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Bellamy CO, Burt AD. Liver in Systemic Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1039-1095. [DOI: 10.1016/b978-0-7020-8228-3.00015-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Lee YM, Kim KS, Jacobs DR, Lee DH. Persistent organic pollutants in adipose tissue should be considered in obesity research. Obes Rev 2017; 18:129-139. [PMID: 27911986 DOI: 10.1111/obr.12481] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 09/23/2016] [Accepted: 09/28/2016] [Indexed: 12/22/2022]
Abstract
Although low doses of persistent organic pollutants (POPs), strong lipophilic chemicals with long half-lives, have been linked to various endocrine, immune, nervous and reproductive system diseases, few obesity studies have considered adipose tissue as an important POPs exposure source. Because the toxicodynamics of POPs relate directly to the dynamics of adiposity, POPs might explain puzzling findings in obesity research. In two people exposed to the same amounts of environmental POPs, the one having more adipose tissue may be advantaged because POPs storage in adipose tissue can reduce burden on other critical organs. Therefore, adipose tissue can play a protective role against the POPs effects. However, two situations increase the POPs release from adipose tissue into the circulation, thereby increasing the risk that they will reach critical organs: (i) weight loss and (ii) insulin resistance. In contrast, weight gain reduces this possibility. Therefore, avoiding harmful health effects of POPs may mostly contradict conventional judgments about obesity and weight change. These contradictory situations can explain the obesity paradox, the adverse effects of intensive intentional weight loss and the protective effects of obesity against dementia. Future studies should consider that adipose tissue is widely contaminated with POPs in modern society.
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Affiliation(s)
- Y-M Lee
- Department of Preventative Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - K-S Kim
- Department of Preventative Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - D R Jacobs
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
| | - D-H Lee
- Department of Preventative Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.,BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Korea
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Verhaag EM, Buist-Homan M, Koehorst M, Groen AK, Moshage H, Faber KN. Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity. PLoS One 2016; 11:e0149782. [PMID: 26950211 PMCID: PMC4780766 DOI: 10.1371/journal.pone.0149782] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 02/04/2016] [Indexed: 12/15/2022] Open
Abstract
Introduction Cholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be explained by a hormetic response in hepatocytes that limits cell death during cholestasis. Aim To investigate the mechanisms that underlie the hormetic response that protect hepatocytes against experimental cholestatic conditions. Methods HepG2.rNtcp cells were preconditioned (24 h) with sub-apoptotic concentrations (0.1–50 μM) of various bile acids, the superoxide donor menadione, TNF-α or the Farsenoid X Receptor agonist GW4064, followed by a challenge with the apoptosis-inducing bile acid glycochenodeoxycholic acid (GCDCA; 200 μM for 4 h), menadione (50 μM, 6 h) or cytokine mixture (CM; 6 h). Levels of apoptotic and necrotic cell death, mRNA expression of the bile salt export pump (ABCB11) and bile acid sensors, as well as intracellular GCDCA levels were analyzed. Results Preconditioning with the pro-apoptotic bile acids GCDCA, taurocholic acid, or the protective bile acids (tauro)ursodeoxycholic acid reduced GCDCA-induced caspase-3/7 activity in HepG2.rNtcp cells. Bile acid preconditioning did not induce significant levels of necrosis in GCDCA-challenged HepG2.rNtcp cells. In contrast, preconditioning with cholic acid, menadione or TNF-α potentiated GCDCA-induced apoptosis. GCDCA preconditioning specifically reduced GCDCA-induced cell death and not CM- or menadione-induced apoptosis. The hormetic effect of GCDCA preconditioning was concentration- and time-dependent. GCDCA-, CDCA- and GW4064- preconditioning enhanced ABCB11 mRNA levels, but in contrast to the bile acids, GW4064 did not significantly reduce GCDCA-induced caspase-3/7 activity. The GCDCA challenge strongly increased intracellular levels of this bile acid, which was not lowered by GCDCA-preconditioning. Conclusions Sub-toxic concentrations of bile acids in the range that occur under normal physiological conditions protect HepG2.rNtcp cells against GCDCA-induced apoptosis, which is independent of FXR-controlled changes in bile acid transport.
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Affiliation(s)
- Esther M. Verhaag
- Department of Gastroenterology and Hepatology, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Manon Buist-Homan
- Department of Gastroenterology and Hepatology, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Martijn Koehorst
- Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Albert K. Groen
- Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- * E-mail:
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Chen Z, Ma X, Zhao Y, Wang J, Zhang Y, Li J, Wang R, Zhu Y, Wang L, Xiao X. Yinchenhao decoction in the treatment of cholestasis: A systematic review and meta-analysis. JOURNAL OF ETHNOPHARMACOLOGY 2015; 168:208-216. [PMID: 25849734 DOI: 10.1016/j.jep.2015.03.058] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 03/26/2015] [Accepted: 03/28/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Yinchenhao decoction, a well-known Chinese herbal formula, has been widely used in Chinese Medicine for thousands of years. However, no systematic review of Yinchenhao decoction in treating cholestasis has been completed. This study aims to evaluate the efficacy and safety of the Yinchenhao decoction in treating cholestasis. MATERIALS AND METHODS The major databases (PubMed, Embase, Cochrane Library, Chinese Biomedical Database, Wanfang database, VIP medicine information system and China National Knowledge Infrastructure) were searched from the databases' inception through November 2014. Randomized controlled trials (RCTs) of Yinchenhao decoction reported in publications for treatment of cholestasis were extracted by two reviewers. The RCTs examined included total efficacy rate and biochemical indices including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL). The Cochrane tool was applied to assess the risk of bias of the trials. The main outcomes of the trials were analyzed using Review Manager 5.3 software. The odds ratio (OR) or mean difference (MD) with a 95% confidence interval (CI) was used to measure the effect. RESULTS Among the 698 studies identified in the literature search, 15 studies involving 1405 subjects with cholestasis were included in the analysis. Yinchenhao decoction demonstrated efficacy in cholestasis treatment whether in a combined application or not. Additionally, the decoction significantly reduced the elevated levels of cholestasis serum markers, such as ALT, AST, TBIL and DBIL, with a significant difference observed in short and long curative time periods. Remarkably, Yinchenhao decoction displayed a significant efficacy in treating the long-term disease. CONCLUSION No serious adverse event was reported. This meta-analysis provides evidence that Yinchenhao decoction is an effective and safe treatment for cholestasis.
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Affiliation(s)
- Zhe Chen
- China Military Institute of Chinese Medicine, Chengdu 611137, China; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiao Ma
- China Military Institute of Chinese Medicine, Chengdu 611137, China; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yanling Zhao
- China Military Institute of Chinese Medicine, Chengdu 611137, China.
| | - Jiabo Wang
- China Military Institute of Chinese Medicine, Chengdu 611137, China
| | - Yaming Zhang
- China Military Institute of Chinese Medicine, Chengdu 611137, China
| | - Jianyu Li
- Department of Integrative Medical Center, 302 Military Hospital of China, Beijing 100039, China
| | - Ruilin Wang
- Department of Integrative Medical Center, 302 Military Hospital of China, Beijing 100039, China
| | - Yun Zhu
- Department of Integrative Medical Center, 302 Military Hospital of China, Beijing 100039, China
| | - Lifu Wang
- Department of Integrative Medical Center, 302 Military Hospital of China, Beijing 100039, China
| | - Xiaohe Xiao
- China Military Institute of Chinese Medicine, Chengdu 611137, China.
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Aktas C, Kanter M, Erboga M, Mete R, Oran M. Melatonin attenuates oxidative stress, liver damage and hepatocyte apoptosis after bile-duct ligation in rats. Toxicol Ind Health 2012; 30:835-44. [PMID: 23095487 DOI: 10.1177/0748233712464811] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The goal of this study was to evaluate the possible protective effects of melatonin against cholestatic oxidative stress, liver damage and hepatocyte apoptosis in the common rats with bile duct ligation (BDL). A total of 24 male Wistar albino rats were divided into three groups: control, BDL and BDL + received melatonin; each group contains eight animals. Melatonin-treated BDL rats received daily melatonin 100 mg/kg/day via intraperitoneal injection. The application of BDL clearly increased the malondialdehyde (MDA) levels and decreased the superoxide dismutase (SOD) and glutathione (GSH) activities. Melatonin treatment significantly decreased the elevated tissue MDA levels and increased the reduced SOD and GSH enzyme levels in the tissues. The changes demonstrate that the bile duct proliferation and fibrosis in expanded portal tracts include the extension of proliferated bile ducts into lobules, mononuclear cells and neutrophil infiltration into the widened portal areas as observed in the BDL group. The data indicate that melatonin attenuates BDL-induced cholestatic liver injury, bile duct proliferation and fibrosis. The α-smooth muscle actin (α-SMA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the BDL were observed to be reduced with the melatonin treatment. These results suggest that administration of melatonin is a potentially beneficial agent to reduce liver damage in BDL by decreasing oxidative stress.
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Affiliation(s)
- Cevat Aktas
- Department of Histology and Embryology, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey
| | - Mehmet Kanter
- Department of Histology and Embryology, Faculty of Medicine, Medeniyet University, Istanbul, Turkey
| | - Mustafa Erboga
- Department of Histology and Embryology, Faculty of Medicine, University of Trakya, Edirne, Turkey
| | - Rafet Mete
- Department of Gastroenterology, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey
| | - Mustafa Oran
- Department of Internal Diseases, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey
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Quaglia A, Burt AD, Ferrell LD, Portmann BC. Systemic disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:935-986. [DOI: 10.1016/b978-0-7020-3398-8.00016-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 178:175-86. [PMID: 21224055 DOI: 10.1016/j.ajpath.2010.11.026] [Citation(s) in RCA: 376] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2010] [Revised: 08/16/2010] [Accepted: 09/02/2010] [Indexed: 02/06/2023]
Abstract
Inflammation contributes to liver injury during cholestasis. The mechanism by which cholestasis initiates an inflammatory response in the liver, however, is not known. Two hypotheses were investigated in the present studies. First, activation of Toll-like receptor 4 (TLR4), either by bacterial lipopolysaccharide or by damage-associated molecular pattern molecules released from dead hepatocytes, triggers an inflammatory response. Second, bile acids act as inflammagens, and directly activate signaling pathways in hepatocytes that stimulate production of proinflammatory mediators. Liver inflammation was not affected in lipopolysaccharide-resistant C3H/HeJ mice after bile duct ligation, indicating that Toll-like receptor 4 is not required for initiation of inflammation. Treatment of hepatocytes with bile acids did not directly cause cell toxicity but increased the expression of numerous proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and other proteins that influence immune cell levels and function. Up-regulation of several of these genes in hepatocytes and in the liver after bile duct ligation required early growth response factor-1, but not farnesoid X receptor. In addition, early growth response factor-1 was up-regulated in the livers of patients with cholestasis and correlated with levels of inflammatory mediators. These data demonstrate that Toll-like receptor 4 is not required for the initiation of acute inflammation during cholestasis. In contrast, bile acids directly activate a signaling network in hepatocytes that promotes hepatic inflammation during cholestasis.
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Froh M, Zhong Z, Walbrun P, Lehnert M, Netter S, Wiest R, Conzelmann L, Gäbele E, Hellerbrand C, Schölmerich J, Thurman RG. Dietary glycine blunts liver injury after bile duct ligation in rats. World J Gastroenterol 2008; 14:5996-6003. [PMID: 18932277 PMCID: PMC2760179 DOI: 10.3748/wjg.14.5996] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of (dietary) glycine against oxidant-induced injury caused by bile duct ligation (BDL).
METHODS: Either a diet containing 5% glycine or a standard diet was fed to male Sprague-Dawley (SD) rats. Three days later, BDL or sham-operation was performed. Rats were sacrificed 1 to 3 d after BDL. The influence of deoxycholic acid (DCA) in the presence or absence of glycine on liver cells was determined by measurement of calcium and chloride influx in cultivated Kupffer cells and lactate dehydrogenase (LDH) activity was determined in the supernatant of cultivated hepatocytes.
RESULTS: Serum alanine transaminase levels increased to about 600 U/L 1 d after BDL. However, enzyme release was blunted by about two third in rats receiving glycine. Release of the alkaline phosphatase and aspartate aminotransferase was also blocked significantly in the group fed glycine. Focal necrosis was observed 2 d after BDL. Glycine partially blocked the histopathological changes. Incubation of Kupffer cells with DCA led to increased intracellular calcium that could be blocked by incubation with glycine. However, systemic blockage of Kupffer cells with gadolinium chloride had no effects on transaminase release. Incubation of isolated hepatocytes with DCA led to a significant release of LDH after 4 h. This release was largely blocked when incubation with glycine was performed.
CONCLUSION: These data indicate that glycine significantly decreased liver injury, most likely by a direct effect on hepatocytes. Kupffer cells do not appear to play an important role in the pathological changes caused by cholestasis.
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Froh M, Conzelmann L, Walbrun P, Netter S, Wiest R, Wheeler MD, Lehnert M, Uesugi T, Scholmerich J, Thurman RG. Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats. World J Gastroenterol 2007; 13:3478-86. [PMID: 17659695 PMCID: PMC4146784 DOI: 10.3748/wjg.v13.i25.3478] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [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 effects of heme oxygenase-1 (HO-1) against oxidant-induced injury caused by bile duct ligation (BDL).
METHODS: Either cobalt protoporphyrin (CoPP), a HO-1 inducer, or saline were injected intraperitoneally in male SD-rats. Three days later, BDL or sham-operations were performed. Rats were sacrificed 3 wk after BDL and livers were harvested for histology. Fibrosis was evaluated by sirius red staining and image analysis. Alpha-smooth muscular actin, which indicates activation of stellate cells, was detected by immunohistochemical staining, and cytokine and collagen-Iα (Col-Iα) mRNA expression was detected using RNase protection assays.
RESULTS: Serum alanine transaminase increased 8-fold above normal levels one day after BDL. Surprisingly, enzyme release was not reduced in rats receiving CoPP. Liver fibrosis was evaluated 3 wk after BDL and the sirius red-positive area was found to be increased to about 7.8%. However, in CoPP pretreated rats sirius red-positive areas were increased to about 11.7% after BDL. Collagen-Iα and TGF-β mRNA increased significantly by BDL. Again, this effect was increased by HO-1 overexpression.
CONCLUSION: Hepatic fibrosis due to BDL is not reduced by the HO-1 inducer CoPP. In contrast, HO-1 overexpression increases liver injury in rats under conditions of experimental chronic cholestasis.
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Affiliation(s)
- Matthias Froh
- Department of Internal Medicine, University of Regensburg, Regensburg 93042, Germany.
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Dulundu E, Ozel Y, Topaloglu U, Toklu H, Ercan F, Gedik N, Sener G. Grape seed extract reduces oxidative stress and fibrosis in experimental biliary obstruction. J Gastroenterol Hepatol 2007; 22:885-92. [PMID: 17565645 DOI: 10.1111/j.1440-1746.2007.04875.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM The aim of this study was to assess the protective effect of grape seed extract (GSE) against oxidative liver injury and fibrosis induced by biliary obstruction in rats. METHODS Wistar albino rats were divided into four groups; control (C), GSE-treated, bile duct ligated (BDL), and BDL and GSE-treated (BDL + GSE) groups. GSE was administered at a dose of 50 mg/kg a day orally for 28 days. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels were determined to assess liver function and tissue damage, respectively. Tumor necrosis factor-alpha (TNF-alpha) and antioxidant capacity (AOC) were assayed in plasma samples. Liver tissues were taken for determination of the hepatic malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content. Production of reactive oxidants was monitored by chemiluminescence (CL) assay. RESULTS Serum AST, ALT, LDH and plasma TNF-alpha were elevated in the BDL group as compared to the control group and were significantly decreased with GSE treatment. Plasma AOC and hepatic GSH level, depressed by BDL, was elevated back to the control level in the GSE-treated BDL group. Increases in tissue MDA level, MPO activity and collagen content due to BDL were also attenuated by GSE treatment. Furthermore, luminol and lucigenin CL values in the BDL group increased dramatically compared to the control and were reduced by GSE treatment. DISCUSSION These results suggest that GSE protects the liver from oxidative damage following bile duct ligation in rats. This effect possibly involves the inhibition of neutrophil infiltration and lipid peroxidation; thus, restoration of oxidant and antioxidant status in the tissue.
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Affiliation(s)
- Ender Dulundu
- Department of Fifth Surgery, Haydarpasa Numune Education and Research Hospital, Istanbul, Turkey
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Sener G, Sehirli AO, Toklu HZ, Yuksel M, Ercan F, Gedik N. Erdosteine treatment attenuates oxidative stress and fibrosis in experimental biliary obstruction. Pediatr Surg Int 2007; 23:233-41. [PMID: 17216233 DOI: 10.1007/s00383-006-1872-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/11/2006] [Indexed: 12/20/2022]
Abstract
Oxidative stress, in particular lipid peroxidation, induces collagen synthesis and causes fibrosis. The aim of this study was to assess the antioxidant and antifibrotic effects of erdosteine on liver fibrosis induced by biliary obstruction in rats. Liver fibrosis was induced in Wistar albino rats by bile duct ligation (BDL). Erdosteine (10 mg/kg, orally) or saline was administered for 28 days. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels were determined to assess liver functions and tissue damage, respectively. Pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6 and antioxidant capacity (AOC) were assayed in plasma samples. Liver tissues were taken for determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content. Production of reactive oxidants was monitored by chemiluminescence assay. Serum AST, ALT, LDH, and plasma cytokines were elevated in the BDL group as compared to controls and were significantly decreased by erdosteine treatment. Hepatic GSH level and plasma AOC, depressed by BDL, were elevated back to control level with erdosteine treatment. Furthermore, hepatic luminol and lucigenin chemiluminescence (CL), MDA level, MPO activity and collagen content in BDL group increased dramatically compared to control and reduced by erdosteine treatment. Since erdosteine administration alleviated the BDL-induced oxidative injury of the liver and improved the hepatic functions, it seems likely that erdosteine with its antioxidant and antifibrotic properties, may be of potential therapeutic value in protecting the liver fibrosis and oxidative injury due to biliary obstruction.
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Affiliation(s)
- Göksel Sener
- School of Pharmacy, Department of Pharmacology, Marmara University, Tibbiye Cad, 34668, Istanbul, Turkey.
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The Liver in Systemic Illness. ZAKIM AND BOYER'S HEPATOLOGY 2006. [PMCID: PMC7155679 DOI: 10.1016/b978-1-4160-3258-8.50061-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Blaszyk H, Wild PJ, Oliveira A, Kelly DG, Burgart LJ. Hepatic copper in patients receiving long-term total parenteral nutrition. J Clin Gastroenterol 2005; 39:318-20. [PMID: 15758626 DOI: 10.1097/01.mcg.0000155135.35315.05] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
GOALS To assess the possibility of iatrogenic hepatic copper overload in adult patients on long-term total parenteral nutrition (TPN). BACKGROUND TPN predisposes to hepatic copper accumulation through disturbances of the enterohepatic bile acid pool, but iatrogenic copper overload through TPN solutions may occur as well. STUDY Quantitative hepatic copper and multiple clinical, biochemical, and histopathologic parameters were compared between patients with long-term TPN associated liver disease (n = 28) and patients with drug-induced cholestatic liver disease (n = 10). RESULTS Eighty-nine percent of TPN patients and all controls had mildly elevated hepatic tissue copper, but 29% of TPN patients had levels above the diagnostic threshold for Wilson's disease. Quantitative hepatic copper correlated positively with serum aspartate aminotransferase (P = 0.001, r = 0.59), total bilirubin (P < 0.001, r = 0.65), and direct bilirubin (P < 0.001, r = 0.63) in TPN patients, but not in controls. The amount of hepatic copper did not correlate with the duration of TPN (median, 1.9 years; range, 0.3-18.0 years) or serum copper levels. TPN patients with significant cholestasis accumulated more copper than patients with no or only minimal cholestasis (P = 0.002). CONCLUSIONS Significant hepatic copper overload in TPN patients occurs through chronic cholestasis in TPN-associated liver disease and is independent from the total duration of TPN. Iatrogenic copper overload through trace elements in TPN solutions does not seem to be a significant factor.
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Affiliation(s)
- Hagen Blaszyk
- Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05401, USA.
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Zhong Z, Froh M, Lehnert M, Schoonhoven R, Yang L, Lind H, Lemasters JJ, Thurman RG. Polyphenols from Camellia sinenesis attenuate experimental cholestasis-induced liver fibrosis in rats. Am J Physiol Gastrointest Liver Physiol 2003; 285:G1004-13. [PMID: 12791596 DOI: 10.1152/ajpgi.00008.2003] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Accumulation of hydrophobic bile acids during cholestasis leads to generation of oxygen free radicals in the liver. Accordingly, this study investigated whether polyphenols from green tea Camellia sinenesis, which are potent free radical scavengers, decrease hepatic injury caused by experimental cholestasis. Rats were fed a standard chow or a diet containing 0.1% polyphenolic extracts from C. sinenesis starting 3 days before bile duct ligation. After bile duct ligation, serum alanine transaminase increased to 760 U/l after 1 day in rats fed a control diet. Focal necrosis and bile duct proliferation were also observed after 1-2 days, and fibrosis developed 2-3 wk after bile duct ligation. Additionally, procollagen-alpha1(I) mRNA increased 30-fold 3 wk after bile duct ligation, accompanied by increased expression of alpha-smooth muscle actin and transforming growth factor-beta and the accumulation of 4-hydroxynenonal, an end product of lipid peroxidation. Polyphenol feeding blocked or blunted all of these bile duct ligation-dependent changes by 45-73%. Together, the results indicate that cholestasis due to bile duct ligation causes liver injury by mechanisms involving oxidative stress. Polyphenols from C. sinenesis scavenge oxygen radicals and prevent activation of stellate cells, thereby minimizing liver fibrosis.
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Affiliation(s)
- Zhi Zhong
- Dept. of Cell and Developmental Biology, CB# 7090, Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7090, USA.
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Zhong Z, Froh M, Wheeler MD, Smutney O, Lehmann TG, Thurman RG. Viral gene delivery of superoxide dismutase attenuates experimental cholestasis-induced liver fibrosis in the rat. Gene Ther 2002; 9:183-91. [PMID: 11859421 DOI: 10.1038/sj.gt.3301638] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2001] [Accepted: 11/11/2001] [Indexed: 12/19/2022]
Abstract
Hydrophobic bile acids lead to generation of oxygen free radicals in mitochondria. Accordingly, this study investigated if gene delivery of superoxide dismutase (SOD) would reduce hepatic injury caused by experimental cholestasis. Rats were given adenovirus (Ad; 3 x 10(9) p.f.u., i.v.) carrying the bacterial control gene lacZ, mitochondrial Mn-SOD or cytosolic Cu/Zn-SOD genes 3 days before bile duct ligation. Both Mn- and Cu/Zn-SOD activity was increased in the liver about four-fold 3 days after viral infection. Serum alanine transaminase increased to about 710 U/l after bile duct ligation, which was blunted by about 70% in rats receiving Ad-Mn-SOD, but by only 30% in rats receiving Ad-Cu/Zn-SOD. Bile duct ligation caused focal necrosis, apoptosis and fibrosis in the liver and increased collagen alpha1 mRNA about 20-fold. These effects were reduced significantly by Ad-Mn-SOD, but not by Ad-Cu/Zn-SOD. In addition, bile duct ligation increased 4-hydroxynonenal, a product of lipid peroxidation, activated NF-kappaB and increased synthesis of TNF(alpha) and TGF-beta. These effects were also blunted significantly by Ad-Mn-SOD, but not by Ad-Cu/Zn-SOD. Taken together, it is concluded that cholestasis causes liver injury by mechanisms involving mitochondrial oxidative stress. Gene delivery of mitochondrial Mn-SOD blocks formation of oxygen radicals and production of toxic cytokines thereby minimizing liver injury caused by cholestasis.
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Affiliation(s)
- Z Zhong
- Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC 27599-7365, USA
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