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Yang Y, Tian Z, Song M, Ma C, Ge Z, Li P. Detecting the Critical States of Type 2 Diabetes Mellitus Based on Degree Matrix Network Entropy by Cross-Tissue Analysis. ENTROPY (BASEL, SWITZERLAND) 2022; 24:1249. [PMID: 36141135 PMCID: PMC9498060 DOI: 10.3390/e24091249] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/18/2022] [Accepted: 09/02/2022] [Indexed: 06/16/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disease caused by multiple etiologies, the development of which can be divided into three states: normal state, critical state/pre-disease state, and disease state. To avoid irreversible development, it is important to detect the early warning signals before the onset of T2DM. However, detecting critical states of complex diseases based on high-throughput and strongly noisy data remains a challenging task. In this study, we developed a new method, i.e., degree matrix network entropy (DMNE), to detect the critical states of T2DM based on a sample-specific network (SSN). By applying the method to the datasets of three different tissues for experiments involving T2DM in rats, the critical states were detected, and the dynamic network biomarkers (DNBs) were successfully identified. Specifically, for liver and muscle, the critical transitions occur at 4 and 16 weeks. For adipose, the critical transition is at 8 weeks. In addition, we found some "dark genes" that did not exhibit differential expression but displayed sensitivity in terms of their DMNE score, which is closely related to the progression of T2DM. The information uncovered in our study not only provides further evidence regarding the molecular mechanisms of T2DM but may also assist in the development of strategies to prevent this disease.
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Affiliation(s)
- Yingke Yang
- School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang 471023, China
| | - Zhuanghe Tian
- School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang 471023, China
| | - Mengyao Song
- School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang 471023, China
| | - Chenxin Ma
- School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang 471023, China
| | - Zhenyang Ge
- College of Agriculture, Henan University of Science and Technology, Luoyang 471023, China
| | - Peiluan Li
- School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang 471023, China
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Batcioglu K, Dogan T, Kustepe E, Uyumlu A, Yilmaztekin Y. Protective effect of Lycium barbarum on renal injury induced by acute pancreatitis in rats. Pharmacogn Mag 2022. [DOI: 10.4103/pm.pm_516_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Hashizume N, Tanaka Y, Asagiri K, Fukahori S, Ishii S, Saikusa N, Yoshida M, Tanikawa K, Asakawa T, Yagi M. Perioperative reactive oxygen species in infants with biliary atresia: A retrospective observational study. Medicine (Baltimore) 2020; 99:e21332. [PMID: 32756118 PMCID: PMC7402746 DOI: 10.1097/md.0000000000021332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Biliary atresia (BA) is a devastating cholestatic disorder of infants that presents during the first several months after birth due to an idiopathic obstruction to the bile flow. Without prompt diagnosis, Kasai portoenterostomy, and deliberate follow-ups, the resulting cholestasis leads to progressive hepatic failure. Oxidative stress is an abnormal phenomenon inside cells or tissues caused by a disturbance in the reactive oxygen species (ROS). We aimed to measure perioperative ROS in BA patients.Data are presented as median (25th, 75th percentiles). We evaluated 15 BA patients (age 55 [48, 69] days) and measured ROS; serum superoxide dismutase (SOD), urinary 8-iso prostaglandin F2α (8-iso-PGF2α) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) preoperatively and 30 days later to compare values with serum liver function tests and histologic grades of liver cholestasis. For compared BA patients, 4 normal subjects as control group (age 55 [27, 75] days) measured ROS and serum liver function tests.In BA patients, the preoperative serum SOD was 6.1 IU/mL (4.7, 7.2), urinary 8-iso-PGF2α was 1969 pg/mg Cre (1697, 2374), and urinary 8-OHdG was 37.1 ng/mg Cre (33.1, 53.7). At the postoperative day 30, the serum SOD was 5.2 IU/mL (4.2, 6.7), urinary 8-iso-PGF2α was 1761 pg/mg Cre (1256, 3036), and urinary 8-OHdG was 42.1 ng/mg Cre (29.65, 72.64). In ROS, there were no significant differences between the 2 periods. In control group, urinary 8-iso-PGF2α was significantly lower than that in preoperative BA patient group. However, other ROS were not significant differences between control group and BA patient group. The concentration of urinary 8-iso-PGF2α was positively correlated with total bilirubin and direct bilirubin levels (preoperatively: r = 0.6921, P = .0042 and r = 0.6639, P = .007, postoperatively: r = 0.6036, P = .0172 and r = 0.6464, P = .0092, respectively). The preoperative ROS were not correlated with histologic grades of liver cholestasis. Various factors such as liver inflammation, lipid malabsorption, and tissue disorders due to jaundice might affect the antioxidant activity and elevated urinary 8-iso-PGF2α. However, at least until 30 days later, urinary 8-OHdG as oxidative DNA damage might persist after the operation whether the cholestasis improved or not.
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Affiliation(s)
- Naoki Hashizume
- Department of Pediatric Surgery, Kurume University School of Medicine
| | - Yoshiaki Tanaka
- Department of Pediatric Surgery, Kurume University School of Medicine
- Division of Medical Safety Management, Kurume University Hospital
| | - Kimio Asagiri
- Department of Pediatric Surgery, Kurume University School of Medicine
- Department of Pediatric Surgery, St Mary's Hospital
| | - Suguru Fukahori
- Department of Pediatric Surgery, Kurume University School of Medicine
| | - Shinji Ishii
- Department of Pediatric Surgery, Kurume University School of Medicine
| | - Nobuyuki Saikusa
- Department of Pediatric Surgery, Kurume University School of Medicine
| | - Motomu Yoshida
- Department of Pediatric Surgery, Kurume University School of Medicine
| | - Ken Tanikawa
- Departments of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Takahiro Asakawa
- Department of Pediatric Surgery, Kurume University School of Medicine
- Department of Pediatric Surgery, St Mary's Hospital
| | - Minoru Yagi
- Department of Pediatric Surgery, Kurume University School of Medicine
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Ahmed AE, Alshehri A, Al-Kahtani MA, Elbehairi SEI, Alshehri MA, Shati AA, Alfaifi MY, Al-Doais AA, Taha R, Morsy K, El-Mansi AA. Vitamin E and selenium administration synergistically mitigates ivermectin and doramectin-induced testicular dysfunction in male Wistar albino rats. Biomed Pharmacother 2020; 124:109841. [PMID: 31972360 DOI: 10.1016/j.biopha.2020.109841] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 01/09/2020] [Accepted: 01/10/2020] [Indexed: 01/09/2023] Open
Abstract
Avermectins are broad-spectrum antiparasitic drugs in veterinary and human medication. The current study aimed to examine the toxic effects of ivermectin (IVM) and doramectin (DRM), with or without co-treatment of vitamin E (Vit.E) and selenium (Se) on apoptosis, oxidative stress and male fertility in Wistar rats. Twenty five adult male animals were divided into five groups; G1; was control (CTL) received saline, G2; IVM (0.2 mg/kg b.w), G3; IVM plus Vit.E/Se (80/1.6 mg/kg b.w, respectively), G4; DRM (0.2 mg/kg b.w), and G5; DRM plus Vit.E/Se. Both IVM and DRM were given by subcutaneous (s.c) injections while Vit.E/Se was orally given. All treatments were administered once weekly for four consecutive weeks. By 24 h after the last treatment, the animals were sacrificed. Blood and tissue samples were collected for hematology, serobiochemistry, histopathology, and molecular assays for hepatic/ renal toxicities, oxidative stress, cell viability and fertility parameters. Apoptosis of the hepatic cells obtained from the treated rats was assayed by detection of annexin-V using the flow cytometric assay (FCA). The proliferating cellular nuclear antigen (PCNA) and DNA fragmentation in the treated rats' testicular tissues were also assayed. Moreover, the direct effects of IVM or DRM with or without concomitant administration of Vit.E/Se on testicular cells isolated from adult rat were also performed in vitro. Apoptosis of those cultured testicular cells in response to the different treatments was assayed by detection of the inhibition-concentration fifty (IC50) using the SRB method, and evaluating the viable versus apoptotic cells microscopically after staining with acridine orange-ethidium bromide (AO/EB). In conclusion, both avermectins induced apoptosis in the living and cultured cells, while those antioxidants; Vit.E and Se, reduced the oxidative stress and cytotoxicity both in vivo and in vitro, either. Furthermore, the reprotoxicity and reduced male fertility were seriously evoked by IVM, but not DRM with dramatic ameliorative effect of Vit.E/Se if concomitantly administered. Avermectins, especially ivermectin, should be given according to the dose recommended by the manufacturer company and repeated dosages should be given with Vit.E/Se.
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Affiliation(s)
- Ahmed Ezzat Ahmed
- Department of Biology, College of Science, King Khalid University, Abha 61413, Saudi Arabia; Department of Theriogenology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt.
| | - Ali Alshehri
- Department of Biology, College of Science, King Khalid University, Abha 61413, Saudi Arabia
| | - M A Al-Kahtani
- Department of Biology, College of Science, King Khalid University, Abha 61413, Saudi Arabia
| | | | - Mohammed A Alshehri
- Department of Biology, College of Science, King Khalid University, Abha 61413, Saudi Arabia
| | - Ali A Shati
- Department of Biology, College of Science, King Khalid University, Abha 61413, Saudi Arabia
| | - Mohammad Y Alfaifi
- Department of Biology, College of Science, King Khalid University, Abha 61413, Saudi Arabia
| | - Amin A Al-Doais
- Department of Biology, College of Science, King Khalid University, Abha 61413, Saudi Arabia
| | - Ramadan Taha
- Department of Biology, College of Science, King Khalid University, Abha 61413, Saudi Arabia
| | - Kareem Morsy
- Department of Biology, College of Science, King Khalid University, Abha 61413, Saudi Arabia; Department of Zoology, Faculty of Science, Cairo University, Cairo 12613, Egypt
| | - Ahmed A El-Mansi
- Department of Biology, College of Science, King Khalid University, Abha 61413, Saudi Arabia; Zoology Dept., Faculty of Science, Mansoura University, Mansoura, Egypt
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Unal Y, Tuncal S, Kosmaz K, Kucuk B, Kismet K, Cavusoglu T, Celepli P, Senes M, Yildiz S, Hucumenoglu S. The Effect of Calcium Dobesilate on Liver Damage in Experimental Obstructive Jaundice. J INVEST SURG 2018; 32:238-244. [PMID: 29589984 DOI: 10.1080/08941939.2018.1451936] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Purpose/Aim of the study: Inflammation and oxidative stress are two significant factors affecting the degree of liver damage in obstructive jaundice. The aim of this study was to evaluate the effect of calcium dobesilate (CaDob), an effective antioxidant and anti-inflammatory drug, on damage to liver caused by experimental obstructive jaundice. MATERIALS AND METHODS 30 rats in total were randomly placed into three groups, each group consisting of 10 rats. The sham group (Group 1) only received solely laparotomy. In the control group (Group 2), ligation was applied to the biliary tract and no treatment was implemented. In the CaDob group (Group 3), following ligation of the biliary tract, 100 mg/kg/day CaDob was implemented via an orogastric tube for a 10-day period. Liver tissue and blood samples were taken for histopathological and biochemical examination. RESULTS The CaDob group had significantly lower test values for serum liver functions when compared to the control group. Statistically lower levels of tissue malondialdehyde (MDA) and fluorescent oxidation products (FOP) were detected in the CaDob group, and the CaDob group had significantly higher levels of sulfydryl (SH) than the control group. Histopathological scores in the CaDob group were found out to be statistically less than the scores the control group received (p < 0.05). CONCLUSIONS CaDob treatment repaired the histpatological changes induced by bile duct ligation. The hepatoprotective effects of CaDob can be associated with its antioxidant properties of the drug.
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Affiliation(s)
- Yilmaz Unal
- a Department of General Surgery , Ankara Education and Research Hospital , Ankara , Turkey
| | - Salih Tuncal
- a Department of General Surgery , Ankara Education and Research Hospital , Ankara , Turkey
| | - Koray Kosmaz
- a Department of General Surgery , Ankara Education and Research Hospital , Ankara , Turkey
| | - Berkay Kucuk
- a Department of General Surgery , Ankara Education and Research Hospital , Ankara , Turkey
| | - Kemal Kismet
- a Department of General Surgery , Ankara Education and Research Hospital , Ankara , Turkey
| | - Turgut Cavusoglu
- a Department of General Surgery , Ankara Education and Research Hospital , Ankara , Turkey
| | - Pinar Celepli
- b Department of Pathology , Ankara Education and Research Hospital , Ankara , Turkey
| | - Mehmet Senes
- c Department of Biochemistry , Ankara Education and Research Hospital , Ankara , Turkey
| | - Selin Yildiz
- c Department of Biochemistry , Ankara Education and Research Hospital , Ankara , Turkey
| | - Sema Hucumenoglu
- b Department of Pathology , Ankara Education and Research Hospital , Ankara , Turkey
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Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Esfandiari A, Azarpira N, Niknahad H. Dithiothreitol supplementation mitigates hepatic and renal injury in bile duct ligated mice: Potential application in the treatment of cholestasis-associated complications. Biomed Pharmacother 2018; 99:1022-1032. [DOI: 10.1016/j.biopha.2018.01.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 12/29/2017] [Accepted: 01/03/2018] [Indexed: 01/18/2023] Open
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Arauz J, Zarco N, Hernández-Aquino E, Galicia-Moreno M, Favari L, Segovia J, Muriel P. Coffee consumption prevents fibrosis in a rat model that mimics secondary biliary cirrhosis in humans. Nutr Res 2017; 40:65-74. [PMID: 28473062 DOI: 10.1016/j.nutres.2017.03.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 03/03/2017] [Accepted: 03/12/2017] [Indexed: 12/25/2022]
Abstract
Investigations demonstrated that oxidative stress plays an important role in injury promotion in cholestatic liver disease. We hypothesized that coffee attenuates cholestasis-induced hepatic necrosis and fibrosis via its antioxidant, anti-inflammatory, and antifibrotic properties. The major aim of this study was to evaluate the hepatoprotective properties of coffee and caffeine in a model of chronic bile duct ligation (BDL) in male Wistar rats. Liver injury was induced by 28-day BDL, and conventional coffee, decaffeinated coffee, or caffeine was administered daily. After treatment, the hepatic oxidative status was estimated by measuring lipid peroxidation, the reduced to oxidized glutathione ratio, and glutathione peroxidase. Fibrosis was assessed by measuring the liver hydroxyproline content. The transforming growth factor-β, connective tissue growth factor, α-smooth muscle actin, collagen 1, and interleukin-10 proteins and mRNAs were measured by Western blot and polymerase chain reaction, respectively. Conventional coffee suppressed most of the changes produced by BDL; however, caffeine showed better antifibrotic effects. Coffee demonstrated antioxidant properties by restoring the redox equilibrium, and it also prevented the elevation of liver enzymes as well as hepatic glycogen depletion. Interestingly, coffee and caffeine administration prevented collagen increases. Western blot assays showed decreased expression levels of transforming growth factor-β, connective tissue growth factor, α-smooth muscle actin, and collagen 1 in the coffee- and caffeine-treated BDL groups. Similarly, coffee decreased the mRNA levels of these proteins. We conclude that coffee prevents liver cirrhosis induced by BDL by attenuating the oxidant processes, blocking hepatic stellate cell activation, and downregulating the main profibrotic molecules involved in extracellular matrix deposition.
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Affiliation(s)
- Jonathan Arauz
- Department of Pharmacology, School of Medicine, Autonomous University of Baja California, Mexicali, Baja California, Mexico
| | - Natanael Zarco
- Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies of the IPN, México City, Mexico
| | - Erika Hernández-Aquino
- Department of Pharmacology, Center for Research and Advanced Studies of the IPN, México City, Mexico
| | - Marina Galicia-Moreno
- Department of Pharmacology, School of Medicine, Autonomous University of Baja California, Mexicali, Baja California, Mexico
| | - Liliana Favari
- Department of Pharmacology, Center for Research and Advanced Studies of the IPN, México City, Mexico
| | - José Segovia
- Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies of the IPN, México City, Mexico
| | - Pablo Muriel
- Department of Pharmacology, Center for Research and Advanced Studies of the IPN, México City, Mexico.
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Solmaz A, Gülçiçek OB, Erçetin C, Yiğitbaş H, Yavuz E, Arıcı S, Erzik C, Zengi O, Demirtürk P, Çelik A, Çelebi F. Nesfatin-1 alleviates extrahepatic cholestatic damage of liver in rats. Bosn J Basic Med Sci 2016; 16:247-253. [PMID: 27524109 DOI: 10.17305/bjbms.2016.1465] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 07/23/2016] [Accepted: 07/23/2016] [Indexed: 01/15/2023] Open
Abstract
Obstructive jaundice (OJ) can be defined as cessation of bile flow into the small intestine due to benign or malignant changes. Nesfatin-1, recently discovered anorexigenic peptide derived from nucleobindin-2 in hypothalamic nuclei, was shown to have anti-inflammatory and antiapoptotic effects. This study is aimed to investigate the therapeutic effects of nesfatin-1 on OJ in rats. Twenty-four adult male Wistar-Hannover rats were randomly assigned to three groups: sham (n = 8), control (n = 8), and nesfatin (n = 8). After bile duct ligation, the study groups were treated with saline or nesfatin-1, for 10 days. Afterward, blood and liver tissue samples were obtained for biochemical analyses, measurement of cytokines, determination of the oxidative DNA damage, DNA fragmentation, and histopathologic analyses. Alanine aminotransferase and gamma-glutamyl transferase levels were decreased after the nesfatin treatment; however, these drops were statistically non-significant compared to control group (p = 0.345, p = 0.114). Malondialdehyde levels decreased significantly in nesfatin group compared to control group (p = 0.032). Decreases in interleukin-6 and tumor necrosis factor-α levels from the liver tissue samples were not statistically significant in nesfatin group compared to control group. The level of oxidative DNA damage was lower in nesfatin group, however this result was not statistically significant (p = 0.75). DNA fragmentation results of all groups were similar. Histopathological examination revealed that there was less neutrophil infiltration, edema, bile duct proliferation, hepatocyte necrosis, basement membrane damage, and parenchymal necrosis in nesfatin compared to control group. The nesfatin-1 treatment could alleviate cholestatic liver damage caused by OJ due to its anti-inflammatory and antioxidant effects.
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Affiliation(s)
- Ali Solmaz
- General Surgery Clinic, Bağcılar Training and Research Hospital, Istanbul, Turkey.
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Glutathione Supplementation Attenuates Oxidative Stress and Improves Vascular Hyporesponsiveness in Experimental Obstructive Jaundice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:486148. [PMID: 26161237 PMCID: PMC4487904 DOI: 10.1155/2015/486148] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 01/31/2015] [Accepted: 01/31/2015] [Indexed: 12/01/2022]
Abstract
We investigated the protective effects and mechanism of glutathione (GSH) on vascular hyporesponsiveness induced by bile duct ligation (BDL) in a rat model. Seventy-two male Sprague-Dawley rats were randomly divided into four groups: a NS group, a GSH group, a BDL + NS group, and a BDL + GSH group. GSH was administrated into rats in the GSH and BDL + GSH groups by gastric gavage. An equal volume of normal saline was, respectively, given in the NS group and BDL + NS group. Blood was gathered for serological determination and thoracic aorta rings were isolated for measurement of isometric tension. Obstructive jaundice led to a significant increase in the serum total bilirubin, AST, and ALT levels. The proinflammatory cytokines levels (TNF-α and IL-1β), concentration of NO, and oxidative stress markers (MDA and 3-NT) were increased as well. All of those were reduced by the treatment of GSH. Meanwhile, contraction of aorta rings to NA and vasorelaxation to ACh or SNP in the BDL group rats were markedly decreased, while GSH administration reversed this change. Our findings suggested that GSH supplementation attenuated overexpressed ONOO(−) from the reaction of excessive NO with O2∙- and protected against obstructive jaundice-induced vascular hyporesponsiveness in rats.
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Long Y, Dong X, Yuan Y, Huang J, Song J, Sun Y, Lu Z, Yang L, Yu W. Metabolomics changes in a rat model of obstructive jaundice: mapping to metabolism of amino acids, carbohydrates and lipids as well as oxidative stress. J Clin Biochem Nutr 2015; 57:50-9. [PMID: 26236101 PMCID: PMC4512893 DOI: 10.3164/jcbn.14-147] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 03/04/2015] [Indexed: 12/11/2022] Open
Abstract
The study examined the global metabolic and some biochemical changes in rats with cholestasis induced by bile duct ligation (BDL). Serum samples were collected in male Wistar rats with BDL (n = 8) and sham surgery (n = 8) at day 3 after surgery for metabolomics analysis using a combination of reversed phase chromatography and hydrophilic interaction chromatography (HILIC) and quadrupole-time-of-flight mass spectrometry (Q-TOF MS). The serum levels of malondialdehyde (MDA), total antioxidative capacity (T-AOC), glutathione (GSH) and glutathione disulfide (GSSG), the activities of superoxide dismutase (SOD) and glutathion peroxidase (GSH-Px) were measured to estimate the oxidative stress state. Key changes after BDL included increased levels of l-phenylalanine, l-glutamate, l-tyrosine, kynurenine, l-lactic acid, LysoPCc (14:0), glycine and succinic acid and decreased levels of l-valine, PCb (19:0/0:0), taurine, palmitic acid, l-isoleucine and citric acid metabolism products. And treatment with BDL significantly decreased the levels of GSH, T-AOC as well as SOD, GSH-Px activities, and upregulated MDA levels. The changes could be mapped to metabolism of amino acids and lipids, Krebs cycle and glycolysis, as well as increased oxidative stress and decreased antioxidant capability. Our study indicated that BDL induces major changes in the metabolism of all 3 major energy substances, as well as oxidative stress.
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Affiliation(s)
- Yue Long
- Department of Anaesthesiology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China ; Department of Anesthesiology, 163th Hospital of PLA, Hunan 410003, China
| | - Xin Dong
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Yawei Yuan
- Department of Anaesthesiology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China
| | - Jinqiang Huang
- Department of Anaesthesiology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China
| | - Jiangang Song
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yumin Sun
- Department of Anaesthesiology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China
| | - Zhijie Lu
- Department of Anaesthesiology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China
| | - Liqun Yang
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Weifeng Yu
- Department of Anaesthesiology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China
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Kuru S, Kismet K, Barlas AM, Tuncal S, Celepli P, Surer H, Ogus E, Ertas E. The Effect of Montelukast on Liver Damage in an Experimental Obstructive Jaundice Model. VISZERALMEDIZIN 2015; 31:131-8. [PMID: 26989383 PMCID: PMC4789965 DOI: 10.1159/000375434] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background Montelukast is a cysteinyl-leukotriene type 1 (CysLT1) selective receptor antagonist. In recent years, investigations have shown that montelukast possesses secondary anti-inflammatory activities and also antioxidant effects. For this reason, we aimed to determine the possible effects of montelukast on liver damage in experimental obstructive jaundice. Methods 30 Wistar-Albino male rats were randomized and divided into three groups of 10 animals each: group I, sham-operated; group II, ligation and division of the common bile duct (BDL) followed by daily intraperitoneal injection of 1 ml of saline; group III, BDL followed by daily intraperitoneal injection of 10 mg/kg montelukast dissolved in saline. The animals were killed on postoperative day 7 by high-dose diethyl ether inhalation. Blood and liver samples were taken for examination. Results In this study, liver malondialdehyde (MDA) (p = 0.001), myeloperoxidase (p = 0.003), and total sulfhydryl (SH) (p = 0.009) were found to be significantly different between the BDL + montelukast and the BDL groups. Plasma total SH (p = 0.002) and MDA (p = 0.027) values were also statistically different between these groups. Statistical analyses of histological activity index scores showed that the histopathological damage in the BDL + montelukast group was significantly less than the damage in the control group (p < 0.05 for all pathological parameters). Conclusion According to the results of this study, montelukast showed a significant hepatoprotective effect in this experimental obstructive jaundice model, which might be due to its antioxidant and anti-inflammatory activities.
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Affiliation(s)
- Serdar Kuru
- Department of General Surgery, Ankara Training and Research Hospital, Ankara, Turkey
| | - Kemal Kismet
- Department of General Surgery, Ankara Training and Research Hospital, Ankara, Turkey
| | - Aziz M Barlas
- Department of General Surgery, Ankara Training and Research Hospital, Ankara, Turkey
| | - Salih Tuncal
- Department of General Surgery, Ankara Training and Research Hospital, Ankara, Turkey
| | - Pinar Celepli
- Department of Pathology, Aksaray State Hospital, Aksaray, Turkey
| | - Hatice Surer
- Department of Biochemistry, Ankara Training and Research Hospital, Ankara, Turkey
| | - Elmas Ogus
- Department of Biochemistry, Ankara Training and Research Hospital, Ankara, Turkey
| | - Ertugrul Ertas
- Department of General Surgery, Ankara Training and Research Hospital, Ankara, Turkey
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12
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Vitamin A supplementation alleviates extrahepatic cholestasis liver injury through Nrf2 activation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:273692. [PMID: 25126202 PMCID: PMC4120926 DOI: 10.1155/2014/273692] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Revised: 06/12/2014] [Accepted: 06/17/2014] [Indexed: 12/15/2022]
Abstract
Aim. To investigate the role of vitamin A in liver damage induced by bile duct ligation (BDL) in rats. Methods. Thirty male Wistar rats were randomly divided into three groups: SHAM group, BDL group, and BDL + VitA group . The concentrations of retinol and retinyl palmitate in the liver were analyzed using HPLC, and liver function was evaluated by the level of TBIL, ALT, AST, and ALP in serum. Hepatic oxidative status was estimated by measuring T-SOD, CAT, GSH, MDA, and AOPP. Nrf2 expression was assessed using immunohistochemistry and western blotting, and EMSA was performed to determine Nrf2 DNA-binding activity. The expression of the downstream factors such as Ho1 and Nqo1 was also examined using immunohistochemistry and western blotting assays. Results. Vitamin A treatment restored levels of retinoids in liver, improved liver function, alleviated oxidative stress, and facilitated the translocation of Nrf2 to the nucleus in the experimental obstructive jaundice. Vitamin A was also found to increase the expression of Nrf2 downstream proteins such as Ho1 and Nqo1. Conclusion. Vitamin A was here found to ameliorate cholestatic liver injury. This effect may be related to the activation of Nrf2/ARE pathway in bile duct ligation rats.
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Salama SA, Omar HA, Maghrabi IA, AlSaeed MS, EL-Tarras AE. Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats. Toxicol Appl Pharmacol 2013; 274:1-6. [PMID: 24215938 DOI: 10.1016/j.taap.2013.10.034] [Citation(s) in RCA: 208] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 10/22/2013] [Accepted: 10/30/2013] [Indexed: 11/15/2022]
Abstract
Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000ft above the sea level). Iron supplementation (2mg elemental iron/kg, once daily for 15days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25mg/kg, once daily for the last 7days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures.
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Affiliation(s)
- Samir A Salama
- High Altitude Research Center, Taif University, Al-Haweiah, Taif 21974, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11751, Egypt; Department of Pharmacology and GTMR Unit, College of Clinical Pharmacy, Taif University, Al-Haweiah, Taif 21974, Saudi Arabia.
| | - Hany A Omar
- Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Ibrahim A Maghrabi
- Department of Clinical Pharmacy, College of Clinical Pharmacy, Taif University, Al-Haweiah, Taif 21974, Saudi Arabia
| | - Mohammed S AlSaeed
- Department of Surgery, College of Medicine, Taif University, Al-Haweiah, Taif 21974, Saudi Arabia
| | - Adel E EL-Tarras
- High Altitude Research Center, Taif University, Al-Haweiah, Taif 21974, Saudi Arabia
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Li M, Zeng T, Liu R, Chen L. Detecting tissue-specific early warning signals for complex diseases based on dynamical network biomarkers: study of type 2 diabetes by cross-tissue analysis. Brief Bioinform 2013; 15:229-43. [DOI: 10.1093/bib/bbt027] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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Kumar A, Rinwa P, Kaur G, Machawal L. Stress: Neurobiology, consequences and management. JOURNAL OF PHARMACY AND BIOALLIED SCIENCES 2013; 5:91-7. [PMID: 23833514 PMCID: PMC3697199 DOI: 10.4103/0975-7406.111818] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 11/21/2012] [Accepted: 12/11/2012] [Indexed: 11/04/2022] Open
Abstract
Stress, both physical and psychological, is attracting increasing attention among neuroresearchers. In the last 20 decades, there has been a surge of interest in the research of stress-induced manifestations and this approach has resulted in the development of more appropriate animal models for stress-associated pathologies and its therapeutic management. These stress models are an easy and convenient method for inducing both psychological and physical stress. To understand the behavioral changes underlying major depression, molecular and cellular studies are required. Dysregulation of the stress system may lead to disturbances in growth and development, and may this may further lead to the development of various other psychiatric disorders. This article reviews the different types of stress and their neurobiology, including the different neurotransmitters affected. There are various complications associated with stress and their management through various pharmacological and non-pharmacological techniques. The use of herbs in the treatment of stress-related problems is practiced in both Indian and Western societies, and it has a vast market in terms of anti-stress medications and treatments. Non-pharmacological techniques such as meditation and yoga are nowadays becoming very popular as a stress-relieving therapy because of their greater effectiveness and no associated side effects. Therefore, this review highlights the changes under stress and stressor and their impact on different animal models in understanding the mechanisms of stress along with their effective and safe management.
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Affiliation(s)
- Anil Kumar
- Department of Pharmacology, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, India
| | - Puneet Rinwa
- Department of Pharmacology, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, India
| | - Gurleen Kaur
- Department of Pharmacology, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, India
| | - Lalit Machawal
- Department of Pharmacology, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, India
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Galván I, Erritzøe J, Karadaş F, Møller AP. High levels of liver antioxidants are associated with life-history strategies characteristic of slow growth and high survival rates in birds. J Comp Physiol B 2012; 182:947-59. [DOI: 10.1007/s00360-012-0671-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 04/14/2012] [Accepted: 04/21/2012] [Indexed: 12/22/2022]
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Donepudi AC, Aleksunes LM, Driscoll MV, Seeram NP, Slitt AL. The traditional ayurvedic medicine, Eugenia jambolana (Jamun fruit), decreases liver inflammation, injury and fibrosis during cholestasis. Liver Int 2012; 32:560-73. [PMID: 22212619 PMCID: PMC3299847 DOI: 10.1111/j.1478-3231.2011.02724.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2011] [Accepted: 11/17/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cholestasis is a common disease of the liver. Chronic cholestasis eventually leads to hepatic cirrhosis and fibrosis, and rodent chronic cholestasis models are used to study aspects of fibrosis and cirrhosis. Cholestasis-induced liver injury and fibrosis are associated with increased oxidative stress and inflammation. Few pharmacological therapies exist for treatment of cholestasis or cirrhosis, but it is known that humans with better nutritional intake are less likely to develop certain types of cirrhosis. Eugenia jambolana (Jamun) is a tropical berry fruit rich in antioxidant anthocyanin compounds. AIM As anthocyanins decrease cellular lipid peroxidation and oxidative stress, it was hypothesized that Jamun fruit extract (JFE) administration could protect against cholestatic liver injury and inflammation in mice. METHOD Starting 24 h after sham or bile-duct ligation (BDL) surgery, male C57Bl/6 mice were administered vehicle or JFE (100 mg/kg, po) for 10 days. RESULTS Mice that underwent BDL had elevated serum ALT levels, which were reduced to 60% by JFE treatment. Likewise, BDL caused hepatic inflammation, macrophage infiltration, fibrosis and necrosis, all of which were largely improved by JFE. Interestingly, hepatoprotection was observed in JFE-treated BDL mice, despite suppressed transporter expression and increased hepatic bile acid concentrations. CONCLUSION Jamun fruit phytochemicals decreased hepatic inflammation and oxidative stress, and protected against hepatocellular injury in mice. Jamun warrants further investigation as a potential antioxidant/anti-inflammatory therapy not only to treat cholestasis but also other liver diseases with an inflammatory component.
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Affiliation(s)
- Ajay C. Donepudi
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881
| | - Lauren M. Aleksunes
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, 170 Frelinghuysen Road, Piscataway, NJ 08854
| | - Maureen V. Driscoll
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881
| | - Navindra P. Seeram
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881
| | - Angela L. Slitt
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881
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Sokolovic D, Nikolic J, Kocic G, Jevtovic-Stoimenov T, Veljkovic A, Stojanovic M, Stanojkovic Z, Sokolovic DM, Jelic M. The effect of ursodeoxycholic acid on oxidative stress level and DNase activity in rat liver after bile duct ligation. Drug Chem Toxicol 2012; 36:141-8. [PMID: 22385135 DOI: 10.3109/01480545.2012.658919] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Accumulation of hydrophobic bile acids (BAs) during cholestasis plays an important role in apoptosis initiation as well as oxidative stress increase in liver cells. Ursodeoxycholic acid (UDCA) acts as a protector in BA-induced cell injury.The aim of the study was to evaluate the effect of UDCA on oxidative stress level and DNase I and II activity caused by liver injury in bile duct ligation (BDL) rats.Wistar rats were divided in four groups: group 1, control (sham-operated); group 2, sham-operated and injected with UDCA (30 mg/kg); group 3,animals with BDL; and group 4,UDCA-treatedcholestatic rats. Animals were sacrificed after 9 days. Malondialdehyde (MDA; lipid peroxidation end-product) level and protein-molecule oxidative modification (carbonyl group content) significantly increased in BDL rat liver. Catalase (CAT) activity in liver tissue was found to be decreased in BDL rats. In addition, xanthine oxidase (XO) activity, which is thought to be one of the key enzymes producing reactive oxygen species, was found to be increased in the cholestatic group. The apoptotic effect in cholestasis was probably triggered by the increased activation of DNase I and II. The protective effect of UDCA on liver tissue damage in BDL rats, in comparison to cholestatic liver, were 1) decrease of MDA levels, 2) increased CAT activity, 3) reduced XO activity, and 4) effect on terminal apoptotic reaction, shown as a decrease in DNase I and II activity.Therefore, UDCA may be useful in the preservation of liver function in cholestasis treatment.
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Affiliation(s)
- Dusan Sokolovic
- Department of Biochemistry, the University of Nis Medical School, Nis, Serbia.
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Differential toxicity of Mn2+ and Mn3+ to rat liver tissues: Oxidative damage, membrane fluidity and histopathological changes. ACTA ACUST UNITED AC 2012; 64:197-203. [DOI: 10.1016/j.etp.2010.08.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2010] [Revised: 06/27/2010] [Accepted: 08/10/2010] [Indexed: 12/23/2022]
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Galicia-Moreno M, Favari L, Muriel P. Trolox mitigates fibrosis in a bile duct ligation model. Fundam Clin Pharmacol 2011; 27:308-18. [PMID: 22211361 DOI: 10.1111/j.1472-8206.2011.01020.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Several studies suggest that free radicals may play a role in cholestatic liver injury. The aim of this work was to evaluate the role of trolox in chronic bile duct ligation (BDL). Liver injury was induced by 28-day BDL to male Wistar rats. Animals were divided in four groups of six rats. Trolox was administered daily (50 mg/kg, p.o.). Alanine aminotransferase (ALT) was quantified in serum. Fibrosis was assessed measuring liver hydroxyproline content. Reduced (GSH) and oxidized (GSSG) glutathione, lipid peroxidation, catalase (CAT), and glutathione peroxidase (GPx) activities were measured in liver. Transforming growth factor-β (TGF-β), interleukin-6 (IL-6), and interleukin-10 (IL-10) were determined by western blot and quantified densitometrically. Our results show that trolox treatment in BDL rats prevented the increase in ALT. Collagen was increased by chronic BDL, but trolox administration preserved the normal collagen concentration. BDL produced high levels of the cytokine TGF-β1, IL-6, and IL-10 levels. Trolox administration was effective to partially prevent the increase of TGF-β1 and IL-6, and it was able to further augment the levels of IL-10. Oxidative stress (assessed by lipid peroxidation and liver glutathione content) was increased by BDL; this process was normalized by trolox. The activities of CAT and GPx were altered by BDL, and trolox prevented these events. We found that there is a close relationship between cholestatic liver damage and oxidative stress generation, and this was effectively prevented by trolox. Our study shows that the beneficial effects of trolox are because of its important antioxidant and immunomodulatory properties.
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Affiliation(s)
- Marina Galicia-Moreno
- Departamento de Farmacología, CINVESTAV-IPN., Apdo Postal 14-740 México, DF 07000, México
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Ghosh S, Sulistyoningrum DC, Glier MB, Verchere CB, Devlin AM. Altered glutathione homeostasis in heart augments cardiac lipotoxicity associated with diet-induced obesity in mice. J Biol Chem 2011; 286:42483-42493. [PMID: 22021075 DOI: 10.1074/jbc.m111.304592] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Obesity-related cardiac lipid accumulation is associated with increased myocardial oxidative stress. The role of the antioxidant glutathione in cardiac lipotoxicity is unclear. Cystathionine β-synthase (Cbs) catalyzes the first step in the trans-sulfuration of homocysteine to cysteine, which is estimated to provide ∼50% of cysteine for hepatic glutathione biosynthesis. As cardiac glutathione is a reflection of the liver glutathione pool, we hypothesize that mice heterozygous for targeted disruption of Cbs (Cbs(+/-)) are more susceptible to obesity-related cardiolipotoxicity because of impaired liver glutathione synthesis. Cbs(+/+) and Cbs(+/-) mice were fed a high fat diet (60% energy) from weaning for 13 weeks to induce obesity and had similar increases in body weight and body fat. This was accompanied by increased hepatic triglyceride but no differences in hepatic glutathione levels compared with mice fed chow. However, Cbs(+/-) mice with diet-induced obesity had greater glucose intolerance and lower total and reduced glutathione levels in the heart, accompanied by lower plasma cysteine levels compared with Cbs(+/+) mice. Higher triglyceride concentrations, increased oxidative stress, and increased markers of apoptosis were also observed in heart from Cbs(+/-) mice with diet-induced obesity compared with Cbs(+/+) mice. This study suggests a novel role for Cbs in maintaining the cardiac glutathione pool and protecting against cardiac lipid accumulation and oxidative stress during diet-induced obesity in mice.
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Affiliation(s)
- Sanjoy Ghosh
- Departments of Pathology and Laboratory Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, V5Z 4H4, Canada
| | - Dian C Sulistyoningrum
- Departments of Pathology and Laboratory Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, V5Z 4H4, Canada
| | - Melissa B Glier
- Departments of Pathology and Laboratory Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, V5Z 4H4, Canada
| | - C Bruce Verchere
- Departments of Pathology and Laboratory Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, V5Z 4H4, Canada
| | - Angela M Devlin
- Departments of Pathology and Laboratory Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, V5Z 4H4, Canada; Department of Pediatrics, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, V5Z 4H4, Canada.
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Huang P, Chen C, Wang H, Li G, Jing H, Han Y, Liu N, Xiao Y, Yu Q, Liu Y, Wang P, Shi Z, Sun Z. Manganese effects in the liver following subacute or subchronic manganese chloride exposure in rats. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2011; 74:615-622. [PMID: 20813406 DOI: 10.1016/j.ecoenv.2010.08.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2010] [Revised: 08/06/2010] [Accepted: 08/11/2010] [Indexed: 05/29/2023]
Abstract
Manganese (Mn) toxicity is most often found in mining and welding industry workers. Accumulation of manganese in the brain can result in a syndrome similar to that of Parkinson's disease. Observations on former Mn-alloy workers suggested that residual effects could last for years after exposure. The objective of this study was to assess effects of Mn in the liver of rats following subacute or subchronic exposure and after recovery. Male Sprague-Dawley rats were exposed to manganese chloride (MnCl(2)) for 30 days, 90 days, or for 90 days followed by a 30-day post-exposure recovery period. Results showed that MnCl(2) exposure resulted in liver injury in rats and the extent of injury correlated positively with exposure time. The effect in mitochondria was stronger than in the membrane or nucleus. Most of the changes in these biomarkers recovered when manganese exposure ceased.
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Affiliation(s)
- Peili Huang
- Department of Toxicology and Sanitary Chemistry, School of Public Health and Family Medicine, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, PR China
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Cash WJ, McCance DR, Young IS, McEneny J, Cadden IS, McDougall NI, Callender ME. Primary biliary cirrhosis is associated with oxidative stress and endothelial dysfunction but not increased cardiovascular risk. Hepatol Res 2010; 40:1098-106. [PMID: 20977566 DOI: 10.1111/j.1872-034x.2010.00717.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM Primary biliary cirrhosis (PBC) is a chronic cholestatic disease which is associated with hypercholesterolaemia. Further, cholestatic diseases are associated with deficiencies of anti-oxidant vitamins. Despite these associations PBC is not associated with an increase in cardiovascular mortality. The aim of this study is to assess if primary biliary cirrhosis is associated with oxidative stress, endothelial dysfunction and alteration of vascular compliance which is a surrogate marker for cardiovascular risk. METHODS Fifty-one PBC patients and 34 control subjects were studied. Lipid soluble vitamins A, and E in addition to ascorbate and carotenoids were measured to assess anti-oxidant status. C-reactive protein, hydroperoxides and adhesion molecules sICAM-l/sVCAM-l were assessed as serological measures of endothelial function. Finally, measures of vascular compliance were assessed by applanation tonometer. RESULTS CRP, sICAM and sVCAM were all significantly higher in PBC patients (469.14 vs 207.13, P < 0.001; 768.12 vs 308.03,P < 0.001; 708.40 vs 461.31, P < 0.001) whilst anti-oxidant vitamin levels were lower in PBC patients, with ascorbate, vitamin E and vitamin A all significantly lower in PBC patients (39.91 vs 72.68, P < 0.001; 2.63 vs 3.14, P = 0.02; 1.08 vs 1.81, P < 0.001). Despite these findings PBC patients have a lower pulse wave velocity than control subjects (8.22 m/s vs 8.78 m/s, P = 0.022). CONCLUSION PBC patients appear to have reduced vascular risk as assessed by pulse wave velocity but concurrently have evidence of endothelial dysfunction, inflammation and anti-oxidant deficiency.
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Affiliation(s)
- William J Cash
- Liver Unit Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital Department of Medicine, Queen's University, Belfast, UK
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Moreno-Otero R, Trapero-Marugán M. Antioxidants for liver disease. Aliment Pharmacol Ther 2010; 32:1292-3; author reply 1293-4. [PMID: 20955448 DOI: 10.1111/j.1365-2036.2010.04441.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Shafaroodi H, Ebrahimi F, Moezi L, Hashemi M, Doostar Y, Ghasemi M, Dehpour AR. Cholestasis induces apoptosis in mice cardiac cells: the possible role of nitric oxide and oxidative stress. Liver Int 2010; 30:898-905. [PMID: 20492516 DOI: 10.1111/j.1478-3231.2010.02249.x] [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] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIMS Acute cholestasis is associated with cardiovascular complications. The purpose of the present study was to investigate the effect of cholestasis on heart apoptosis and the involvement of nitric oxide (NO) and oxidative stress in the possible altered apoptosis of cholestatic hearts. METHODS Cholestasis was induced by bile duct-ligation, and sham-operated mice served as controls. Three days after the surgery, heart tissues were evaluated for apoptosis and the level of malondialdehyde (MDA), and the activities of catalase (CAT), glutathione peroxidase (GSHPx) and superoxide dismutase (SOD) have been studied in cardiac tissues. The role of treatment with l-NAME, a non-selective inhibitor of NO synthase, or with d-NAME, an inactive isomer of l-NAME, on cholestatic and sham cardiac apoptosis, level of MDA and CAT, SOD and GSHPx activities was also investigated. The content of NO in cardiac tissue was also determined. RESULTS Cholestatic hearts showed structural abnormalities and increased apoptosis compared with sham hearts. Treatment with l-NAME, but not d-NAME, improved both structural abnormalities and enhanced apoptosis of cholestatic hearts. Cholestatic hearts also had an increased level of MDA and decreased activities of CAT and GSHPx, which were not modified by d-NAME treatment. By l-NAME treatment, the level of MDA decreased and activities of CAT, GSHPx and SOD increased in BDL mice. The content of NO was higher in cholestatic cardiac tissue, which was decreased by l-NAME treatment. CONCLUSION In conclusion, apoptosis in cholestatic heart might have occurred because of NO overproduction, which could induce oxidative stress in the heart of cholestatic mice.
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Affiliation(s)
- Hamed Shafaroodi
- Department of Pharmacology and Toxicology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
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Eşrefoğlu M, Ara C. Beneficial Effect of Caffeic Acid Phenethyl Ester (CAPE) on Hepatocyte Damage Induced by Bile Duct Ligation: An Electron Microscopic Examination. Ultrastruct Pathol 2010; 34:273-8. [DOI: 10.3109/01913121003788729] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Gastric healing effect of melatonin against different gastroinvasive agents in cholestatic rats. ACTA ACUST UNITED AC 2009; 17:65-70. [PMID: 19767181 DOI: 10.1016/j.pathophys.2009.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2009] [Accepted: 08/25/2009] [Indexed: 11/21/2022]
Abstract
BACKGROUND AND OBJECTIVE The frequency of gastrointestinal ulceration is higher in jaundiced patients than in healthy population. The aim of this study was to assess the effect of pretreatment with melatonin, a potent scavenger of reactive oxygen species, on stress-induced gastric ulcers of cholestatic rats. MATERIALS AND METHODS Cholestasis was induced by surgical ligation of bile-duct and sham-operated rats served as sham animals. The animals received saline or melatonin (1, 3 or 10mg/kg) before stress induction. Three different types of gastroinvasive agents including ethanol, indomethacin or water immersion were used as stress agents to induce gastric ulceration. RESULTS Gastric mucosal damage induced by different gastroinvasive agents was significantly greater in bile-duct-ligated rats than in sham ones. Melatonin was protective against ethanol-, indomethacin- and water immersion-induced gastric damage in bile-duct-ligated and sham rats, dose-dependently, but the protective effect of melatonin was greater in cholestatic rats than sham rats in all three different series of experiments. CONCLUSIONS In conclusion, pretreatment of rats with melatonin protected gastric mucosa of cholestatic rats more effectively than the sham ones possibly by a mechanism involving the scavenging of free radicals.
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Cadoret A, Rey C, Wendum D, Elriz K, Tronche F, Holzenberger M, Housset C. IGF-1R contributes to stress-induced hepatocellular damage in experimental cholestasis. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 175:627-35. [PMID: 19628767 PMCID: PMC2716962 DOI: 10.2353/ajpath.2009.081081] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/05/2009] [Indexed: 12/19/2022]
Abstract
The insulin-like growth factor type 1 receptor (IGF-1R) controls aging and cellular stress, both of which play major roles in liver disease. Stimulation of insulin-like growth factor signaling can generate cell death in vitro. Here, we tested whether IGF-1R contributes to stress insult in the liver. Cholestatic liver injury was induced by bile duct ligation in control and liver-specific IGF-1R knockout (LIGFREKO) mice. LIGFREKO mice displayed less bile duct ligation-induced hepatocyte damage than controls, while no differences in bile acid serum levels or better adaptation to cholestasis by efflux transporters were found. We therefore tested whether stress pathways contributed to this phenomenon; oxidative stress, ascertained by both malondialdehyde content and heme oxygenase-1 expression, was similar in knockout and control animals. However, together with a lower level of eukaryotic initiation factor-2 alpha phosphorylation, the endoplasmic reticulum stress protein CHOP and its downstream pro-apoptotic target Bax were induced to lesser extents in LIGFREKO mice than in controls. Expression levels of cytokeratin 19, transforming growth factor-beta1, alpha-smooth muscle actin, and collagen alpha1(I) in LIGFREKO mice were all lower than in controls, indicating reduced ductular and fibrogenic responses and increased cholestasis tolerance in these mutants. This stress resistance phenotype was also evidenced by longer post-bile duct ligation survival in mutants than controls. These results indicate that IGF-1R contributes to cholestatic liver injury, and suggests the involvement of both CHOP and Bax in this process.
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Affiliation(s)
- Axelle Cadoret
- Inserm UMR_S 938, CdR Saint-Antoine, Faculté de Médecine Pierre et Marie Curie, Site Saint-Antoine, 27 rue Chaligny, 75012 Paris, France
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Chen WY, Chen CJ, Liao JW, Mao FC. Chromium attenuates hepatic damage in a rat model of chronic cholestasis. Life Sci 2009; 84:606-614. [PMID: 19302800 DOI: 10.1016/j.lfs.2009.02.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2008] [Revised: 02/02/2009] [Accepted: 02/04/2009] [Indexed: 12/21/2022]
Abstract
AIMS Oxidative stress is involved in cholestasis-induced hepatic damage. Therefore, antioxidant therapy is a recommended therapeutic strategy. Studies have illustrated that chromium can enhance antioxidative capacity leading to a resolution of oxidative stress. The aim of this study was to assess whether chromium has protective effects against cholestasis-related liver damage. MAIN METHODS Cholestasis was produced by bile duct ligation (BDL) in male Sprague-Dawley rats for 3 weeks. Rats were randomly divided into four groups. Control and BDL groups were subjected to sham and BDL operation, respectively, and were supplemented with placebo for 3 weeks. The BDL-post Cr group was supplemented with chromium chloride for 3 weeks after BDL operation. The BDL-pre Cr group was supplemented with chromium chloride for 6 weeks starting from 3 weeks before BDL operation. KEY FINDINGS In comparison with the control group, the BDL group showed hepatic damage as evidenced by elevation in serum biochemicals, ductular reaction, and fibrosis. These pathophysiological changes were attenuated in the BDL-Pre Cr and BDL-Post Cr groups. However, there was no significant difference between these two groups. The anti-fibrotic effect of chromium was accompanied by reductions in alpha-smooth muscle actin-positive matrix-producing cells and Smad 2/3 activity critical to the fibrogenic potential of transforming growth factor beta 1 (TGF-beta1). In addition, chromium effectively attenuated BDL-induced hepatic oxidative stress. SIGNIFICANCE The data indicate that chromium attenuates BDL-induced cholestatic liver injury, bile duct proliferation, and fibrosis. The hepatoprotective effect of chromium is associated with antioxidative potential.
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Affiliation(s)
- Wen-Ying Chen
- Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
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Rodríguez-Rivera A, Galicia-Moreno M, Reyes-Gordillo K, Segovia J, Vergara P, Moreno MG, Shibayama M, Tsutsumi V, Muriel P. Methyl palmitate prevents CCl(4)-induced liver fibrosis. J Appl Toxicol 2009; 28:1021-6. [PMID: 18626905 DOI: 10.1002/jat.1368] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Liver fibrosis is characterized by an excess of collagen fiber deposition, and it is known that Kupffer cells play an important role by immunomodulation of the toxic response. Methyl palmitate (MP) is an effective Kupffer cell inhibitor. The aim of this work was to evaluate the effect of MP on experimental liver fibrosis. Four groups were formed: the control group, which received the vehicles only; CCl(4) group (0.4 g kg(-1), i.p., three times a week, for eight weeks); CCl(4) plus MP (300 mg kg(-1), i.p., daily); and MP alone. Alanine aminotransferase was increased by CCl(4), and MP did not prevent this increase. Lipid peroxidation was increased markedly by CCl(4); again, MP was not able to prevent this effect. Fibrosis increased nearly 6-fold (measured as liver hydroxyproline content) in the CCl(4) group; MP preserved the normal content of collagen. These results were corroborated by histopathology. To elucidate the antifibrogenic mechanism of MP, we measured the production of TGF-beta; CCl(4) increased this cytokine several-fold, and MP abolished this increase. Collectively the present results indicate that MP possesses a strong antifibrogenic effect at least in the CCl(4) model of fibrosis. The antifibrotic effect of MP is probably associated with its ability to reduce TGF-beta content, maybe by immunomodulation of Kupffer cells functioning.
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Emre MH, Polat A, Eşrefoğlu M, Karabulut AB, Gül M. Effects of melatonin and acetylsalicylic acid against hepatic oxidative stress after bile duct ligation in rat. ACTA ACUST UNITED AC 2008; 95:349-63. [PMID: 19009911 DOI: 10.1556/aphysiol.2008.0001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
UNLABELLED The aim of this study was to assess the effect of melatonin and acetylsalicylic acid (ASA) on hepatic damage induced by bile duct ligation (BDL). MATERIAL AND METHODS Male Sprague-Dawley rats were subjected to either sham operation or common BDL before treatment with ASA, melatonin or vehicle. Hepatic superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) enzyme activities and reduced glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO) levels were evaluated. RESULTS Our results have indicated that BDL caused a significant increase in lipid peroxidation whereas a statistically insignificant decrease in GSH level and some of the antioxidant enzyme activities. Both MEL and ASA administrations, either separately or together, decreased MDA whereas co-administration of MEL with ASA increased GSH levels in BDL rats. CONCLUSIONS CAT activity and MEL level decreased in the liver tissues of rats with BDL after administration of either melatonin alone or with ASA. However, melatonin and ASA administration increases liver tissue GSH levels in BDL ligated rats
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Affiliation(s)
- M H Emre
- Department of Physiology, Inonu University, Medical School, 44280 Malatya, Turkey.
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Galicia-Moreno M, Rodríguez-Rivera A, Reyes-Gordillo K, Segovia J, Shibayama M, Tsutsumi V, Vergara P, Moreno MG, Fernández-Martínez E, Pérez-Álvarez VM, Muriel P. Trolox Down-Regulates Transforming Growth Factor-β and Prevents Experimental Cirrhosis. Basic Clin Pharmacol Toxicol 2008; 103:476-81. [DOI: 10.1111/j.1742-7843.2008.00324.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Atamer A, Bilici A, Yenice N, Selek S, Ilhan N, Atamer Y. The importance of paraoxonase 1 activity, nitric oxide and lipid peroxidation in hepatosteatosis. J Int Med Res 2008; 36:771-6. [PMID: 18652773 DOI: 10.1177/147323000803600419] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
This study evaluated the changes in oxidative status in hepatosteatosis patients in terms of lipid peroxidation, nitric oxide (NO) and paraoxonase 1 (PON1) activity. A total of 49 patients with hepatosteatosis (29 males and 20 females, mean age 47.2 +/- 3.6 years) and 25 healthy subjects (15 males and 10 females, mean age 46.1 +/- 3.2 years) were enrolled in the study. Serum PON1 was measured spectrophotometrically, malondialdehyde (MDA), an end-product of lipid peroxidation, was determined using the thiobarbituric acid method, and NO was assessed using the Griess reaction. Lipid and other biochemical parameters were determined by routine laboratory methods. PON1 activity and NO levels were significantly decreased and MDA levels significantly increased in hepatosteatosis patients compared with healthy subjects. PON1 activity was correlated with MDA level and NO level. In conclusion, oxidative stress seems significantly to suppress PON1 synthesis in hepatosteatosis patients. In addition, oxidative stress and oxidant-antioxidant imbalance may be part of the cytotoxic mechanisms leading to liver cell injury.
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Affiliation(s)
- A Atamer
- Department of Internal Medicine, Diyarbakir Training and Research Hospital, Diyarbakir, Turkey.
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Muñoz-Castañeda JR, Túnez I, Herencia C, Ranchal I, González R, Ramírez LM, Arjona A, Barcos M, Espejo I, Cruz A, Montilla P, Padillo FJ, Muntané J. Melatonin exerts a more potent effect than S-adenosyl-l-methionine against iron metabolism disturbances, oxidative stress and tissue injury induced by obstructive jaundice in rats. Chem Biol Interact 2008; 174:79-87. [DOI: 10.1016/j.cbi.2008.05.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2008] [Revised: 05/02/2008] [Accepted: 05/06/2008] [Indexed: 11/15/2022]
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Oral L-arginine protects against cyclosporine-induced hepatotoxicity in rats. ACTA ACUST UNITED AC 2008; 60:411-9. [PMID: 18583116 DOI: 10.1016/j.etp.2008.04.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2007] [Accepted: 04/08/2008] [Indexed: 11/21/2022]
Abstract
Cyclosporine A (CyA) leads to liver injury, probably by causing the production of free radicals and resulting in nitric oxide (NO) deficiency. We evaluated CyA-mediated liver damage histopathologically to determine the possible beneficial effects of L-arginine (L-Arg). In this study, 7 groups of Sprague-Dawley rats; (1) Control group; (2) 0.9% NaCl group; (3) CyA group: 7.5mg/kg/day; (4) L-Arg group: 2g/lt/day; (5) l-NAME (N-nitro-L-arginine methyl ester) group: 5mg/100ml/day; (6) CyA+L-Arg group: L-Arg (2g/lt/day)+CyA (7.5mg/kg/day); and (7) CyA+L-NAME group: CyA (7.5mg/kg/day)+L-NAME (5mg/100ml/day) were included. At the end of the treatments, animals were killed and hepatic tissues were treated for morphological (hematoxylin and eosin) and biochemical (NO and malondialdehyde, MDA) analyses, and serum was processed for biochemical (alanine transaminase (ALT), aspartate transaminase (AST), bilirubin, alkaline phosphatase (ALP) and total protein) study. The results indicated that CyA-induced hepatotoxicity was characterized by sinusoidal dilatation, hepatocellular vacuolization, neutrophilic infiltration and hepatocellular necrosis. These findings were less pronounced in the CyA+L-Arg group than CyA alone group. L-NAME group showed moderate changes. The CyA+L-NAME (Group 7) had more severe changes. We found changes in tissue NO and MDA levels. We think that the tissue damage caused by CyA is mild and reversible at the period when biochemical parameters are just starting to become abnormal and that L-Arg may have a protective effect against CyA damage on liver.
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Song M, Song Z, Barve S, Zhang J, Chen T, Liu M, Arteel GE, Brewer GJ, McClain CJ. Tetrathiomolybdate protects against bile duct ligation-induced cholestatic liver injury and fibrosis. J Pharmacol Exp Ther 2008; 325:409-16. [PMID: 18299419 PMCID: PMC4222180 DOI: 10.1124/jpet.107.131227] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Tetrathiomolybdate (TM), a potent copper-chelating drug, was initially developed for the treatment of Wilson's disease. Our working hypothesis is that the fibrotic pathway is copper-dependent. Because biliary excretion is the major pathway for copper elimination, a bile duct ligation (BDL) mouse model was used to test the potential protective effects of TM. TM was given in a daily dose of 0.9 mg/mouse by means of intragastric gavage 5 days before BDL. All the animals were killed 5 days after surgery. Plasma liver enzymes and total bilirubin were markedly decreased in TM-treated BDL mice. TM also inhibited the increase in plasma levels of tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 seen in BDL mice. Cholestatic liver injury was markedly attenuated by TM treatment as shown by histology. Hepatic collagen deposition was significantly decreased, and it was paralleled by a significant suppression of hepatic smooth muscle alpha-actin and fibrogenic gene expression in TM-treated BDL mice. Although the endogenous antioxidant ability was enhanced, oxidative stress as shown by malondialdehyde and 4-hydroxyalkenals, hepatic glutathione/oxidized glutathione ratio, was not attenuated by TM treatment, suggesting the protective mechanism of TM may be independent of oxidative stress. In summary, TM attenuated BDL-induced cholestatic liver injury and fibrosis in mice, in part by inhibiting TNF-alpha and TGF-beta1 secretion. The protective mechanism seems to be independent of oxidative stress. Our data provide further evidence that TM might be a potential therapy for hepatic fibrosis.
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Affiliation(s)
- Ming Song
- Division of Gastroenterology/Hepatology, Department of Internal Medicine, University of Louisville School of Medicine, 550 S. Jackson St., Louisville, KY 40202, USA
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Gomez-Pinilla PJ, Camello PJ, Pozo MJ. Protective effect of melatonin on Ca2+ homeostasis and contractility in acute cholecystitis. J Pineal Res 2008; 44:250-60. [PMID: 18339120 DOI: 10.1111/j.1600-079x.2007.00520.x] [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] [Indexed: 12/29/2022]
Abstract
Impaired Ca2+ homeostasis and smooth muscle contractility co-exist in acute cholecystitis (AC) leading to gallbladder dysfunction. There is no pharmacological treatment for this pathological condition. Our aim was to evaluate the effects of melatonin treatment on Ca2+ signaling pathways and contractility altered by cholecystitis. [Ca2+]i was determined by epifluorescence microscopy in fura-2 loaded isolated gallbladder smooth muscle cells, and isometric tension was recorded from gallbladder muscle strips. Malondialdehyde (MDA) and reduced glutathione (GSH) contents were determined by spectrophotometry and cycloxygenase-2 (COX-2) expression was quantified by western blot. Melatonin was tested in two experimental groups, one of which underwent common bile duct ligation for 2 days and another that was later de-ligated for 2 days. Inflammation-induced impairment of Ca2+ responses to cholecystokinin and caffeine were recovered by melatonin treatment (30 mg/kg). This treatment also ameliorated the detrimental effects of AC on Ca2+ influx through both L-type and capacitative Ca2+ channels, and it was effective in preserving the pharmacological phenotype of these channels. Despite its effects on Ca2+ homeostasis, melatonin did not improve contractility. After de-ligation, Ca2+ influx and contractility were still impaired, but both were recovered by melatonin. These effects of melatonin were associated to a reduction of MDA levels, an increase in GSH content and a decrease in COX-2 expression. These findings indicate that melatonin restores Ca2+ homeostasis during AC and resolves inflammation. In addition, this indoleamine helps in the subsequent recovery of functionality.
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Kilicoglu B, Gencay C, Kismet K, Serin Kilicoglu S, Erguder I, Erel S, Sunay AE, Erdemli E, Durak I, Akkus MA. The ultrastructural research of liver in experimental obstructive jaundice and effect of honey. Am J Surg 2008; 195:249-56. [PMID: 18083132 DOI: 10.1016/j.amjsurg.2007.04.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2007] [Revised: 04/10/2007] [Accepted: 04/10/2007] [Indexed: 01/08/2023]
Abstract
BACKGROUND To examine the effects of honey on oxidative stress and apoptosis in experimental obstructive jaundice model. METHOD Thirty rats were divided into 3 groups: group I, sham-operated; group II, ligation and division of the common bile duct (BDL); group III, BDL followed by oral supplementation of honey 10 g/kg/d. Liver samples were examined under light microscope and transmission electron microscope. Hepatocyte apoptosis was quantitated using the terminal deoxy-nucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Plasma and blood malondialdehyde (MDA) and glutation activities were measured for determining the oxidative stress. RESULTS The liver levels of MDA and GSH were significantly different between the honey and BDL groups (P = .006 and .001, respectively). However, there was no significant difference between the plasma MDA and GSH levels of these groups (P > .05). In group III, significant reductions in the size of enlarged hepatocytes and the edema were demonstrated. The dilatation of the bile canaliculi dramatically turned to original dimention. By TUNEL assay, it was shown that administration of honey decreased the number of apoptotic cells. CONCLUSIONS In the present study, we found that honey diminished the negative effects of BDL on the hepatic ultrastructure. We conclude that this effect might be due to its antioxidant and anti-inflammatory activities.
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Affiliation(s)
- Bulent Kilicoglu
- Ankara Training and Research Hospital, 4th General Surgery Department, Ankara, Turkey
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Sakuma Y, Sasaki J, Futami A, Yamasaki K, Matsuoka K, Honda C, Endo K, Tsukada M. Changes in the components of biliary and plasma lipids in selenium-deficient rats. Chem Phys Lipids 2007; 148:70-6. [PMID: 17524380 DOI: 10.1016/j.chemphyslip.2007.04.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2007] [Accepted: 04/07/2007] [Indexed: 11/22/2022]
Abstract
We constructed a chronic oxidative stress model in which Se-deficient diet was fed to male Wister rats for 8 weeks. As expected, effects of oxidative damage, including Fe accumulation and increase in peroxidized lipids, were identified in the liver owing to the lack of glutathione peroxidase. Although the oxidative stress caused Fe accumulation in the liver, the Fe concentration in bile of the SeD rat was almost the same as that in the control rats. The constant excretion of Fe into bile supported the Fe accumulation in the liver. No differences were observed in the principal components of biliary lipids, i.e., bile acids, phospholipids, and cholesterol, between the two groups; moreover, these trends were also reflected in the plasma. Due to the trapping of reactive oxygen species, only bilirubin concentrations in the bile and plasma were decreased in the SeD group, when compared with those in the control group. Measurement of bilirubin concentration may be used as a supplemental oxidative stress marker.
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Affiliation(s)
- Yasunobu Sakuma
- Department of Physical Chemistry, Showa Pharmaceutical University, Higashi-Tamagawagakuen 3-3165, Machida, Tokyo 194-8543, Japan
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Lee TY, Chang HH, Wu MY, Lin HC. Yin-Chen-Hao-Tang ameliorates obstruction-induced hepatic apoptosis in rats. J Pharm Pharmacol 2007; 59:583-90. [PMID: 17430643 DOI: 10.1211/jpp.59.4.0014] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
The accumulation of hydrophobic bile acids in the liver is considered to play a pivotal role in the induction of apoptosis of hepatocytes during cholestasis. Thus, factors that affect apoptosis may be used to modulate liver fibrosis. Yin-Chen-Hao-Tang (YCHT) decoctions have been recognised as a hepatoprotective agent for jaundice and various types of liver diseases. We used an experimental rat model of bile-duct ligation (BDL) to test whether YCHT plays a regulatory role in the pathogenesis of hepatic apoptosis. BDL-plus-YCHT groups received 250 or 500 mg kg (-1) YCHT by gavage once daily for 27 days. YCHT significantly ameliorated the portal hypertensive state and serum TNF-alpha compared with the vehicle-treated control group. In BDL-plus-YCHT-treated rats, hepatic glutathione contents were significantly higher than than in BDL-only rats. BDL caused a prominent liver apoptosis that was supported by an increase in Bax and cytochrome c protein and increased expression of Bax and Bcl-2 messenger RNA. The normalising effect of YCHT on expression of Bax and Bcl-2 mRNA was dependent on the dose of YCHT, 500 mg kg (-1) having the greater effect on both Bax and Bcl-2 of mRNA levels. Additionally, YCHT treatment down-regulated both hepatic caspase-3 and -8 activities of BDL rats. This study demonstrates the anti-apoptotic properties of YCHT and suggests a potential application of YCHT in the clinical management of hepatic disease resulting from biliary obstruction.
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MESH Headings
- Animals
- Apoptosis/drug effects
- Artemisia/chemistry
- Bile Ducts/surgery
- Caspase 3/drug effects
- Caspase 3/metabolism
- Caspase 8/drug effects
- Caspase 8/metabolism
- Cholestasis, Extrahepatic/drug therapy
- Cholestasis, Extrahepatic/physiopathology
- Cytochromes c/chemistry
- Cytochromes c/drug effects
- Disease Models, Animal
- Drugs, Chinese Herbal/administration & dosage
- Drugs, Chinese Herbal/chemistry
- Drugs, Chinese Herbal/pharmacology
- Gardenia/chemistry
- Gene Expression/drug effects
- Glutathione/chemistry
- Glutathione/drug effects
- Hepatocytes/drug effects
- Hepatocytes/pathology
- Hypertension, Portal/drug therapy
- Ligation
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Male
- Medicine, Chinese Traditional
- Phytotherapy
- RNA, Messenger/drug effects
- RNA, Messenger/metabolism
- Rats
- Rats, Sprague-Dawley
- Rheum/chemistry
- Tumor Necrosis Factor-alpha/blood
- Tumor Necrosis Factor-alpha/drug effects
- bcl-2-Associated X Protein/chemistry
- bcl-2-Associated X Protein/drug effects
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Affiliation(s)
- Tzung-Yan Lee
- Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan.
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Payabvash S, Kiumehr S, Nezami BG, Zandieh A, Anvari P, Tavangar SM, Dehpour AR. Endogenous opioids modulate hepatocyte apoptosis in a rat model of chronic cholestasis: the role of oxidative stress. Liver Int 2007; 27:538-47. [PMID: 17403194 DOI: 10.1111/j.1478-3231.2007.01457.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
AIMS/BACKGROUND There are increasing number of evidences indicating the contribution of endogenous opioids in the pathophysiology of cholestatic liver disease. The aim of the present study was to determine the role of the endogenous-opioid system in the modulation of hepatocytes apoptosis and liver oxidant/anti-oxidant balance during chronic cholestasis in rats. METHODS We induced cholestasis in rats by bile duct ligation (BDL). Naltrexone, an opioid antagonist, was administered at different doses (2.5, 5, 10, 20 and 40 mg/kg/day) to cholestatic animals for 5 weeks. RESULTS Naltrexone prevented the cholestasis-induced decrease of hepatic glutathione levels at higher doses (20 and 40 mg/kg/day). In the next phase of the study, we evaluated the effects of 20 mg/kg/day naltrexone treatment on hepatic damage indices and liver oxidant/anti-oxidant balance in 5-week BDL rats. There was a marked increase in the number of apoptotic hepatocytes as well as serum liver enzymes and hepatic lipid peroxidation levels in cholestatic rats compared with sham-operated animals 5 weeks after the operation. Liver anti-oxidant enzyme activities were significantly reduced in cholestatic rats compared with controls. Chronic treatment with naltrexone significantly improved all the aforementioned indices in comparison with saline-treated cholestatic rats. CONCLUSION Our findings demonstrate that the administration of opioid antagonist is protective against hepatic damage in a rat model of chronic cholestasis. We suggest that increased levels of endogenous opioids contribute to hepatocytes apoptosis in cholestasis, possibly through downregulation of liver anti-oxidant defense.
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Affiliation(s)
- Seyedmehdi Payabvash
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Lee TY, Chang HH, Chen JH, Hsueh ML, Kuo JJ. Herb medicine Yin-Chen-Hao-Tang ameliorates hepatic fibrosis in bile duct ligation rats. JOURNAL OF ETHNOPHARMACOLOGY 2007; 109:318-24. [PMID: 16989967 DOI: 10.1016/j.jep.2006.07.042] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2006] [Revised: 07/12/2006] [Accepted: 07/31/2006] [Indexed: 05/11/2023]
Abstract
The accumulation of hydrophilic bile acids in the liver is considered to play a pivotal role in the induction of hepatic injury. Yin-Chen-Hao-Tang (YCHT) decoction is an aqueous extract from three different herbs: Artemisia capillaries Thunb (Compositae), Gardenia jasminoides Ellis (Rubiaceae), Rheum officinale Baill (Polygonaceae), which has been recognized as a hepatoprotective agent for various types of liver diseases. Therefore, we used an experimental of biliary atresia model to test that YCHT plays a regulatory role in the pathogenesis of hepatic fibrosis. Hepatic damage with fibrosis was produced by common bile duct ligation (BDL) for 27 days in experimental cholestasis animal model. After surgery, YCHT (250 and 500mg/kg BW) oral administration once a day continued for 27 days. BDL caused a prominent liver collagen deposition that was supported by the increased alpha-SMA protein and mRNA expression of procollagen I. YCHT significantly decreased hepatic alpha-SMA protein levels and decreased in hydroxyproline and thiobarbituric acid reactive substances (TBARS) levels of BDL rats. On the other hand, the normalizing effect of YCHT (250mg/kg) on the TGF-beta1mRNA expression was independent on the dose of YCHT, 500mg/kg was not effectively changed the quantitative composition of mRNA levels. The study shows that hepatic hydroxyproline accumulation caused by hydrophilic bile acids accompanied by elevated hepatic lipid peroxidation, and hepatic collagen levels can be decreased in the presence of YCHT. In conclusion, long-term administration of YCHT in rats ameliorated the hydropholic bile acids induced hepatic injury that probably related to a reduced oxidant stress and degree of hepatic fibrosis.
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Affiliation(s)
- Tzung-Yan Lee
- Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Tao-Yuan, Taiwan, ROC.
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Wang G, Shen H, Rajaraman G, Roberts MS, Gong Y, Jiang P, Burczynski F. Expression and antioxidant function of liver fatty acid binding protein in normal and bile-duct ligated rats. Eur J Pharmacol 2007; 560:61-8. [PMID: 17292345 DOI: 10.1016/j.ejphar.2007.01.015] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2006] [Revised: 12/21/2006] [Accepted: 01/08/2007] [Indexed: 11/17/2022]
Abstract
Liver fatty acid binding protein has recently been shown to possess antioxidant properties but its role in liver disease, such as cholestasis, is not known. Since oxidative stress has been recognized as an important contributing factor in liver disease, we investigated the expression and antioxidative function of this protein using the bile-duct ligated model of cholestasis. Rats were divided into 3 groups: sham, bile-duct ligated and bile-duct ligated plus clofibrate. Animals were sacrificed at various time points after bile-duct ligation. RT-PCR and Western blot were used to analyze liver fatty acid binding protein expression. Cellular lipid peroxidation products were assessed by measuring thiobarbituric acid-reactive substances. Liver function was evaluated by measuring serum total bilirubin, alanine aminotransferase and ammonia. Liver fatty acid binding protein mRNA and protein levels were reduced to 51% and 20% of sham, respectively at 2 weeks following bile-duct ligation (p<0.05). The decreased liver fatty acid binding protein was associated with a statistical increase in hepatic lipid peroxidation products (224%) and decrease in hepatic function. Clofibrate treatment restored protein level and improved hepatic function. Clofibrate treatment also reduced hepatic lipid peroxidation products by 68% as compared with the bile-duct ligated group (p<0.05). Liver fatty acid binding protein likely has important antioxidant function during hepatocellular oxidative stress.
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Affiliation(s)
- Guqi Wang
- Faculty of Pharmacy, Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland, 4102 Australia
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Soylu AR, Aydogdu N, Basaran UN, Altaner S, Tarcin O, Gedik N, Umit H, Tezel A, Dokmeci G, Baloglu H, Ture M, Kutlu K, Kaymak K. Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats. World J Gastroenterol 2006; 12:6835-41. [PMID: 17106933 PMCID: PMC4087439 DOI: 10.3748/wjg.v12.i42.6835] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [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 whether antioxidants vitamin E and C can retard development of hepatic fibrosis in the biliary-obstructed rats.
METHODS: Fifty Wistar albino rats were randomly assigned to 5 groups (10 rats in each). Bile duct was ligated in 40 rats and they were treated as follows: group vitC, vitamin C 10 mg/kg sc daily; group vitE, vitamin E 15 mg/kg sc daily; group vitEC, both of the vitamins; bile duct-ligated (BDL, control) group, physiological saline sc. The fifth group was assigned to sham operation. At the end of fourth week, the rats were decapitated, and hepatic tissue biochemical collagen content and collagen surface area were measured. Hepatic tissue specimens were histopathologically evaluated according to Scheuer system. Serum hyaluronate levels were measured by ELISA method.
RESULTS: Despite being higher than sham group, hepatic collagen level was significantly decreased in each of the vitC, vitE and vitEC groups (32.7 ± 1.2, 33.8 ± 2.9, 36.7 ± 0.5 μg collagen/mg protein, respectively) compared to BDL (48.3 ± 0.6 mg collagen/g protein) (P < 0.001 for each vitamin group). Each isolated vitamin C, isolated vitamin E and combined vitamin E/C supplementation prevented the increase in hepatic collagen surface density (7.0% ± 1.1%, 6.2% ± 1.7%, 12.3% ± 2.0%, respectively) compared to BDL (17.4% ± 5.6%) (P < 0.05 for each). The same beneficial effect of vitamin C, vitamin E and combined vitamin E/C treatment was also observed on the decrease of serum hyaluronate levels compared to BDL group (P < 0.001). The relative liver and spleen weights, serum transaminases, cholestatic enzymes, bilirubins and histopathological inflammation scores were not different between the antioxidant treatment groups and the control. However, fibrosis staging scores were obviously reduced only in the vitamin E/C combination group (vit EC: 2.4 ± 0.8 vs BDL: 3.1 ± 0.7; P < 0.05).
CONCLUSION: Each antioxidant vitamin E, vitamin C and their combination retard hepatic fibrosis in biliary-obstructed rats. Oxidative stress may play a role in the pathogenesis of hepatic fibrosis in secondary biliary cirrhosis.
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Spee B, Arends B, Ingh TS, Penning LC, Rothuizen J. Copper Metabolism and Oxidative Stress in Chronic Inflammatory and Cholestatic Liver Diseases in Dogs. J Vet Intern Med 2006. [DOI: 10.1111/j.1939-1676.2006.tb00706.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Polat A, Emre MH. Effects of melatonin or acetylsalicylic acid on gastric oxidative stress after bile duct ligation in rats. J Gastroenterol 2006; 41:433-9. [PMID: 16799884 DOI: 10.1007/s00535-006-1783-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2005] [Accepted: 01/17/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND Antioxidant enzyme activities decrease after bile duct ligation. The aim of this study was to assess the effect of melatonin and acetylsalicylic acid on antioxidant enzyme activities in gastric oxidative stress induced by bile duct ligation. METHODS Sixty-four animals were divided into eight groups of eight rats each. Male Sprague-Dawley rats were subjected to either a sham operation or common bile duct ligation (BDL) before treatment with melatonin (MEL) or acetylsalicylic acid (ASA). Gastric superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, and malondialdehyde (MDA) and nitric oxide (NO) levels were determined by spectrophotometers and evaluated. RESULTS Our results indicated that BDL caused a significant increase in lipid peroxidation, whereas coadministration of MEL with ASA significantly decreased MDA and NO levels in BDL rats. Moreover, coadministration of MEL and ASA increased antioxidant enzyme activities after the BDL, and these increases were statistically significant for CAT and GPx. On the other hand, the increase in SOD activity was not significant. CONCLUSIONS Melatonin administration, either alone or together with acetylsalicylic acid, decreases lipid peroxidation and increases antioxidant enzyme activities in gastric tissues of rats after bile duct ligation. ASA administration, however, either alone or with a vehicle, increases lipid peroxidation and decreases antioxidant enzyme activities.
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Affiliation(s)
- Alaaddin Polat
- Department of Physiology, Medical School, Inonu University, Malatya, Turkey
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Mine T. Influence of melatonin and acetylsalicylic acid on lipid peroxidation and antioxidant enzyme activities in gastric mucosa. J Gastroenterol 2006; 41:507-8. [PMID: 16799898 DOI: 10.1007/s00535-006-1837-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Fernández-Martínez E, Pérez-Alvarez V, Tsutsumi V, Shibayama M, Muriel P. Chronic bile duct obstruction induces changes in plasma and hepatic levels of cytokines and nitric oxide in the rat. ACTA ACUST UNITED AC 2006; 58:49-58. [PMID: 16617007 DOI: 10.1016/j.etp.2006.03.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2005] [Accepted: 03/02/2006] [Indexed: 01/13/2023]
Abstract
Chronic bile duct ligation (BDL) is a useful model of cirrhosis. However, its parallel plasma and liver changes in levels of cytokines and nitric oxide (NO), involved in liver damage, remain unknown. The aims of this work were to quantify both the plasma and hepatic levels of five cytokines and NO in cirrhotic rats, 28 days after bile BDL, and to analyze their relationship with liver damage markers. One group of male Wistar rats was bile duct ligated and another group was sham operated, both groups were sacrificed 28 days after BDL. Plasma and liver cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6, -1beta, -10 (IL-6, -1beta, -10) and interferon-gamma (IFN-gamma), were measured by ELISA. Plasma and hepatic NO was determined as NO(2)(-)+NO(3)(-) by an enzymatic method. Alkaline phosphatase, gamma-glutamyl transpeptidase, alanine aminotransferase and bilirubins were determined in plasma. Collagen, lipid peroxidation and glycogen were quantified in liver. Two histopathological staining techniques were performed. BDL-induced cirrhosis was corroborated by the elevated liver damage markers and histopathological analysis. Chronic BDL significantly increased (P<0.05) most of plasma and hepatic cytokine levels and diminished the hepatic IFN-gamma amount. NO was increased in both tissues, but such change was only significant in plasma. Biliary cirrhosis produces interesting changes in plasma and hepatic levels of cytokines and NO. This finding in chronic BDL model in rats has not been previously described in both tissues for such cytokines and NO. Cytokines and NO imbalance favor establishment and perpetuation of cirrhosis.
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Affiliation(s)
- Eduardo Fernández-Martínez
- Centro de Investigación en Biología de la Reproducción, Universidad Autónoma del Estado de Hidalgo, Hidalgo, México
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50
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Ming Z, Fan YJ, Yang X, Lautt WW. Synergistic protection by S-adenosylmethionine with vitamins C and E on liver injury induced by thioacetamide in rats. Free Radic Biol Med 2006; 40:617-24. [PMID: 16458192 PMCID: PMC2925887 DOI: 10.1016/j.freeradbiomed.2005.09.034] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2005] [Revised: 08/18/2005] [Accepted: 09/12/2005] [Indexed: 01/19/2023]
Abstract
Free radicals are involved in the pathogenesis of acute liver injury induced by thioacetamide (TAA). We investigated the effects of S-adenosylmethionine (SAMe) combined with/without vitamins C and E on TAA-induced acute liver injury in rats. TAA was given intraperitoneally (200 mg kg-1). Antioxidant treatments (SAMe, 25 mg kg-1; vitamin C, 100 mg kg-1; vitamin E, 200 mg kg-1, intraperitoneal) were given 1 h later. Liver histology, enzymology, and ability to release hepatic insulin-sensitizing substance (HISS) were assessed. TAA caused liver tissue injury, increased liver enzymes, and decreased insulin sensitivity (p<0.01). Blockade of HISS release by atropine did not further decrease insulin sensitivity in rats with TAA insult, indicating that the decrease in insulin sensitivity was HISS dependent. Treatment with SAMe alone or vitamins C+E slightly improved liver histology but not the changes in liver enzymes and insulin sensitivity. Combined treatment with SAMe plus vitamins C+E greatly protected the liver from tissue injury, the increase in liver enzymes, and the decrease in insulin sensitivity. In conclusion, acute liver injury causes HISS-dependent insulin resistance (HDIR). There are synergistic antioxidative effects among the antioxidants, SAMe and vitamins C and E, that protect the liver from TAA-induced HDIR, suggesting that antioxidant treatment may best be done using a balanced "cocktail."
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Affiliation(s)
- Zhi Ming
- Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, A210–753, McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T6
| | - Yi-jun Fan
- Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0W3
| | - Xi Yang
- Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0W3
| | - W. Wayne Lautt
- Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, A210–753, McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T6
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