultures against NMDA-mediated injury. We found that MT-I/II expression was increased by NMDA in MT+/+ cultures but was not detectable in MT⁻/⁻ cultures. NMDA concentration-dependently induced oxidative injury in both MT+/+ and MT⁻/⁻ cultures as evidenced by decrease of cell viability, increases of lipid peroxidation and DNA damage. However, these toxic effects were greater in MT⁻/⁻ than MT+/+ cultures. NMDA significantly increased reactive oxygen species (ROS) generation and disrupted mitochondrial membrane potential in neurons in MT+/+ cultures, and these effects were exaggerated in MT⁻/⁻ cultures. Our findings clearly show that basal MT-I/II provides protection against NMDA-mediated oxidative injury in cortical neuron/astrocyte cultures, and suggest that the protective effects are possibly associated with inhibition of ROS generation and preservation of mitochondrial membrane potential.
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Affiliation(s)
- Xiaoqian Yu
- Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, 20# Dongdajie Rd, Fengtai District, Beijing 100071, PR China
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Tupe RS, Tupe SG, Tarwadi KV, Agte VV. Effect of different dietary zinc levels on hepatic antioxidant and micronutrients indices under oxidative stress conditions. Metabolism 2010; 59:1603-11. [PMID: 20359724 DOI: 10.1016/j.metabol.2010.02.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2009] [Revised: 02/12/2010] [Accepted: 02/25/2010] [Indexed: 11/18/2022]
Abstract
Dietary zinc (Zn) status exerts a powerful influence on the degree of oxidative damage caused by free radicals. We examined the effect of dietary Zn variations with oxidative stress (OS) treatment on antioxidant status, liver function, and status of vitamins in male Wistar rats. Oxidative stress was generated by intraperitoneal injections of tert-butyl hydroperoxide; and dietary Zn variations done were Zn deficient, normal, and excess, with 8, 30, and 60 mg Zn per kilogram diet, respectively. After 21-day dietary regimen, the animals were killed; and plasma aspartate aminotransferase, alanine aminotransferase, hepatic antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase), Zn, reduced glutathione, lipid peroxidation (LPO), and hepatic riboflavin, nicotinic acid, and ascorbic acid estimations were done. The alanine aminotransferase and aspartate aminotransferase levels were elevated in rats with OS and Zn-deficient diet, which were restored to normal levels with excess dietary Zn. Hepatic antioxidant enzymes and reduced glutathione levels were significantly decreased with concomitant increase in LPO due to OS induction in animals with Zn-deficient diet. Corresponding enhanced enzyme activities, higher hepatic Zn, and lowered LPO were observed in animals with normal- and excess-Zn diet. A dose-dependent increase in hepatic nicotinic acid accumulation was observed as the dietary Zn level increased from deficient to excess; however, there was no influence on riboflavin and ascorbic acid status. The results suggest that Zn may have a therapeutic potential in treatment of oxidative liver damage along with enhanced nicotinic acid absorption.
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Affiliation(s)
- Rashmi S Tupe
- Biometry and Nutrition Group, Animal Sciences Division, Agharkar Research Institute, Pune-411004, India
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Fu Z, Guo J, Jing L, Li R, Zhang T, Peng S. Enhanced toxicity and ROS generation by doxorubicin in primary cultures of cardiomyocytes from neonatal metallothionein-I/II null mice. Toxicol In Vitro 2010; 24:1584-91. [PMID: 20600803 DOI: 10.1016/j.tiv.2010.06.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2010] [Revised: 06/02/2010] [Accepted: 06/17/2010] [Indexed: 11/30/2022]
Abstract
The clinical use of doxorubicin (Dox), a potent anticancer drug, is limited by its concurrent dose-dependent cardiotoxicity. We previously found that metallothionein-I/II (MT-I/II) null mice are more vulnerable to Dox-induced cardiomyopathy, but it is unknown whether depletion of MT would sensitize cardiomyocytes to Dox toxicity in vitro since the protective effect of MT still remains controversial. In the present study, a primary culture system of cardiomyocytes from neonatal MT-I/II null (MT(-/-)) and corresponding wild type (MT(+/+)) mice was established to unequivocally determine the effect of MT deficiency on Dox-induced toxicity. MT concentrations in the MT(-/-) cardiomyocytes were about 2.5-fold lower than those in MT(+/+) cardiomyocytes. MT(-/-) cardiomyocytes were more sensitive to Dox-induced cytotoxicity than MT(+/+) cardiomyocytes as measured by morphological alterations, lactate dehydrogenase leakage, cell viability, and apoptosis. Dox time- and concentration-dependently increased reactive oxygen species (ROS) formation in MT(+/+) cardiomyocytes, and this effect was exaggerated in MT(-/-) cardiomyocytes. Antioxidant N-acetylcysteine (NAC) and glutathione (GSH) significantly rescued MT(+/+) but not MT(-/-)cardiomyocytes from Dox-induced cell death and ROS generation. These findings suggest that basal MT provide protection against Dox-induced toxicity in cardiomyocytes, particularly highlight the important role of MT as a cellular antioxidant on scavenging ROS.
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Affiliation(s)
- Ze Fu
- Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Fengtai District, Beijing, PR China
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Chen X. Protective effects of quercetin on liver injury induced by ethanol. Pharmacogn Mag 2010; 6:135-41. [PMID: 20668581 PMCID: PMC2900062 DOI: 10.4103/0973-1296.62900] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2009] [Revised: 01/08/2010] [Accepted: 05/05/2010] [Indexed: 01/01/2023] Open
Abstract
Quercetin, a natural compound of multiple origins, has broad biopharmacological effects, such as antioxidant, directly scavenging free radical, and hepatoprotectivity effects. This study is designed to investigate the interveneous effect of quercetin on liver injury induced by ethanol in rats. The rats that were orally treated with 50% ethanol for continuous ten days, which resulted in cell necrosis, fibrosis and inflammatory infiltration, were included in this study. Higher contents of AST, ALT ADH, γ-GT, TG in plasma and MDA in liver tissue, and lower content of GSH in liver tissue were highlighted in ethanol-treated rats when compared with healthy ones. The levels of cytokines such as IL-1β, IL-1, IL-6, IL-8, and TNF-α in rats plasma were also significantly enhanced, and level of IL-10 was obviously lowered through ethanol treatment. By preventive and synchronism treatment with quercetin for fourteen days, the contents of AST, ALT ADH, γ-GT, TG and MDA, and levels of IL-1β, IL-1, IL-6, IL-8, and TNF-α were significantly reduced, whereas GSH and level of IL-10 were obviously increased. It may be deduced that quercetin, by multiple mechanisms interplay, demonstrated somewhat protective effect on liver injury induced by ethanol in rats.
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Affiliation(s)
- Xi Chen
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, 151 Malianwa North Road, Haidian District, Beijing 100193, PR China
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Abstract
BACKGROUND Zinc (Zn) administration at non-toxic doses protects against the hepatotoxicity produced by many agents, but the underlying mechanisms remain elusive. AIM To examine the basis of Zn-induced generalised hepatoprotective effects. METHODS Rats and mice were given Zn at known hepatoprotective levels (100 mumol ZnCl2/kg/day, s.c., for 4 days) and molecular responses were assessed. RESULTS Zn treatment produced changes in 5% of the genes on custom-designed mouse liver array and Rat Toxicology-II array. Changes in gene expression were further confirmed and extended by real-time reverse transcriptase-polymerase chain reaction. Zn treatment dramatically increased the expression of the metallothionein (Mt), and modestly increased the expression of acute-phase protein genes (ceruloplasmin, Stat3, egr1, Cxc chemokines and heat-shock proteins). For genes encoding for antioxidant enzymes, some were increased (Nrf2 and Nqo1), while others remained unaltered (Cu, Zn SOD and glutathione S-transferases). Expressions of cytokine and pro-inflammatory genes were not affected, while genes related to cell proliferation (cyclin D1) were modestly upregulated. Some metabolic enzyme genes, including cytochrome P450s and UDP-glucuronosyltransferase, were modestly suppressed, perhaps to switch cellular metabolic energy to acute-phase responses. Liver Zn content was increased between 1.6- and 2.1-fold, while hepatic MT protein was increased between 50 and 200-fold. Mice typically showed greater responses than rats. CONCLUSION Such gene expression changes, particularly the dramatic induction of MT and Nrf2 antioxidant pathway, occur in the absence of overt liver injury, and are probably important in the hepatoprotective effects of Zn against toxic insults.
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Affiliation(s)
- Jie Liu
- Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Research Triangle Park, NC
| | - Zhan-Xiang Zhou
- Department of Medicine, University of Louisville, Louisville, KY
| | - Wei Zhang
- Laboratory of Pharmacology, NIEHS, Research Triangle Park, NC
| | - Matthew W. Bell
- Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Research Triangle Park, NC
| | - Michael P. Waalkes
- Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Research Triangle Park, NC
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Varghese J, Faith M, Jacob M. Zinc prevents indomethacin-induced renal damage in rats by ameliorating oxidative stress and mitochondrial dysfunction. Eur J Pharmacol 2009; 614:114-21. [DOI: 10.1016/j.ejphar.2009.04.053] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2008] [Revised: 03/23/2009] [Accepted: 04/29/2009] [Indexed: 01/17/2023]
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Abstract
PURPOSE OF REVIEW Zinc plays an essential role in numerous biochemical pathways. Zinc deficiency affects many organ systems, including the integumentary, gastrointestinal, central nervous system, immune, skeletal, and reproductive systems. This article aims to discuss zinc metabolism and highlights a few of the diseases associated with zinc deficiency. RECENT FINDINGS Zinc deficiency results in dysfunction of both humoral and cell-mediated immunity and increases the susceptibility to infection. Supplementation of zinc has been shown to reduce the incidence of infection as well as cellular damage from increased oxidative stress. Zinc deficiency is also associated with acute and chronic liver disease. Zinc supplementation protects against toxin-induced liver damage and is used as a therapy for hepatic encephalopathy in patients refractory to standard treatment. Zinc deficiency has also been implicated in diarrheal disease, and supplementation has been effective in both prophylaxis and treatment of acute diarrhea. SUMMARY This article is not meant to review all of the disease states associated with zinc deficiency. Rather, it is an introduction to the influence of the many roles of zinc in the body, with an extensive discussion of the influence of zinc deficiency in selected diseases. Zinc supplementation may be beneficial as an adjunct to treatment of many disease states.
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Ohtsuji M, Katsuoka F, Kobayashi A, Aburatani H, Hayes JD, Yamamoto M. Nrf1 and Nrf2 play distinct roles in activation of antioxidant response element-dependent genes. J Biol Chem 2008; 283:33554-62. [PMID: 18826952 DOI: 10.1074/jbc.m804597200] [Citation(s) in RCA: 269] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Nrf1 is a member of the vertebrate Cap'n'Collar (CNC) transcription factor family that commonly contains a unique basic-leucine zipper domain. Among CNC family members, Nrf2 is known to regulate a battery of antioxidant and xenobiotic-metabolizing enzyme genes through the antioxidant response element (ARE). Although Nrf1 has also been shown to bind the ARE, it is unclear whether it plays a distinct role from Nrf2 in regulating genes with this element. To address this issue in vivo, we generated mice bearing a hepatocyte-specific disruption of the Nrf1 gene. AlthoughNrf2 knock-out mice did not exhibit liver damage when they were maintained in an unstressed condition, hepatocyte-specific deletion of Nrf1 caused liver damage resembling the human disease non-alcoholic steatohepatitis. Gene expression analysis revealed that the disruption of Nrf1 causes stress that activates a number of ARE-driven genes in an Nrf2-dependent manner, indicating that Nrf2 cannot compensate completely for loss of Nrf1 function in the liver. In contrast, expression of metallothionein-1 and -2 (MT1 and MT2) genes, each of which harbors at least one ARE in its regulatory region, was decreased in the Nrf1-null mutant mice. Whereas Nrf1 and Nrf2 bound the MT1 ARE with comparable affinity, Nrf1 preferentially activated the reporter gene expression through the MT1 ARE. This study has, thus, identified the first ARE-dependent gene that relies exclusively on Nrf1, suggesting that it plays a distinct functional role in regulating ARE-driven genes.
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Affiliation(s)
- Makiko Ohtsuji
- Graduate School of Comprehensive Human Sciences, Japan Science and Technology Corp., 1-1-1 Tennoudai, Tsukuba 305-8577, Japan
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Zhou Z, Liu J, Song Z, McClain CJ, Kang YJ. Zinc supplementation inhibits hepatic apoptosis in mice subjected to a long-term ethanol exposure. Exp Biol Med (Maywood) 2008; 233:540-8. [PMID: 18375824 DOI: 10.3181/0710-rm-265] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocyte apoptosis has been documented in both clinical and experimental alcoholic liver disease. This study was undertaken to examine the effect of dietary zinc supplementation on hepatic apoptosis in mice subjected to a long-term ethanol exposure. Male adult 129S6 mice fed an ethanol-containing liquid diet for 6 months developed hepatitis, as indicated by neutrophil infiltration and elevation of hepatic keratinocyte chemoattractant (KC) and monocyte chemoattractant protein-1 (MCP-1) levels. Apoptotic cell death was detected in ethanol-exposed mice by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and was confirmed by the increased activities of caspase-3 and -8. Zinc supplementation attenuated alcoholic hepatitis and reduced the number of TUNEL-positive cells in association with inhibition of caspase activities. Ethanol exposure caused oxidative stress, as indicated by reactive oxygen species accumulation, mitochondrial glutathione depletion, and decreased metallothionein levels in the liver, which were suppressed by zinc supplementation. The mRNA levels of tumor necrosis factor (TNF)-alpha, TNF-R1, FasL, Fas, Fas-associated factor-1, and caspase-3 in the liver were upregulated by ethanol exposure, which were attenuated by zinc supplementation. Zinc supplementation also prevented ethanol-elevated serum and hepatic TNF-alpha levels and TNF-R1 and Fas proteins in the liver. In conclusion, zinc supplementation prevented hepatocyte apoptosis in mice subjected to long-term ethanol exposure, and the action of zinc is likely through suppression of oxidative stress and death receptor-mediated pathways.
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Affiliation(s)
- Zhanxiang Zhou
- The University of Louisville School of Medicine, Department of Medicine, 511 South Floyd Street, MDR Room 529, Louisville, KY 40292, USA.
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Kang X, Song Z, McClain CJ, Kang YJ, Zhou Z. Zinc supplementation enhances hepatic regeneration by preserving hepatocyte nuclear factor-4alpha in mice subjected to long-term ethanol administration. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 172:916-25. [PMID: 18349129 DOI: 10.2353/ajpath.2008.070631] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Alcoholic liver disease is associated with sustained liver damage and impaired regeneration, as well as significant zinc deficiency. This study was undertaken to examine whether dietary zinc supplementation could improve liver regeneration by increasing the expression of genes involved in hepatic cellular proliferation in a mouse model of alcoholic liver disease. Adult 129S6 mice fed an ethanol-containing liquid diet for 6 months developed alcoholic liver disease as measured by serum alanine transferase activity and histopathological changes. Zinc supplementation to ethanol-exposed mice enhanced liver regeneration as indicated by increased numbers of proliferation cell nuclear antigen (PCNA)-positive and bromodeoxyuridine (BrdU)-labeled hepatocytes. Zinc-enhanced liver regeneration was associated with an increase in hepatocyte nuclear factor-4alpha (HNF-4alpha), a liver-enriched, zinc-finger transcription factor. Studies using cultured HepG2 cells showed that zinc deficiency suppressed cell proliferation and cell proliferation-related proteins, including hepatocyte growth factor (HGF), insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 1 (IGFBP1), metallothionein (MT), and cyclin D1, as well as HNF-4alpha. HNF-4alpha gene silencing inhibited cell proliferation in association with decreased protein levels of IGF-I, IGFBP1, MT, and cyclin D1. The present study provides evidence that zinc supplementation enhances liver regeneration at least in part by HNF-4alpha through the up-regulation of cell proliferation-related proteins, suggesting that dietary zinc supplementation may have beneficial effects in alcoholic liver disease.
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Affiliation(s)
- Xinqin Kang
- Department of Medicine, University of Louisville School of Medicine, 511 South Floyd Street, Louisville, KY 40292, USA
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Ma J, Liu XY, Noh KH, Kim MJ, Song YS. Protective Effects of Persimmon Leaf and Fruit Extracts against Acute Ethanol-Induced Hepatotoxicity. Prev Nutr Food Sci 2007. [DOI: 10.3746/jfn.2007.12.4.202] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Formigari A, Irato P, Santon A. Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: biochemical and cytochemical aspects. Comp Biochem Physiol C Toxicol Pharmacol 2007; 146:443-459. [PMID: 17716951 DOI: 10.1016/j.cbpc.2007.07.010] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2007] [Revised: 07/23/2007] [Accepted: 07/25/2007] [Indexed: 11/19/2022]
Abstract
Copper, zinc and iron are essential metals for different physiological functions, even though their excess can lead to biological damage. This review provides a background of toxicity related to copper, iron and zinc excess, biological mechanisms of their homeostasis and their respective roles in the apoptotic process. The antioxidant action of metallothionein has been highlighted by summarizing the most important findings that confirm the role of zinc in cellular protection in relation to metallothionein expression and apoptotic processes. In particular, we show that a complex and efficient antioxidant system, the induction of metallothionein and the direct action of zinc have protective roles against oxidative damage and the resulting apoptosis induced by metals with redox proprieties. In addition, to emphasize the protective effects of Zn and Zn-MT in Cu and Fe-mediated oxidative stress-dependent apoptosis, some aspects of apoptotic cell death are shown. The most widely used cytochemical techniques also have been examined in order to critically evaluate the available data from a methodological point of view. The observations on the role of Zn and MT could potentially develop new applications for this metal and MT in biomedical research.
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Stamoulis I, Kouraklis G, Theocharis S. Zinc and the liver: an active interaction. Dig Dis Sci 2007; 52:1595-612. [PMID: 17415640 DOI: 10.1007/s10620-006-9462-0] [Citation(s) in RCA: 115] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2006] [Accepted: 05/19/2006] [Indexed: 02/06/2023]
Abstract
Zinc is an essential trace element, exerting important antioxidant, anti-inflammatory, and antiapoptotic effects. It affects growth and development and participates in processes such as aging and cancer induction. The liver is important for the regulation of zinc homeostasis, while zinc is necessary for proper liver function. Decreased zinc levels have been implicated in both acute and chronic liver disease states, and zinc deficiency has been implicated in the pathogenesis of liver diseases. Zinc supplementation offers protection in experimental animal models of acute and chronic liver injury, but these hepatoprotective properties have not been fully elucidated. In the present review, data on zinc homeostasis, its implication in the pathogenesis of liver diseases, and its effect on acute and chronic liver diseases are presented. It is concluded that zinc could protect against liver diseases, although up to now the underlying pathophysiology of zinc and liver interactions have not been defined.
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Affiliation(s)
- Ioannis Stamoulis
- Department of Forensic Medicine and Toxicology, University of Athens, Medical School, Goudi, Athens, Greece
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Bouaziz H, Croute F, Boudawara T, Soleilhavoup JP, Zeghal N. Oxidative stress induced by fluoride in adult mice and their suckling pups. ACTA ACUST UNITED AC 2007; 58:339-49. [PMID: 17270411 DOI: 10.1016/j.etp.2006.11.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2006] [Accepted: 11/13/2006] [Indexed: 02/04/2023]
Abstract
To assess renal and liver damages in pregnant and lactating mice as well as in their suckling pups, Wistar female mice were given 500 ppm NaF (226 ppm F-) in drinking water from the 15th day of pregnancy until day 14 after delivery. All mice were sacrificed on day 14 after parturition. In the present work, we evaluated the effects of sodium fluoride on histopathological aspects of kidney, antioxidant status, lipid peroxidation levels and on the expression of four stress proteins (namely, the cytosolic heat shock proteins: HSP72, 73, 90 and the reticulum-associated GRP94). Histological studies have shown many abnormalities in mothers and their pups. Biochemical results showed that lipid peroxidation increased in NaF-treated mice, as evidenced by high kidney and liver thiobarbituric acid reactive substance (TBARS) levels. Alteration of the antioxidant system was confirmed by the significant decline of serum total antioxidant status and of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in red blood cells. Besides, fluoride treatment induced a decrease in serum levels of non-enzymatic antioxidants such as uric acid and of some oligoelements: zinc and copper, known to be cofactors of superoxide dismutase (SOD-Cu-Zn). Compared to control group, the 72kDa protein was found to be overexpressed in kidney of 14-day-old mice only. HSP90 expression in liver appeared moderately inhibited in mothers, but decreased significantly in their pups. No significant changes were detected in the expression of 94kDa protein in both liver and kidney. Results showed that fluoride given to dams led to an oxidative stress in mothers as well as in offspring able to induce enhanced lipid peroxidation levels and protein conformational changes, as suggested by stress protein (HSP, GRP) expression changes.
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Affiliation(s)
- Hanen Bouaziz
- Laboratoire de Physiologie Animale, Département des Sciences de la Vie, Faculté des Sciences de Sfax, Route de la Soukra-Km 3.5, BP 802, 3018 Sfax, Tunisia
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Abstract
The biologic function of metallothionein (MT) has been a perplexing topic ever since the discovery of this protein. Many studies have suggested that MT plays a role in the homeostasis of essential metals such as zinc and copper, detoxification of toxic metals such as cadmium, and protection against oxidative stress. However, mechanistic insights into the actions of MT have not been adequately achieved. MT contains high levels of sulfur. The mutual affinity of sulfur and transition metals makes the binding of these metals to MT thermodynamically stable. Under physiologic conditions, zinc-MT is the predominant form of the metal-binding protein. The recognition of the redox regulation of zinc release from or binding to MT provides an alternate perspective on biologic function of MT. Oxidation of the thiolate cluster by a number of mild cellular oxidants causes zinc release and formation of MT-disulfide (or thionin if all metals are released from MT, but this is unlikely to occur in vivo), which have been demonstrated in vivo. Therefore, the thermodynamic stability of zinc binding makes MT an ideal zinc reservoir in vivo, and the redox regulation of zinc mobilization enables MT function in zinc homeostasis. MT-disulfide can be reduced by glutathione in the presence of selenium catalyst, restoring the capacity of the protein to bind zinc. This MT redox cycle may play a crucial role in MT biologic function. It may link to the homeostasis of essential metals, detoxification of toxic metals and protection against oxidative stress.
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Affiliation(s)
- Y James Kang
- Department of Medicine, University of Louisville School of Medicine, 511 S. Floyd Street, MDR 530, Louisville, KY 40202, USA.
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Shankar K, Hidestrand M, Liu X, Xiao R, Skinner CM, Simmen FA, Badger TM, Ronis MJJ. Physiologic and genomic analyses of nutrition-ethanol interactions during gestation: Implications for fetal ethanol toxicity. Exp Biol Med (Maywood) 2006; 231:1379-97. [PMID: 16946407 DOI: 10.1177/153537020623100812] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Nutrition-ethanol (EtOH) interactions during gestation remain unclear primarily due to the lack of appropriate rodent models. In the present report we utilize total enteral nutrition (TEN) to specifically understand the roles of nutrition and caloric intake in EtOH-induced fetal toxicity. Time-impregnated rats were intragastrically fed either control or diets containing EtOH (8-14 g/kg/day) at a recommended caloric intake for pregnant rats or rats 30% undernourished, from gestation day (GD) 6-20. Decreased fetal weight and litter size (P < 0.05) and increased full litter resorptions (33% vs. 0%), were observed in undernourished dams compared to adequately fed rats given the same dose of EtOH, while undernutrition alone did not produce any fetal toxicity. Undernutrition led to impairment of EtOH metabolism, increased blood EtOH concentrations (160%), and decreased maternal hepatic ADH1 mRNA, protein, and activity. Microarray analyses of maternal hepatic gene expression on GD15 revealed that 369 genes were altered by EtOH in the presence of undernutrition, as compared to only 37 genes by EtOH per se (+/-2-fold, P < 0.05). Hierarchical clustering and gene ontology analysis revealed that stress and external stimulus responses, transcriptional regulation, cellular homeostasis, and protein metabolism were affected uniquely in the EtOH-under-nutrition group, but not by EtOH alone. Microarray data were confirmed using real-time RT-PCR. Undernourished EtOH-fed animals had 2-fold lower IGF-1 mRNA and 10-fold lower serum IGF-1 protein levels compared to undernourished controls (P < 0.0005). Examination of maternal GH signaling via STAT5a and -5b revealed significant reduction in both gene and protein expression produced by both EtOH and undernutrition. However, despite significantly elevated fetal BECs, fetal IGF-1 mRNA and protein were not affected by EtOH or EtOH-undernutrition combinations. Our data suggest that undernutrition potentiates the fetal toxicity of EtOH in part by disrupting maternal GH-IGF-1, signaling thereby decreasing maternal uterine capacity and placental growth.
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Affiliation(s)
- Kartik Shankar
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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Bolkent S, Arda-Pirincci P, Bolkent S, Yanardag R, Tunali S, Yildirim S. Influence of zinc sulfate intake on acute ethanol-induced liver injury in rats. World J Gastroenterol 2006; 12:4345-51. [PMID: 16865776 PMCID: PMC4087745 DOI: 10.3748/wjg.v12.i27.4345] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of metallothionein and proliferating cell nuclear antigen (PCNA) on the morphological and biochemical effects of zinc sulfate in ethanol-induced liver injury.
METHODS: Wistar albino rats were divided into four groups. Group I; intact rats, group II; control rats given only zinc, group III; animals given absolute ethanol, group IV; rats given zinc and absolute ethanol. Ethanol-induced injury was produced by the 1 mL of absolute ethanol, administrated by gavage technique to each rat. Animals received 100 mg/kg per day zinc sulfate for 3 d 2 h prior to the administration of absolute ethanol.
RESULTS: Increases in metallothionein immunoreactivity in control rats given only zinc and rats given zinc and ethanol were observed. PCNA immunohistochemistry showed that the number of PCNA-positive hepatocytes was increased significantly in the livers of rats administered ethanol + zinc sulfate. Acute ethanol exposure caused degenerative morphological changes in the liver. Blood glutathione levels decreased, serum alkaline phosphatase and aspartate transaminase activities increased in the ethanol group when compared to the control group. Liver glutathione levels were reduced, but lipid peroxidation increased in the livers of the group administered ethanol as compared to the other groups. Administration of zinc sulfate in the ethanol group caused a significant decrease in degenerative changes, lipid peroxidation, and alkaline phosphatase and aspartate transaminase activities, but an increase in liver glutathione.
CONCLUSION: Zinc sulfate has a protective effect on ethanol-induced liver injury. In addition, cell proliferation may be related to the increase in metallothionein immunoreactivity in the livers of rats administered ethanol + zinc sulfate.
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Affiliation(s)
- Sema Bolkent
- Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University, Cerrahpasa 34098, Istanbul, Turkey.
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Pawa S, Ali S. Boron ameliorates fulminant hepatic failure by counteracting the changes associated with the oxidative stress. Chem Biol Interact 2006; 160:89-98. [PMID: 16442087 DOI: 10.1016/j.cbi.2005.12.002] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2005] [Revised: 11/30/2005] [Accepted: 12/05/2005] [Indexed: 11/29/2022]
Abstract
Boron has well-defined biological effects and may be of therapeutic benefit. In the current paper, the effect of boron in the form of borax was tested in experimental animal model of fulminant hepatic failure (FHF). The syndrome was induced in female Wistar rats by three consecutive daily intraperitoneal injections of thioacetamide (400 mg/kg). In the treatment groups, rats received borax (4.0 mg/kg) orally for three consecutive days followed by thioacetamide. The group administered with thioacetamide plus vehicle, and the borax alone treated rats served as controls. In all groups, rats were terminated 4 h after administering the last dose of thioacetamide, and the tissue/serum was used to measure hepatic levels of thiobarbituric acid reactive substances, reduced glutathione, and various enzymes associated with oxidative stress including peroxide metabolizing enzymes and xanthine oxidase. In thioacetamide treated group, many fold increase in the activity level of serum marker enzymes suggesting FHF was observed that could be brought down significantly in rats receiving boron. Modulation and a correlation in the activity level of oxidant generating enzyme and lipid peroxidation as well as hepatic glutathione level was also observed in rats receiving thioacetamide. In the group receiving boron followed by thioacetamide, these changes could be minimized moderately. The activity level of the peroxide metabolizing enzymes and the tripeptide glutathione, which decreased following thioacetamide treatment were moderately elevated in the group receiving boron followed by thioacetamide. The data clearly shows that borax partly normalizes the liver and offsets the deleterious effects observed in FHF by modulating the oxidative stress parameters.
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Affiliation(s)
- Sonica Pawa
- Department of Biochemistry, Faculty of Science, Jamia Hamdard, Hamdard University, Hamdard Nagar, New Delhi 1100 62, India
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Abstract
Alcoholic liver disease (ALD) is associated with decreases in zinc (Zn) and its major binding protein, metallothionein (MT), in the liver. Studies using animal models have shown that Zn supplementation prevents alcohol-induced liver injury under both acute and chronic alcohol exposure conditions. There are hepatic and extrahepatic actions of Zn in the prevention of alcoholic liver injury. Zn supplementation attenuates ethanol-induced hepatic Zn depletion and suppresses ethanol-elevated cytochrome P450 2E1 (CYP2E1) activity, but increases the activity of alcohol dehydrogenase in the liver; an action that is likely responsible for Zn suppression of alcohol-induced oxidative stress. Zn also enhances glutathione-related antioxidant capacity in the liver. At the cellular level, Zn inhibits alcohol-induced hepatic apoptosis partially through suppression of the Fas/FasL-mediated pathway. Zn supplementation preserves intestinal integrity and prevents endotoxemia, leading to inhibition of endotoxin-induced tumor necrosis factor-alpha (TNF-alpha) production in the liver. Zn also directly inhibits the signaling pathway involved in endotoxin-induced TNF-alpha production. These hepatic and extrahepatic effects of Zn are independent of MT. However, low levels of MT in the liver sensitize the organ to alcohol-induced injury, and elevation of MT enhances the endogenous Zn reservoir and makes Zn available when oxidative stress is imposed. Zn has a high potential to be developed as an effective agent in the prevention and treatment of ALD.
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Affiliation(s)
- Y James Kang
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA.
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Szuster-Ciesielska A, Daniluk J, Bojarska-Junak A. Apoptosis of blood mononuclear cells in alcoholic liver cirrhosis. The influence of in vitro ethanol treatment and zinc supplementation. Toxicology 2005; 212:124-34. [PMID: 15964121 DOI: 10.1016/j.tox.2005.04.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2005] [Revised: 03/21/2005] [Accepted: 04/21/2005] [Indexed: 01/15/2023]
Abstract
Ethanol consumption induces apoptosis in a variety of tissues, among others in liver and lymphoid tissue. Zinc has been shown to influence apoptosis of blood mononuclear cells by inhibiting the mitochondrial pathway of cell death. The aim of this study was to examine the influence of zinc on spontaneous and in vitro alcohol-induced apoptosis of peripheral blood mononuclear cells (PBMCs) of patients with alcoholic cirrhosis. PBMCs were isolated from the blood of 26 patients with cirrhosis and 20 healthy controls. PBMCs and among them CD4+ T helper cells of cirrhotic patients exhibited accelerated spontaneous (without treatment) apoptosis in vitro. When apoptosis was induced in vitro by treating cells with 80 mM ethanol, CD8+ T lymphocytes of a healthy control were more sensitive to ethanol treatment than those of cirrhotic patients. Thirty micromolar zinc supplementation inhibited both spontaneous and ethanol-induced apoptosis of immune cells derived from the blood of the healthy control and cirrhotic patients. In sera of patients with cirrhosis, an elevated level of IL-12, but also sFas (CD95) and sFas ligand (sFasL) was detected. Moreover, in vitro, PBMCs of cirrhotic patients spontaneously released more sFas and sFasL than control PBMCs. Ethanol treatment significantly increased sFas, but decreased sFasL release from PBMCs of cirrhotic patients, while it only slightly affected control cells. As zinc supplementation did not significantly influence sFas or sFasL release, it seems likely that it is rather the mitochondrial pathway of ethanol-related immune cell death that may be inhibited by zinc supplementation.
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Zhou Z, Wang L, Song Z, Saari JT, McClain CJ, Kang YJ. Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 166:1681-90. [PMID: 15920153 PMCID: PMC1602418 DOI: 10.1016/s0002-9440(10)62478-9] [Citation(s) in RCA: 141] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Alcoholic liver disease is associated with zinc decrease in the liver. Therefore, we examined whether dietary zinc supplementation could provide protection from alcoholic liver injury. Metallothionein-knockout and wild-type 129/Sv mice were pair-fed an ethanol-containing liquid diet for 12 weeks, and the effects of zinc supplementation on ethanol-induced liver injury were analyzed. Zinc supplementation attenuated ethanol-induced hepatic zinc depletion and liver injury as measured by histopathological and ultrastructural changes, serum alanine transferase activity, and hepatic tumor necrosis factor-alpha in both metallothionein-knockout and wild-type mice, indicating a metallothionein-independent zinc protection. Zinc supplementation inhibited accumulation of reactive oxygen species, as indicated by dihydroethidium fluorescence, and the consequent oxidative damage, as assessed by immunohistochemical detection of 4-hydroxynonenal and nitrotyrosine and quantitative analysis of malondialdehyde and protein carbonyl in the liver. Zinc supplementation suppressed ethanol-elevated cytochrome P450 2E1 activity but increased the activity of alcohol dehydrogenase in the liver, without affecting the rate of blood ethanol elimination. Zinc supplementation also prevented ethanol-induced decreases in glutathione concentration and glutathione peroxidase activity and increased glutathione reductase activity in the liver. In conclusion, zinc supplementation prevents alcoholic liver injury in an metallothionein-independent manner by inhibiting the generation of reactive oxygen species (P450 2E1) and enhancing the activity of antioxidant pathways.
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Affiliation(s)
- Zhanxiang Zhou
- University of Louisville School of Medicine, Department of Medicine, 511 South Floyd St., MDR 529, Louisville, KY 40292, USA.
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Min KS, Morishita F, Tetsuchikawahara N, Onosaka S. Induction of hepatic and renal metallothionein synthesis by ferric nitrilotriacetate in mice: the role of MT as an antioxidant. Toxicol Appl Pharmacol 2005; 204:9-17. [PMID: 15781289 DOI: 10.1016/j.taap.2004.08.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2004] [Accepted: 08/17/2004] [Indexed: 11/29/2022]
Abstract
Metallothionein (MT) demonstrates strong antioxidant properties, yet the physiological relevance of its antioxidant action is not clear. Injection of mice with ferric nitrilotriacetate (Fe-NTA) caused a dose-dependent increase in hepatic and renal MT. Fe-NTA caused a greater increase in hepatic and renal MT concentration (2.5- and 4-fold) compared with FeCl(3) at the same dose of ferric ion. MT mRNA levels were markedly elevated in both of tissues. Thiobarbituric acid (TBA) values in both tissues reached a maximum after 2-4 h. The MT concentrations were significantly increased after 2-4 h in liver and after 8-16 h in kidneys. Plasma concentrations of cytokines such as IL-6 and TNFalpha were elevated by 4 h; IL-6 levels were 24 times higher after Fe-NTA than that after injection of FeCl(3). Pretreatment of mice with ZnSO(4) attenuated nephrotoxicity induced by Fe-NTA after 2 h, but was not effective 4 h after injection. After a Fe-NTA injection, a loss of Cd-binding properties of preinduced MT was observed only in kidneys of Zn-pretreated mice but not in liver. Treatment with BSO, glutathione (GSH) depletor, intensified a loss of its Cd-binding properties after a Fe-NTA injection. These results indicate that induction of MT synthesis may result from reactive oxygen species (ROS) generated by Fe-NTA, and MT may act in vivo as a complementary antioxidant.
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Affiliation(s)
- Kyong-Son Min
- Faculty of Nutrition, Kobe Gakuin University, Ikawadani-cho, Kobe, 651-2180, Japan.
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Pani G, Fusco S, Colavitti R, Borrello S, Maggiano N, Cravero AAM, Farré SM, Galeotti T, Koch OR. Abrogation of hepatocyte apoptosis and early appearance of liver dysplasia in ethanol-fed p53-deficient mice. Biochem Biophys Res Commun 2005; 325:97-100. [PMID: 15522206 DOI: 10.1016/j.bbrc.2004.09.213] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2004] [Indexed: 12/23/2022]
Abstract
Ethanol consumption represents a major risk factor for cancer development, and a significant fraction of hepatocarcinomas arises in alcoholic liver cirrhosis. Increasing evidence indicates that ethanol acts as a tumor promoter on genetically initiated cells, by increasing the intracellular concentration of reactive oxygen species and promoting tissue necrosis/regeneration and cell proliferation. The tumor suppressor p53 restrains the expansion of carcinogen-initiated cells by inducing cell cycle arrest and apoptosis; accordingly, p53-deficient mice develop spontaneous and chemically induced neoplasms at a much higher frequency than normal mice. In normal mice exposed to a subacute (3 weeks) ethanol intoxication, a significant increase in the number of apoptotic hepatocytes was observed in concomitance with the up-regulation of the mitochondrial superoxide scavenger MnSOD, a reliable indicator of oxidative stress. Cell death occurred in the absence of liver inflammation and necrosis. Ethanol-induced hepatocyte apoptosis was completely abrogated in the p53 null background, suggesting that the tumor suppressor is necessary for hepatocyte death by ethanol. Accordingly, p53 -/- MEF were, unlike wild type cells, completely insensitive up to 0.5M ethanol in the culture medium. Strikingly, marked and widespread signs of dysplasia, with nuclear pleomorphisms and initial loss of normal architecture, heralding malignant transformation, were scored in all the mutant mice exposed to ethanol, but not in the control-fed littermates nor in ethanol-fed normal mice. These observations suggest that p53-dependent apoptosis restrains the tumorigenic effect of ethanol on liver cells, in agreement with the frequent loss of p53 function in HCC, and reveal an unexpected carcinogenic potential of alcohol which appears to be independent from the induction of cirrhosis and hepatocyte regeneration.
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Affiliation(s)
- Giovambattista Pani
- Institute of General Pathology, Catholic University Medical School, Rome, Italy.
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Tetsuchikawahara N, Min KS, Onosaka S. Attenuation of Zinc-Induced Acute Pancreatitis by Zinc Pretreatment: Dependence on Induction of Metallothionein Synthesis. ACTA ACUST UNITED AC 2005. [DOI: 10.1248/jhs.51.379] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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